[18]F-fluoroethyl-l-tyrosine positron emission tomography for radiotherapy target delineation: Results from a Radiation Oncology credentialing program.

Background and purpose: The [18]F-fluoroethyl-l-tyrosine (FET) PET in Glioblastoma (FIG) study is an Australian prospective, multi-centre trial evaluating FET PET for newly diagnosed glioblastoma management. The Radiation Oncology credentialing program aimed to assess the feasibility in Radiation Oncologist (RO) derivation of standard-of-care target volumes (TVMR) and hybrid target volumes (TVMR+FET) incorporating pre-defined FET PET biological tumour volumes (BTVs). Materials and methods: Central review and analysis of TVMR and TVMR+FET was undertaken across three benchmarking cases. BTVs were pre-defined by a sole nuclear medicine expert. Intraclass correlation coefficient (ICC) confidence intervals (CIs) evaluated volume agreement. RO contour spatial and boundary agreement were evaluated (Dice similarity coefficient [DSC], Jaccard index [JAC], overlap volume [OV], Hausdorff distance [HD] and mean absolute surface distance [MASD]). Dose plan generation (one case per site) was assessed. Results: Data from 19 ROs across 10 trial sites (54 initial submissions, 8 resubmissions requested, 4 conditional passes) was assessed with an initial pass rate of 77.8 %; all resubmissions passed. TVMR+FET were significantly larger than TVMR (p < 0.001) for all cases. RO gross tumour volume (GTV) agreement was moderate-to-excellent for GTVMR (ICC = 0.910; 95 % CI, 0.708-0.997) and good-to-excellent for GTVMR+FET (ICC = 0.965; 95 % CI, 0.871-0.999). GTVMR+FET showed greater spatial overlap and boundary agreement compared to GTVMR. For the clinical target volume (CTV), CTVMR+FET showed lower average boundary agreement versus CTVMR (MASD: 1.73 mm vs. 1.61 mm, p = 0.042). All sites passed the planning exercise. Conclusions: The credentialing program demonstrated feasibility in successful credentialing of 19 ROs across 10 sites, increasing national expertise in TVMR+FET delineation.

Transformer CycleGAN with uncertainty estimation for CBCT based synthetic CT in adaptive radiotherapy.

Objective. Clinical implementation of synthetic CT (sCT) from cone-beam CT (CBCT) for adaptive radiotherapy necessitates a high degree of anatomical integrity, Hounsfield unit (HU) accuracy, and image quality. To achieve these goals, a vision-transformer and anatomically sensitive loss functions are described. Better quantification of image quality is achieved using the alignment-invariant Fréchet inception distance (FID), and uncertainty estimation for sCT risk prediction is implemented in a scalable plug-and-play manner.Approach. Baseline U-Net, generative adversarial network (GAN), and CycleGAN models were trained to identify shortcomings in each approach. The proposed CycleGAN-Best model was empirically optimized based on a large ablation study and evaluated using classical image quality metrics, FID, gamma index, and a segmentation analysis. Two uncertainty estimation methods, Monte-Carlo Dropout (MCD) and test-time augmentation (TTA), were introduced to model epistemic and aleatoric uncertainty.Main results. FID was correlated to blind observer image quality scores with a Correlation Coefficient of -0.83, validating the metric as an accurate quantifier of perceived image quality. The FID and mean absolute error (MAE) of CycleGAN-Best was 42.11 ± 5.99 and 25.00 ± 1.97 HU, compared to 63.42 ± 15.45 and 31.80 HU for CycleGAN-Baseline, and 144.32 ± 20.91 and 68.00 ± 5.06 HU for the CBCT, respectively. Gamma 1%/1 mm pass rates were 98.66 ± 0.54% for CycleGAN-Best, compared to 86.72 ± 2.55% for the CBCT. TTA and MCD-based uncertainty maps were well spatially correlated with poor synthesis outputs.Significance. Anatomical accuracy was achieved by suppressing CycleGAN-related artefacts. FID better discriminated image quality, where alignment-based metrics such as MAE erroneously suggest poorer outputs perform better. Uncertainty estimation for sCT was shown to correlate with poor outputs and has clinical relevancy toward model risk assessment and quality assurance. The proposed model and accompanying evaluation and risk assessment tools are necessary additions to achieve clinically robust sCT generation models.

Stereotactic body radiotherapy for early-stage lung cancer: a systematic review on the choice of photon energy and linac flattened/unflattened beams.

SBRT is an effective local treatment for patients with early-stage non-small cell lung cancer (NSCLC). This treatment is currently used in patients who have poor lung function or who decline surgery. As SBRT usually has small PTV margins, reducing the beam-on-time (BOT) is beneficial for accurate dose delivery by minimising intrafraction motion as well as improved patient comfort. Removal of the linear accelerator flattening filter can provide a higher dose rate which results in a faster treatment. In addition, the choice of photon energy can also affect the dose distribution to the target and the organs-at-risk (OAR). In this systematic review, studies analysing the choice of various photon beam energies, with a flattening filter or flattening filter free (FFF), were compared for their overall dosimetric benefit in the SBRT treatment for early-stage NSCLC. It was found that FFF treatment delivers a comparatively more conformal dose distribution, as well as a better homogeneity index and conformity index, and typically reduces BOT by between 30 and 50%. The trade-off may be a minor increase in monitor units for FFF treatment found in some studies but not others. Target conformity and OAR sparing, particularly lung doses appear better with 6MV FFF, but 10MV FFF was marginally more advantageous for skin sparing and BOT reduction. The favourable beam modality for clinical use would depend on the individual case, for which tumour size and depth, radiotherapy technique, as well as fractionation scheme need to be taken into account.

Risk of cardiac implantable device malfunction in cancer patients receiving proton therapy: an overview.

Age is a risk factor for both cardiovascular disease and cancer, and as such radiation oncologists frequently see a number of patients with cardiac implantable electronic devices (CIEDs) receiving proton therapy (PT). CIED malfunctions induced by PT are nonnegligible and can occur in both passive scattering and pencil beam scanning modes. In the absence of an evidence-based protocol, the authors emphasise that this patient cohort should be managed differently to electron- and photon- external beam radiation therapy (EBRT) patients due to distinct properties of proton beams. Given the lack of a PT-specific guideline for managing this cohort and limited studies on this important topic; the process was initiated by evaluating all PT-related CIED malfunctions to provide a baseline for future reporting and research. In this review, different modes of PT and their interactions with a variety of CIEDs and pacing leads are discussed. Effects of PT on CIEDs were classified into a variety of hardware and software malfunctions. Apart from secondary neutrons, cumulative radiation dose, dose rate, CIED model/manufacturer, distance from CIED to proton field, and materials used in CIEDs/pacing leads were all evaluated to determine the probability of malfunctions. The importance of proton beam arrangements is highlighted in this study. Manufacturers should specify recommended dose limits for patients undergoing PT. The establishment of an international multidisciplinary team dedicated to CIED-bearing patients receiving PT may be beneficial.

Long-Term Outcomes of TROG 13.01 SAFRON II Randomized Trial of Single- Versus Multifraction Stereotactic Ablative Body Radiotherapy for Pulmonary Oligometastases.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In a randomized phase II clinical trial, the Trans Tasman Radiation Oncology Group compared single- versus multifraction stereotactic ablative body radiotherapy (SABR) in 90 patients with 133 oligometastases to the lung. The study found no differences in safety, efficacy, systemic immunogenicity, or survival between arms, with single-fraction SABR picked as the winner on the basis of cost-effectiveness. In this article, we report the final updated survival outcome analysis. The protocol mandated no concurrent or post-therapy systemic therapy until progression. Modified disease-free survival (mDFS) was defined as any progression not addressable by local therapy, or death. At a median follow-up of 5.4 years, the 3- and 5-year estimates for overall survival (OS) were 70% (95% CI, 59 to 78) and 51% (95% CI, 39 to 61). There were no significant differences between the multi- and single-fraction arms for OS (hazard ratio [HR], 1.1 [95% CI, 0.6 to 2.0]; P = .81). The 3- and 5-year estimates for disease-free survival were 24% (95% CI, 16 to 33) and 20% (95% CI, 13 to 29), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.6]; P = .92). The 3- and 5-year estimates for mDFS were 39% (95% CI, 29 to 49) and 34% (95% CI, 24 to 44), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.8]; P = .90). In this patient population, where patients receive SABR in lieu of systemic therapy, one-in-three patients are alive without disease in the long term. There were no differences in outcomes by fractionation schedule.

Intrafraction motion during CyberKnife® prostate SBRT: impact of imaging frequency and patient factors.

PURPOSE:  To determine the relationship between imaging frequencies and prostate motion during CyberKnife stereotactic body radiotherapy (SBRT) for prostate cancer. METHODS:  Intrafraction displacement data for 331 patients who received treatment with CyberKnife for prostate cancer were retrospectively analysed. Prostate positions were tracked with a large variation in imaging frequencies. The percent of treatment time that patients remained inside various motion thresholds for both real and simulated imaging frequencies was calculated. Results: 84,920 image acquisitions over 1635 fractions were analysed. Fiducial distance travelled between consecutive images were less than 2, 3, 5, and 10 mm for 92.4%, 94.4%, 96.2%, and 97.7% of all consecutive imaging pairs respectively. The percent of treatment time that patients received adequate geometric coverage increased with more frequent imaging intervals. No significant correlations between age, weight, height, BMI, rectal, bladder or prostate volumes and intrafraction prostate motion were observed. CONCLUSIONS: There are several combinations of imaging intervals and movement thresholds that may be suitable for consideration during treatment planning with respect to imaging and calculation of the margin between the clinical target volume and planning target volume (CTV-to-PTV), resulting in adequate geometric coverage for approximately 95% of treatment time. Rectal toxicities and treatment duration need to be considered when implementing combinations clinically.

Effects of Photon Radiation on DNA Damage, Cell Proliferation, Cell Survival, and Apoptosis of Murine and Human Mesothelioma Cell Lines.

Purpose: To characterize the cellular responses of murine and human mesothelioma cell lines to different doses of photon radiation with a long-term aim of optimizing a clinically relevant in vivo model in which to study the interaction of radiation therapy and immunotherapy combinations. Methods and Materials: Two murine mesothelioma cell lines (AB1 and AE17) and 3 human cell lines (BYE, MC, and JU) were used in the study. Cells were treated with increasing doses of photon radiation. DNA damage, DNA repair, cell proliferation, and apoptosis at different time points after irradiation were quantified by flow cytometry, and cell survival probability was examined using clonogenic survival assay. Results: DNA damage increased with escalating dose in all cell lines. Evident G2/M arrest and reduced cell proliferation were observed after irradiation with 8 Gy. DNA repair was uniformly less efficient at higher compared with lower radiation-fraction doses. The apoptosis dose response varied between cell lines, with greater apoptosis observed at 16 Gy with human BYE and murine AB1 cell lines but less for other studied cell lines, regardless of dose and time. The α/ß ratio from the cell survival fraction of human mesothelioma cell lines was smaller than from murine ones, suggesting human cell lines in our study were more sensitive to a change of dose per fraction than were murine mesothelioma cell lines. However, in all studied cell lines, colony formation was completely inhibited at 8 Gy. Conclusions: A threshold dose of 8 Gy appeared to be appropriate for hypofractionated radiation therapy. However, the radiation therapy doses between 4 and 8 Gy remain to be systematically analyzed. These observations provide an accurate picture of the in vitro response of mesothelioma cell lines to photon irradiation and characterize the heterogeneity between human and murine cell lines. This information may guide in vivo experiments and the strengths and limitations of extrapolation from murine experimentation to potential human translation.

Immune marker expression of irradiated mesothelioma cell lines.

Background: Though immune checkpoint inhibition has recently shown encouraging clinical efficacy in mesothelioma, most patients do not respond. Combining immune checkpoint inhibition with radiotherapy presents an attractive option for improving treatment responses owing to the various immunomodulatory effects of radiation on tumors. However, the ideal dosing and scheduling of combined treatment remains elusive, as it is poorly studied in mesothelioma. The present study characterizes the dose- and time-dependent changes to expression of various immune markers and cytokines important to antitumor responses following irradiation of mesothelioma cell lines. Methods: Two murine (AB1, AE17) and two human (BYE, JU77) mesothelioma cell lines were treated with titrated gamma-radiation doses (1-8 Gy) and the expression of MHC class-I, MHC class-II and PD-L1 was measured over a series of post-irradiation timepoints (1-72 hours) by flow cytometry. Levels of cytokines IL-1α, IL-1ß, IL-6, IL-10, IL-12p70, IL-17A, IL-23, IL-27, MCP-1, IFN-ß, IFN-γ, TNF-α, and GM-CSF were measured by multiplex immunoassay in murine cell lines following 8 Gy radiation. Results: Following irradiation, a dose-dependent upregulation of MHC-I and PD-L1 was observed on three of the four cell lines studied to varying extents. For all cell lines, the increase in marker expression was most pronounced 72 hours after radiation. At this timepoint, increases in levels of cytokines IFN-ß, MCP-1 and IL-6 were observed following irradiation with 8 Gy in AB1 but not AE17, reflecting patterns in marker expression. Conclusions: Overall, this study establishes the dose- and time-dependent changes in immune marker expression of commonly studied mesothelioma cell lines following radiation and will inform future study into optimal dosing and scheduling of combined radiotherapy and immune checkpoint inhibition for mesothelioma.

CyberKnife Xsight versus fiducial-based target-tracking: a novel 3D dosimetric comparison in a dynamic phantom.

BACKGROUND: The CyberKnife Xsight lung-tracking system (XLTS) provides an alternative to fiducial-based target-tracking systems (FTTS) for non-small-cell lung cancer (NSCLC) patients without invasive fiducial insertion procedures. This study provides a method for 3D independent dosimetric verification of the accuracy of the FTTS compared to the XLTS without relying on log-files generated by the CyberKnife system. METHODS: A respiratory motion trace was taken from a 4D-CT of a real lung cancer patient and applied to a modified QUASAR™ respiratory motion phantom. A novel approach to 3D dosimetry was developed using Gafchromic EBT3 film, allowing the 3D dose distribution delivered to the moving phantom to be reconstructed. Treatments were planned using the recommended margins for one and three fiducial markers and XLTS 2-view, 1-view and 0-view target-tracking modalities. The dose delivery accuracy was analysed by comparing the reconstructed dose distributions to the planned dose distributions using gamma index analysis. RESULTS: For the 3%/2 mm gamma criterion, gamma passing rates up to 99.37% were observed for the static deliveries. The 3-fiducial and 1-fiducial-based deliveries exhibited passing rates of 93.74% and 97.82%, respectively, in the absence of target rotation. When target rotation was considered, the passing rate for 1-fiducial tracking degraded to 91.24%. The passing rates observed for XLTS 2-view, 1-view and 0-view target-tracking were 92.78%, 96.22% and 76.08%, respectively. CONCLUSIONS: Except for the XLTS 0-view, the dosimetric accuracy of the XLTS was comparable to the FTTS under equivalent treatment conditions. This study gives us further confidence in the CyberKnife XLTS and FTTS systems.

Clinical evidence for synergy between immunotherapy and radiotherapy (SITAR).

Previous preclinical and clinical trials have shown promising antitumour activity and toxicity profile when employing the 'Synergy between Immunotherapy and Radiotherapy' (SITAR) strategy. Approximately, one in seven radiation therapy studies currently recruiting is investigating SITAR. This article reviews the range of cancers known to respond to immunotherapy and publications analysing SITAR. It sets the background for work that needs to be done in future clinical trials. It also reviews the potential toxicities of immunotherapy and discusses areas where caution is required when combining treatments.

Comparison of conventional versus customised Eurosil-4 Pink bolus for radiotherapy of the chest wall.

INTRODUCTION: In radiotherapy, the presence of air gaps near a tumour can lead to underdose to the tumour. In this study, the impact of air gaps on dose to the surface was evaluated. 3D-printing was used to construct a Eurosil-4 Pink bolus customised to the patient and its dosimetric properties were compared with that of Paraffin wax bolus. METHODS: Surface dose was measured for flat sheets of Eurosil-4 Pink bolus with different thicknesses. Different air gap thicknesses were inserted between the bolus and the surface, and dose was measured for each air gap using 10 cm × 10 cm fields. This was repeated with the effective field size calculated from the patient plan. Surface dose was measured for varying angles of incidence. A customised chest phantom was used to compare dose for two customised Eurosil-4 Pink boluses, and commonly used Paraffin wax bolus. RESULTS: The surface dose was found to be highest for 1.1 cm thick bolus. The decrease in surface dose for the Eurosil-4 Pink bolus was minimal for the 10 cm × 10 cm field, but higher for the effective field size and larger angles of incidence. For instance, the dose was reduced by 6.2% as a result of 1 cm air gap for the effective field size and 60 degree angle of incidence. The doses measured using Gafchromic film under the customised Eurosil-4 Pink boluses were similar to that of the Paraffin wax bolus, and higher than prescribed dose. CONCLUSIONS: The impact of air gaps can be significant for small field sizes and oblique beams. A customised Eurosil-4 Pink bolus has promising physical and dosimetric properties to ensure sufficient dose to the tumour, even for treatments where larger impact of air gaps is suspected.

Randomised controlled trial on the effect of simethicone bowel preparation on rectal variability during image-guided radiation therapy for prostate cancer (SPoRT study).

INTRODUCTION: The purpose of this study was to assess whether simethicone reduces the rectal volume (RV) and gas volume (GV), to increase treatment accuracy and to decrease toxicity of prostate radiation therapy. METHODS: 30 patients were randomised to simethicone or no intervention. Cone-beam computed tomography (CBCT) scans were performed on Days 1-3 and weekly until completion of radiation. RV and GV were measured using volume delineation. Toxicity data were collected. RESULTS: 264 CBCTs were analysed. RV and GV were not significantly different in the simethicone group compared with the control group at each time point (P >0.05) after adjusting for Week 0 values as a covariate. The simethicone group showed an average reduction in RV and GV of 10% and 21%, respectively, compared with the control group (P >0.05). Standard deviations were calculated over 10 time points, which were grouped to represent the first 2-3 weeks of radiation therapy versus subsequent weeks. These were not significantly different between the simethicone and control group. However, there was a statistically significant decrease in the variability of RV at time points 6-10 compared with time points 1-5 within the simethicone group (P = 0.012), but no significant difference was found between these grouped time points in the control group (P = 0.581). The toxicity questionnaires showed no significant difference between the groups. CONCLUSIONS: Simethicone did not decrease the RV or GV overall. However, simethicone appeared to significantly decrease the RV variability from Week three onwards. This suggests that taking simethicone two to three weeks before starting radiation therapy may reduce RV variability, although a larger study is needed to confirm this.

Single-Fraction vs Multifraction Stereotactic Ablative Body Radiotherapy for Pulmonary Oligometastases (SAFRON II): The Trans Tasman Radiation Oncology Group 13.01 Phase 2 Randomized Clinical Trial.

IMPORTANCE: Evidence is lacking from randomized clinical trials to guide the optimal approach for stereotactic ablative body radiotherapy (SABR) in patients with pulmonary oligometastases. OBJECTIVE: To assess whether single-fraction or multifraction SABR is more effective for the treatment of patients with pulmonary oligometastases. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, unblinded, phase 2 randomized clinical trial of 90 patients across 13 centers in Australia and New Zealand enrolled patients with 1 to 3 lung oligometastases less than or equal to 5 cm from any nonhematologic malignant tumors located away from the central airways, Eastern Cooperative Oncology Group performance status 0 or 1, and all primary and extrathoracic disease controlled with local therapy. Enrollment was from January 1, 2015, to December 31, 2018, with a minimum patient follow-up of 2 years. INTERVENTIONS: Single fraction of 28 Gy (single-fraction arm) or 4 fractions of 12 Gy (multifraction arm) to each oligometastasis. MAIN OUTCOMES AND MEASURES: The main outcome was grade 3 or higher treatment-related adverse events (AEs) occurring within 1 year of SABR. Secondary outcomes were freedom from local failure, overall survival, disease-free survival, and patient-reported outcomes (MD Anderson Symptom Inventory-Lung Cancer and EuroQol 5-dimension visual analog scale). RESULTS: Ninety participants were randomized, of whom 87 were treated for 133 pulmonary oligometastases. The mean (SD) age was 66.6 [11.6] years; 58 (64%) were male. Median follow-up was 36.5 months (interquartile range, 24.8-43.9 months). The numbers of grade 3 or higher AEs related to treatment at 1 year were 2 (5%; 80% CI, 1%-13%) in the single-fraction arm and 1 (3%; 80% CI, 0%-10%) in the multifraction arm, with no significant difference observed between arms. One grade 5 AE occurred in the multifraction arm. No significant differences were found between the multifraction arm and single-fraction arm for freedom from local failure (hazard ratio [HR], 0.5; 95% CI, 0.2-1.3; P = .13), overall survival (HR, 1.5; 95% CI, 0.6-3.7; P = .44), or disease-free survival (HR, 1.0; 95% CI, 0.6-1.6; P > .99). There were no significant differences observed in patient-reported outcomes. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, neither arm demonstrated evidence of superior safety, efficacy, or symptom burden; however, single-fraction SABR is more efficient to deliver. Therefore, single-fraction SABR, as assessed by the most acceptable outcome profile from all end points, could be chosen to escalate to future studies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01965223.

In vivo noninvasive preclinical tumor hypoxia imaging methods: a review.

Tumors exhibit areas of decreased oxygenation due to malformed blood vessels. This low oxygen concentration decreases the effectiveness of radiation therapy, and the resulting poor perfusion can prevent drugs from reaching areas of the tumor. Tumor hypoxia is associated with poorer prognosis and disease progression, and is therefore of interest to preclinical researchers. Although there are multiple different ways to measure tumor hypoxia and related factors, there is no standard for quantifying spatial and temporal tumor hypoxia distributions in preclinical research or in the clinic. This review compares imaging methods utilized for the purpose of assessing spatio-temporal patterns of hypoxia in the preclinical setting. Imaging methods provide varying levels of spatial and temporal resolution regarding different aspects of hypoxia, and with varying advantages and disadvantages. The choice of modality requires consideration of the specific experimental model, the nature of the required characterization and the availability of complementary modalities as well as immunohistochemistry.

Connecting a simulated virtual patient program with experiential practicums: Perspectives from year three students.

BACKGROUND AND PURPOSE: Research indicates that the simulated learning tools known as virtual patients (VPs) are valued by pharmacy students and impact students' knowledge and confidence. However, research is needed to understand how students can be supported to make intended connections between VP cases and real-life clinical scenarios. The purpose of this study was to examine whether and how VP cases influence students' clinical reasoning skills, confidence, thought processes, and preparedness for their experiential practicums. EDUCATIONAL ACTIVITY AND SETTING: Third-year entry-to-practice doctor of pharmacy students who had completed at least one VP case in second year prior to their experiential practicums were surveyed in fall 2018 after having completed their experiential practicums. Surveys were structured to solicit student perceptions related to how students bridged VP cases and real-life clinical scenarios and were analyzed using a mixed-methods design. FINDINGS: Forty-three students completed the survey. Students perceived that VP cases most significantly impacted their clinical reasoning skills due to the opportunity cases afforded them to explore patient data and navigate relevant information. The largest limitation of VP cases to students' learning was that the cases differed from their experiences. Students' suggestions included opportunities for more practice using VP cases and an expanded repertoire of medical conditions offered through case exposure. SUMMARY: More research is needed to understand how to help students connect VP cases to their experiential practicums to make them more effective learning tools.

Enhancing the efficacy of immunotherapy using radiotherapy.

Recent clinical breakthroughs in cancer immunotherapy, especially with immune checkpoint blockade, offer great hope for cancer sufferers - and have greatly changed the landscape of cancer treatment. However, whilst many patients achieve clinical responses, others experience minimal benefit or do not respond to immune checkpoint blockade at all. Researchers are therefore exploring multimodal approaches by combining immune checkpoint blockade with conventional cancer therapies to enhance the efficacy of treatment. A growing body of evidence from both preclinical studies and clinical observations indicates that radiotherapy could be a powerful driver to augment the efficacy of immune checkpoint blockade, because of its ability to activate the antitumor immune response and potentially overcome resistance. In this review, we describe how radiotherapy induces DNA damage and apoptosis, generates immunogenic cell death and alters the characteristics of key immune cells in the tumor microenvironment. We also discuss recent preclinical work and clinical trials combining radiotherapy and immune checkpoint blockade in thoracic and other cancers. Finally, we discuss the scheduling of immune checkpoint blockade and radiotherapy, biomarkers predicting responses to combination therapy, and how these novel data may be translated into the clinic.

Timing of fluorodeoxyglucose positron emission tomography maximum standardized uptake value for diagnosis of local recurrence of non-small cell lung cancer after stereotactic body radiation therapy.

INTRODUCTION: After treatment with stereotactic body radiation therapy (SBRT), local recurrence of non-small cell cancer (NSCLC) can be difficult to differentiate from radiation-induced changes. Maximum standardized uptake value (SUVmax), measured with 18-F-Fluorodeoxyglucose positron emission tomography (FDG-PET), can have false positives due to acute radiation inflammation. The primary study objective was to determine the utility of SUVmax > 5 to identify local recurrence later than 9 months after SBRT. METHOD: A retrospective review was performed of FDG-PET scans for suspicious CT findings after SBRT treatment of stage 1 NSCLC. SUVmax was measured including surrounding opacification. Outcome measures were local recurrence, progression free survival, and overall survival. Receiver operator curve analysis, sensitivity, specificity, and Kaplan-Meier analysis were performed. RESULTS: Of 118 patients treated, 42 patients had eligible FDG-PET scans. They received SBRT (48-60Gy in 3-8 fractions) for 49 NSCLC and had 101 follow-up PET scans. The median time to first PET scan was 9.3 months, and the median follow-up period was 22.4 months. Local recurrence was diagnosed in 12 patients, at a median of 16 months. Due to selection bias, the included patients had poorer outcomes than the entire cohort, with progression free survival (PFS) at 1, 2, and 3 years of 82.7%, 57.8%, and 45.8%; and overall survival of 97.9%, 79.9%, and 59.1%, respectively. Thirty FDG-PET scans were performed within 9 months, of which 17% were false positives. A total of 71 FDG-PET scans were performed beyond 9 months, and the median SUVmax was significantly higher for patients with local recurrence (7.48 vs. 2.14, P < .0001). SUVmax > 5 has a sensitivity of 91% (95% CI 62%-99.8%) and 100% (89.1%-100%). CONCLUSION: For local recurrence of NSCLC, SUVmax > 5 on FDG-PET scan has good sensitivity and specificity after 6 months, but is highest beyond 9 months after SBRT.

Stereotactic radiosurgery for intracranial IgG4-related disease.

We report the case of a 20-year-old woman with intracranial IgG4-related disease, initially misdiagnosed as a meningioma on biopsy and treated with radiosurgery as it was in an eloquent location and not resectable. Her intracranial IgG4 disease had a near-complete response to radiosurgery and is still controlled six years later, so this case represents what we believe to be the first reported use of radiotherapy in the treatment of intracranial IgG4-related disease.

First Australian experience of treating localised prostate cancer patients with CyberKnife stereotactic radiotherapy: early PSA response, acute toxicity and quality of life.

INTRODUCTION: This study is to evaluate biochemical response, acute toxicity and health-related quality-of-life (QOL) outcomes among prostate cancer patients following stereotactic body radiation therapy (SBRT) in the first Australian CyberKnife facility. METHODS: Forty-five consecutive patients with clinically localised prostate cancer were treated with SBRT using CyberKnife technology and enrolled in this study. Protocol treatment consisted of 36.25 Gy in five fractions. PSA and acute toxicity was assessed at each follow-up visit and QOL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Global Health Status (GHS) C30 and PR25 questionnaires and the Karnofsky Performance Status (KPS). Distance of travel for treatment was recorded. RESULTS: The median prostate-specific antigen (PSA) level declined from the initial value of 6.9 ng/mL to 1.5 ng/mL at 6 months and 0.6 ng/mL at 18 months post-treatment. Results were similar in patients who did not receive hormone therapy. Acute grade 1 gastrointestinal (GI) and genitourinary (GU) toxicities were found in 11.1% and 24.4% of patients respectively. Acute grade 2 GI and GU toxicities were found in 2.2% and 11.1% of patients respectively. There were no grade 3 and grade 4 toxicities. Mean urinary symptom score was 14.8 at baseline, 17.2 at 6 weeks and 18.3 at 6 months (P > 0.05). Mean bowel symptom score was 2.7 at baseline, 4.2 at 6 weeks and 6.3 at 6 months (P > 0.05). The mean GHS score improved from 81.3 at baseline to 82.4 at 6 weeks, and was 75.6 at 6 months (P > 0.05, not significant). Compared to baseline KPS, there was a significant mean decrease from baseline of 96.7 to 93.3 at the 6-week follow-up (P = 0.0043), which then recovered to 94.3 at the 6-month follow-up (P = 0.1387). CONCLUSIONS: Early results show promising PSA response. Acute toxicity seemed comparable to results from conventionally fractionated radiotherapy and to international prostate SBRT studies. EORTC PR25 and C30 scores did not reveal any significant change from baseline, and although there was a decrease in KPS, the absolute decrease was small.

Stereotactic ablative body radiotherapy for inoperable primary kidney cancer: a prospective clinical trial.

OBJECTIVE: To assess the feasibility and safety of stereotactic ablative body radiotherapy (SABR) for renal cell carcinoma (RCC) in patients unsuitable for surgery. Secondary objectives were to assess oncological and functional outcomes. MATERIALS AND METHODS: This was a prospective interventional clinical trial with institutional ethics board approval. Inoperable patients were enrolled, after multidisciplinary consensus, for intervention with informed consent. Tumour response was defined using Response Evaluation Criteria In Solid Tumors v1.1. Toxicities were recorded using Common Terminology Criteria for Adverse Events v4.0. Time-to-event outcomes were described using the Kaplan-Meier method, and associations of baseline variables with tumour shrinkage was assessed using linear regression. Patients received either single fraction of 26 Gy or three fractions of 14 Gy, dependent on tumour size. RESULTS: Of 37 patients (median age 78 years), 62% had T1b, 35% had T1a and 3% had T2a disease. One patient presented with bilateral primaries. Histology was confirmed in 92%. In total, 33 patients and 34 kidneys received all prescribed SABR fractions (89% feasibility). The median follow-up was 24 months. Treatment-related grade 1-2 toxicities occurred in 26 patients (78%) and grade 3 toxicity in one patient (3%). No grade 4-5 toxicities were recorded and six patients (18%) reported no toxicity. Freedom from local progression, distant progression and overall survival rates at 2 years were 100%, 89% and 92%, respectively. The mean baseline glomerular filtration rate was 55 mL/min, which decreased to 44 mL/min at 1 and 2 years (P < 0.001). Neutrophil:lymphocyte ratio correlated to % change in tumour size at 1 year, r2 = 0.45 (P < 0.001). CONCLUSION: The study results show that SABR for primary RCC was feasible and well tolerated. We observed encouraging cancer control, functional preservation and early survival outcomes in an inoperable cohort. Baseline neutrophil:lymphocyte ratio may be predictive of immune-mediated response and warrants further investigation.