Commissioning and validation of a Monte Carlo algorithm for spine stereotactic radiosurgery.

PURPOSE: A 6FFF Monte Carlo (MC) dose calculation algorithm was commissioned for spine stereotactic radiosurgery (SRS). Model generation, validation, and ensuing model tuning are presented. METHODS: The model was generated using in-air and in-water commissioning measurements of field sizes between 10 and 400 mm2 . Commissioning measurements were compared to simulated water tank MC calculations to validate output factors, percent depth doses (PDDs), profile sizes and penumbras. Previously treated Spine SRS patients were re-optimized with the MC model to achieve clinically acceptable plans. Resulting plans were calculated on the StereoPHAN phantom and subsequently delivered to the microDiamond and SRSMapcheck to verify calculated dose accuracy. Model tuning was performed by adjusting the model's light field offset (LO) distance between physical and radiological positions of the MLCs, to improve field size and StereoPHAN calculation accuracy. Following tuning, plans were generated and delivered to an anthropomorphic 3D-printed spine phantom featuring realistic bone anatomy, to validate heterogeneity corrections. Finally, plans were validated using polymer gel (VIPAR based formulation) measurements. RESULTS: Compared to open field measurements, MC calculated output factors and PDDs were within 2%, profile penumbra widths were within 1 mm, and field sizes were within 0.5 mm. Calculated point dose measurements in the StereoPHAN were within 0.26% ± 0.93% and -0.10% ± 1.37% for targets and spinal canals, respectively. Average SRSMapcheck per-plan pass rates using a 2%/2 mm/10% threshold relative gamma analysis was 99.1% ± 0.89%. Adjusting LOs improved open field and patient-specific dosimetric agreement. Anthropomorphic phantom measurements were within -1.29% ± 1.00% and 0.27% ± 1.36% of MC calculated for the vertebral body (target) and spinal canal, respectively. VIPAR gel measurements confirmed good dosimetric agreement near the target-spine junction. CONCLUSION: Validation of a MC algorithm for simple fields and complex SRS spine deliveries in homogeneous and heterogeneous phantoms has been performed. The MC algorithm has been released for clinical use.

Dosimetric Effects of Dynamic Jaw Tracking and Collimator Angle Optimization in Non-Coplanar Cranial Arc Radiotherapy.

The stereotactic treatment of single cranial targets using noncoplanar volumetric modulated arc therapy (VMAT) allows for effective dose delivery to the target, while sparing normal brain tissue. In this study, the dosimetric effect of adding dynamic jaw tracking and automatic collimator angle selection in the optimization of single target cranial VMAT plans was investigated. Twenty-two cranial targets, previously treated with VMAT without dynamic jaw tracking and automatic collimator angle optimization (CAO) were chosen for replanning. Target volumes ranged from 0.441cc to 25.863cc with doses between 18Gy and 30Gy delivered in 1 to 5 fractions. Original plans were reoptimized with automatic CAO, keeping all other objectives the same (CAO plans). Next, original plans were reoptimized with both dynamic jaw tracking and CAO (DJT plans). Original, CAO, and DJT target doses were compared using the Paddick gradient index (GI) and the Paddick inverse conformity index (ICI), while normal tissue dose was compared using the volume of the normal brain receiving 5Gy, 10Gy, and 12Gy. The normal tissue volume was normalized to target size to allow cross comparison between plans. A one-sided t-test was performed to determine whether the changes in the plan metrics were statistically significant. CAO plans had improved GIs compared to the originals (p = 0.03) with insignificant changes in other plan metrics (p > 0.20). The addition of dynamic jaw tracking in DJT plans greatly improved ICIs and normal brain metrics (p < 0.01) compared to the CAO plans with minor improvement in ICIs (p = 0.07). The combined effect of adding dynamic jaw tracking and collimator optimization led to improvements in all metrics of the DJT plans when compared to the original (p < 0.02). The addition of dynamic jaw tracking and CAO led to improvements in both target and normal tissue dose metrics for single-target noncoplanar cranial VMAT plans.

A Direct Patient-Provider Relationship With the Medical Physicist Reduces Anxiety in Patients Receiving Radiation Therapy.

PURPOSE: The complex technological processes involved in radiation therapy can be intimidating to patients, causing increased treatment-related anxiety and reduced satisfaction. An intervention was implemented to provide direct consultations between patients and medical physicists to reduce patient anxiety and improve patient satisfaction. A randomized clinical trial was conducted to test the intervention's effect on anxiety, distress, treatment adherence, technical understanding, and satisfaction in patients receiving radiation therapy. METHODS AND MATERIALS: Eligible patients were recruited into "intervention" and "standard of care" arms within a phase 2 screening randomized trial. Intervention-arm patients met with a medical physicist who provided technical information and addressed patient questions or concerns at the time of treatment simulation and before the first treatment. In addition to baseline information collected before randomization, participants were surveyed (1) before simulation, (2) before the first treatment, and (3) before the completion of treatment to evaluate the study endpoints. Primary endpoints included patient anxiety and distress. Secondary endpoints included patient treatment adherence, overall satisfaction, and technical understanding of treatment. Patients in the intervention arm were surveyed before and after each physicist meeting. RESULTS: Participant anxiety was significantly reduced in the intervention arm (difference, -0.29; 95% confidence interval, -0.57 to -0.02; P = .038). No differences in distress or treatment adherence were observed between groups. Although measures of technical understanding and satisfaction were evaluated as exploratory objectives, participants in the intervention group were more likely to feel that technical aspects of treatment were adequately explained (difference, 0.78; 95% confidence interval, 0.03-1.54), and all measures of technical understanding and satisfaction were considerably higher in the intervention group at the time of the first visit. CONCLUSIONS: The establishment of a direct patient-provider relationship with the medical physicist reduced anxiety in patients receiving radiation therapy. In addition, increases in patient understanding of the technical aspects of care and in satisfaction were observed at the initiation of treatment.

p62/SQSTM1-induced caspase-8 aggresomes are essential for ionizing radiation-mediated apoptosis.

The autophagy-lysosome pathway and apoptosis constitute vital determinants of cell fate and engage in a complex interplay in both physiological and pathological conditions. Central to this interplay is the archetypal autophagic cargo adaptor p62/SQSTM1/Sequestosome-1 which mediates both cell survival and endoplasmic reticulum stress-induced apoptosis via aggregation of ubiquitinated caspase-8. Here, we investigated the role of p62-mediated apoptosis in head and neck squamous cell carcinoma (HNSCC), which can be divided into two groups based on human papillomavirus (HPV) infection status. We show that increased autophagic flux and defective apoptosis are associated with radioresistance in HPV(-) HNSCC, whereas HPV(+) HNSCC fail to induce autophagic flux and readily undergo apoptotic cell death upon radiation treatments. The degree of radioresistance and tumor progression of HPV(-) HNSCC respectively correlated with autophagic activity and cytosolic levels of p62. Pharmacological activation of the p62-ZZ domain using small molecule ligands sensitized radioresistant HPV(-) HNSCC cells to ionizing radiation by facilitating p62 self-polymerization and sequestration of cargoes leading to apoptosis. The self-polymerizing activity of p62 was identified as the essential mechanism by which ubiquitinated caspase-8 is sequestered into aggresome-like structures, without which irradiation fails to induce apoptosis in HNSCC. Our results suggest that harnessing p62-dependent sequestration of ubiquitinated caspase-8 provides a novel therapeutic avenue in patients with radioresistant tumors.

Photodynamic Therapy as a Potent Radiosensitizer in Head and Neck Squamous Cell Carcinoma.

Despite recent advances in therapeutic modalities such as radiochemotherapy, the long-term prognosis for patients with advanced head and neck squamous cell carcinoma (HNSCC), especially nonviral HNSCC, remains very poor, while survival of patients with human papillomavirus (HPV)-associated HNSCC is greatly improved after radiotherapy. The goal of this study is to develop a mechanism-based treatment protocol for high-risk patients with HPV-negative HNSCC. To achieve our goal, we have investigated molecular mechanisms underlying differential radiation sensitivity between HPV-positive and -negative HNSCC cells. Here, we found that autophagy is associated with radioresistance in HPV-negative HNSCC, whereas apoptosis is associated with radiation sensitive HPV-positive HNSCC. Interestingly, we found that photodynamic therapy (PDT) directed at the endoplasmic reticulum (ER)/mitochondria initially induces paraptosis followed by apoptosis. This led to a substantial increase in radiation responsiveness in HPV-negative HNSCC, while the same PDT treatment had a minimal effect on HPV-positive cells. Here, we provide evidence that the autophagic adaptor p62 mediates signal relay for the induction of apoptosis, promoting ionizing radiation (XRT)-induced cell death in HPV-negative HNSCC. This work proposes that ER/mitochondria-targeted PDT can serve as a radiosensitizer in intrinsically radioresistant HNSCC that exhibits an increased autophagic flux.

Development of an in vivo technique for dose verification at the prone breast board / skin interface.

Due to the limited height of commercial prone breast boards, large or pendulous breasts may contact the base layer of the board during simulation and throughout the course of treatment. Our clinic has historically identified and marked this region of contact to ensure reproducible setup. However, this situation may result in unwanted hotspots where the breast rests atop the board due to electron scatter. In this study, we performed in-vivo dosimetric measurements to evaluate the surface dose in regions of contact with the immobilization device. The average dose and hotspot were identified and evaluated to determine whether plan modifications were necessary to avoid excess skin toxicity at the skin/breast board interface. The film method results were validated against a commissioned in vivo OSLD dosimetry system. Radiochromic film measurements agreed with OSLD readings (n = 18) overall within 1%, σ = 6.4%, with one deviation of >10%. Pertinent information for the physician includes the average, maximum, and minimum doses received at the film interface. Future readings will not require OSLD verification. Physicians now have access to additional spatial data to correlate skin toxicity with doses delivered at the skin/breast board interface. This new technique is now an established procedure at our clinic, and can inform future efforts to model enhanced methods to calculate the dosimetric effects from the prone breast board in the treatment planning system.

Isoflavone-mediated radioprotection involves regulation of early endothelial cell death and inflammatory signaling in Radiation-Induced lung injury.

Purpose: Vascular damage and inflammation are limiting toxic effects of lung cancer radiotherapy, which lead to pneumonitis and pulmonary fibrosis. We have demonstrated that soy isoflavones (SIF) mitigate these toxic effects at late time points after radiation. However, the process by which SIF impacts the onset of radiation-induced inflammation remains to be elucidated. We have now investigated early events of radiation-induced inflammation and identified cellular and molecular signaling patterns by endothelial cells that could be modified by SIF to control vascular damage and the initiation of lung inflammation.Materials and methods: Histopathological, cellular and molecular studies were performed on mouse lungs from C57Bl/6 mice treated with 10 Gy of thoracic radiation (XRT) in conjunction with daily oral SIF treatment given prior and after radiation. Parallel studies were performed in-vitro using EA.hy926 endothelial cell line with SIF and radiation. Immunohistochemistry, western blots analysis, and flow cytometry were performed on lung tissue or EA.hy926 cells to analyze endothelial cells, their patterns of cell death or survival, and signaling molecules involved in inflammatory events.Results: Histopathological differences in inflammatory infiltrates and vascular injury in lungs, including vascular endothelial cells, were observed with SIF treatment at early time points post-XRT. XRT-induced expression of proinflammatory adhesion molecule ICAM-1 cells was reduced by SIF in-vitro and in-vivo in endothelial cells. Molecular changes in endothelial cells with SIF treatment in conjunction with XRT included increased DNA damage, reduced cell viability and cyclin B1, and inhibition of nuclear translocation of NF-κB. Analysis of cell death showed that SIF treatment promoted apoptotic endothelial cell death and decreased XRT-induced type III cell death. In-vitro molecular studies indicated that SIF + XRT increased apoptotic caspase-9 activation and production of IFNß while reducing the release of inflammatory HMGB-1 and IL-1α, the cleavage of pyroptotic gasdermin D, and the release of active IL-1ß, which are all events associated with type III cell death.Conclusions: SIF + XRT caused changes in patterns of endothelial cell death and survival, proinflammatory molecule release, and adhesion molecule expression at early time points post-XRT associated with early reduction of immune cell recruitment. These findings suggest that SIF could mediate its radioprotective effects in irradiated lungs by limiting excessive immune cell homing via vascular endothelium into damaged lung tissue and curtailing the overall inflammatory response to radiation.

Multi-institutional evaluation of end-to-end protocol for IMRT/VMAT treatment chains utilizing conventional linacs.

We conducted a multi-institutional assessment of a recently developed end-to-end monthly quality assurance (QA) protocol for external beam radiation therapy treatment chains. This protocol validates the entire treatment chain against a baseline to detect the presence of complex errors not easily found in standard component-based QA methods. Participating physicists from 3 institutions ran the end-to-end protocol on treatment chains that include Imaging and Radiation Oncology Core (IROC)-credentialed linacs. Results were analyzed in the form of American Association of Physicists in Medicine (AAPM) Task Group (TG)-119 so that they may be referenced by future test participants. Optically stimulated luminescent dosimeter (OSLD), EBT3 radiochromic film, and A1SL ion chamber readings were accumulated across 10 test runs. Confidence limits were calculated to determine where 95% of measurements should fall. From calculated confidence limits, 95% of measurements should be within 5% error for OSLDs, 4% error for ionization chambers, and 4% error for (96% relative gamma pass rate) radiochromic film at 3% agreement/3 mm distance to agreement. Data were separated by institution, model of linac, and treatment protocol (intensity-modulated radiation therapy [IMRT] vs volumetric modulated arc therapy [VMAT]). A total of 97% of OSLDs, 98% of ion chambers, and 93% of films were within the confidence limits; measurements were found outside these limits by a maximum of 4%, < 1%, and < 1%, respectively. Data were consistent despite institutional differences in OSLD reading equipment and radiochromic film calibration techniques. Results from this test may be used by clinics for data comparison. Areas of improvement were identified in the end-to-end protocol that can be implemented in an updated version. The consistency of our data demonstrates the reproducibility and ease-of-use of such tests and suggests a potential role for their use in broad end-to-end QA initiatives.

Commissioning of a dedicated commercial Co-60 total body irradiation unit.

We describe the commissioning of the first dedicated commercial total body irradiation (TBI) unit in clinical operation. The Best Theratronics GammaBeam 500 is a Co-60 teletherapy unit with extended field size and imaging capabilities. Radiation safety, mechanical and imaging systems, and radiation output are characterized. Beam data collection, calibration, and external dosimetric validation are described. All radiation safety and mechanical tests satisfied relevant requirements and measured dose distributions meet recommendations of American Association of Physicists in Medicine (AAPM) Report #17. At a typical treatment distance, the dose rate in free space per unit source activity using the thick flattening filter is 1.53 × 10-3 cGy*min-1 *Ci-1 . With a 14,000 Ci source, the resulting dose rate at the midplane of a typical patient is approximately 17 and 30 cGy/min using the thick and thin flattening filters, respectively, using the maximum source to couch distance. The maximum useful field size, defined by the 90% isodose line, at this location is 225 × 78 cm with field flatness within 5% over the central 178 × 73 cm. Measured output agreed with external validation within 0.5%. End-to-end testing was performed in a modified Rando phantom. In-house MATLAB software was developed to calculate patient-specific dose distributions using DOSXYZnrc, and fabricate custom 3D-printed forms for creating patient-specific lung blocks. End-to-end OSLD and diode measurements both with and without lung blocks agreed with Monte Carlo calculated doses to within 5% and in-phantom film measurements validated dose distribution uniformity. Custom lung block transmission measurements agree well with design criteria and provide clinically favorable dose distributions within the lungs. Block placement is easily facilitated using the flat panel imaging system with an exposure time of 0.01 min. In conclusion, a novel dedicated TBI unit has been commissioned and clinically implemented. Its mechanical, dosimetric, and imaging capabilities are suitable to provide state-of-the-art TBI for patients as large as 220 cm in height and 78 cm in width.

Navigating the medical physics education and training landscape.

PURPOSE: The education and training landscape has been profoundly reshaped by the ABR 2012/2014 initiative and the MedPhys Match. This work quantifies these changes and summarizes available reports, surveys, and statistics on education and training. METHODS: We evaluate data from CAMPEP-accredited program websites, annual CAMPEP graduate and residency program reports, and surveys on the MedPhys Match and Professional Doctorate degree (DMP). RESULTS: From 2009-2015, the number of graduates from CAMPEP-accredited graduate programs rose from 210 to 332, while CAMPEP-accredited residency positions rose from 60 to 134. We estimate that approximately 60% of graduates of CAMPEP-accredited graduate programs intend to enter clinical practice, however, only 36% of graduates were successful in acquiring a residency position in 2015. The maximum residency placement percentage for a graduate program is 70%, while the median for all programs is only 22%. Overall residency placement percentage for CAMPEP-accredited program graduates from 2011-2015 was approximately 38% and 25% for those with a PhD and MS, respectively. The disparity between the number of clinically oriented graduates and available residency positions is perceived as a significant problem by over 70% of MedPhys Match participants responding to a post-match survey. Approximately 32% of these respondents indicated that prior knowledge of this situation would have changed their decision to pursue graduate education in medical physics. CONCLUSION: These data reveal a substantial disparity between the number of residency training positions and graduate students interested in these positions, and a substantial variability in residency placement percentage across graduate programs. Comprehensive data regarding current and projected supply and demand within the medical physics workforce are needed for perspective on these numbers. While the long-term effects of changes in the education and training infrastructure are still unclear, available survey data suggest that these changes could negatively affect potential entrants to the profession.