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.

Outcomes of stereotactic radiotherapy for cranial and extracranial metastatic renal cell carcinoma: a systematic review.

BACKGROUND: Stereotactic radiotherapy is a non-invasive, ablative technique which may be particularly effective in treating metastatic renal cell carcinoma (RCC). The study objective was to analyse outcomes and toxicity of stereotactic radiotherapy in metastatic RCC. MATERIAL AND METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review of Medline was performed in March 2013. Exclusion criteria included mixed histology studies and case series. Local control, overall survival and toxicities were analysed. RESULTS: From 148 publications identified, 16 and 10 publications for cranial and extracranial metastatic RCC met inclusion criteria, respectively. There were 810 intracranial patients and 2433 targets. The weighted local control was 92%. Overall survival ranged from 6.7 to 25.6 months. Significant Grade 3-4 toxicity ranged from 0% to 6%. The weighted rate of treatment-related mortality was 0.6%, all secondary to intratumoral haemorrhage. There were 389 extracranial patients and 730 targets. The weighted local control was 89%. Median overall survival ranged from 11.7 to 22 months. Grade 3-4 toxicity ranged from 0% to 4%. Treatment-related mortality was 0.5%. CONCLUSION: Stereotactic radiotherapy is associated with excellent local control and low rates of toxicity for intracranial and extracranial metastatic RCC. Future randomised studies are required to confirm the additional benefit of Stereotactic Ablative Body Radiotherapy (SABR) above standard conservative or palliative approaches.

Complementary and alternative medicine use and disclosure amongst Australian radiotherapy patients.

PURPOSE: Information on complementary and alternative medicine (CAM) use in Australian radiotherapy patients is sparse. This study investigated the type and prevalence of CAM amongst an Australian regional radiotherapy patient cohort and the disclosure of information to the consultant radiation oncologist. METHODS: A single hardcopy questionnaire survey was provided to patients regarding the use of CAM and discussion with the treating medical practitioner. The National Centre for Complementary and Alternative Medicine (NCCAM) classification was used to group responses. The study was open for a period of 4 months, and all patients on treatment during this period were approached. RESULTS: A total of 170 questionnaires were distributed to eligible patients, and 152 patients returned a completed questionnaire (89.4 % response rate). Sixty-nine of the 152 patients (45.4 %) reported active CAM use. Of the 69 patients who used CAM, mind-body medicine (n = 54, 78.3 %) and biological-based therapies (n = 54, 78.3 %) were the commonest NCCAM group, whilst manipulative/body-based therapies (n = 44, 63.8 %), whole medical systems (n = 7, 10.1 %) and energy therapies (n = 5, 7.2 %) were the least common. The most common therapies were vitamins and mineral supplementation (n = 33, 47.8 %) and massage therapy (n = 18, 26.1 %). Of note, only 29 participants stated that they had discussed CAM therapies with their radiation oncologist. CONCLUSIONS: CAM use was prevalent amongst cancer patients undergoing radiotherapy, but frequently not discussed with the treating radiation oncologist. Considering the high prevalence of CAM, further resources could be justifiably directed at providing this service for cancer patients to foster a more holistic approach to their care.

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.

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.

[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.

Ten-year results of quality assurance in radiotherapy chart round.

BACKGROUND: The Royal Australian and New Zealand College of Radiologists (RANZCR) initiated a unique instrument to audit the quality of patient notes and radiotherapy prescriptions. We present our experience collected over ten years from the use of the RANZCR audit instrument. METHODS: In this study, the results of data collected prospectively from January 1999 to June 2009 through the audit instrument were assessed. Radiotherapy chart rounds were held weekly in the uro-oncology tumour stream and real time feedback was provided. Electronic medical records were retrospectively assessed in September 2009 to see if any omissions were subsequently corrected. RESULTS: In total 2597 patients were audited. One hundred and thirty seven (5%) patients had one hundred and ninety nine omissions in documentation or radiotherapy prescription. In 79% of chart rounds no omissions were found at all, in 12% of chart rounds one omission was found and in 9% of chart rounds two or more omissions were found. Out of 199 omissions, 95% were of record keeping and 2% were omissions in the treatment prescription. Of omissions, 152 (76%) were unfiled investigation results of which 77 (51%) were subsequently corrected. CONCLUSIONS: Real-time audit with feedback is an effective tool in assessing the standards of radiotherapy documentation in our department, and also probably contributed to the high level of attentiveness. A large proportion of omissions were investigation results, which highlights the need for an improved system of retrieval of investigation results in the radiation oncology department.

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.

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.

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.

A systematic review of stereotactic radiotherapy ablation for primary renal cell carcinoma.

UNLABELLED: What's known on the subject? and What does the study add? At present, little is known about the role of stereotactic ablative body radiotherapy in the treatment of primary renal cell carcinoma. The published evidence to date totals 126 patients worldwide. The majority of evidence is retrospective in nature. The present study adds context to the current literature by providing an overall summary of the evidence. OBJECTIVE: • To critically assess the use of stereotactic ablative body radiotherapy (SABR) for the treatment of primary renal cell carcinoma with particular focus on local control and toxicity outcomes. METHODS: • A systematic search on PubMed was performed in January 2012 independently by two radiation oncologists using structured search terms. • Secondary manual searches were performed on citations in relevant publications and abstracts in major radiotherapy journals. • Outcomes, techniques, biological doses and scientific rigour of the studies were analysed. RESULTS: • In total 10 publications (seven retrospective and three prospective) were identified. A wide range of techniques, doses and dose fractionation schedules were found. • A total of 126 patients were treated with between one and six fractions of SABR. Median or mean follow-up ranged from 9 to 57.5 months. A weighted local control was reported of 93.91% (range 84%-100%). • The weighted rate of severe grade 3 or higher adverse events was 3.8% (range 0%-19%). The weighted rate of grade 1-2 minor adverse events was 21.4% (range 0%-93%). The most commonly employed fractionation schedule was 40 Gy delivered over five fractions. CONCLUSIONS: • Current literature suggests that SABR for primary renal cell carcinoma can be delivered with promising rates of local control and acceptable toxicity. • However, there was insufficient evidence to recommend a consensus view for dose fractionation or technique. • This indicates the need for further prospective studies assessing the role of this technique in medically inoperable patients.

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.

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.

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.

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.

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.

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.

Impact of post-therapy positron emission tomography on prognostic stratification and surveillance after chemoradiotherapy for cervical cancer.

BACKGROUND: A study was undertaken to investigate the detection of relapse and survival outcomes in patients with cervical cancer treated with curative intent chemoradiotherapy, and evaluated with a post-therapy (18) F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan. METHODS: Between January 2002 and June 2007, 105 consecutive patients were prospectively enrolled into a registry study designed to assess outcomes of chemoradiotherapy. A FDG-PET scan was performed between 3 and 12 months (median, 4.9 months) post-treatment at clinician discretion. Tumor response was graded as complete metabolic response, partial metabolic response, or progressive metabolic disease. RESULTS: Median follow-up was 36 months. At post-therapy FDG-PET, 73 (70%) patients had complete metabolic response, 10 (9%) had partial metabolic response, and 22 (21%) had progressive metabolic disease. Overall survival at 3 years was 77% in all patients, and 95% for those with complete metabolic response. On multivariate analysis, complete metabolic response (P < .0001) and pretreatment tumor volume (P = .041) were strong predictors for overall survival. The number of involved lymph nodes (P < .005) and International Federation of Gynecology and Obstetrics stage (P = .04) were predictive of relapse-free survival. In total, 18 patients relapsed at a single site, and 13 underwent salvage, with a 3-year survival of 67%. Patients with complete metabolic response had a distant failure rate 36-fold less than those with partial metabolic response (P < .0001). After complete metabolic response, only 1 patient (1.6%) relapsed without symptoms and was detected through physical examination. CONCLUSIONS: The presence of a complete metabolic response at post-therapy FDG-PET is a powerful predictor for survival after chemoradiation. The very low rate of recurrence in patients with a complete metabolic response justifies a conservative follow-up approach for these patients, because relapse is usually symptomatic and not detected by routine clinical review.

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.

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.