Robust Optimization for Prostate Radiation Therapy: Assessment of Delivered Dose by Incorporating Intrafraction Prostate Position Deviations.

Purpose: To assess the robustness of the dose delivered to the clinical target volume (CTV) between planning target volume (PTV)-based and robust optimization planning approaches in localized prostate cancer radiation therapy. Methods and Materials: Retrospective data of 20 patients with prostate cancer, including radiation therapy and real-time prostate position, were analyzed. Two sets of volumetric modulated arc therapy plans were generated per patient: PTV-based and robust optimization. PTV-based planning used a 7-mm CTV-PTV margin, whereas robust planning considered same-magnitude position deviations. Differences in CTV dose delivered to 99% volume (D99), PTV dose delivered to 95% volume (D95), and bladder and rectum V40 (volume receiving 40 Gy) and V60 (volume receiving 60 Gy) values were evaluated. The target position, determined by in-house position monitoring system, was incorporated for dose assessment with and without position deviation correction. Results: In the robust optimization approach, compared with PTV-based planning, the mean (standard deviation) V40 and V60 values of the bladder were reduced by 5.2% (4.1%) and 5.1% (1.9%), respectively. Similarly, for the rectum, the reductions were 0.8% (0.5%) and 0.6% (0.6%). In corrected treatment scenarios, both planning approaches resulted in a mean (standard deviation) CTV D99 difference of 0.1 Gy (0.1 Gy). In the not corrected scenario, PTV-based planning reduced CTV D99 by 0.1 Gy (0.5 Gy), whereas robust planning reduced it by 0.2 Gy (0.6 Gy). There was no statistically significant difference observed in the planned and delivered rectum and bladder dose for both corrected and not corrected scenarios. Conclusions: Robust optimization resulted in lower V40 and V60 values for the bladder compared with PTV-based planning. However, no difference in CTV dose accuracy was found between the 2 approaches.

Evaluating the relationship between contouring variability and modelled treatment outcome for prostate bed radiotherapy.

Objectives.Contouring similarity metrics are often used in studies of inter-observer variation and automatic segmentation but do not provide an assessment of clinical impact. This study focused on post-prostatectomy radiotherapy and aimed to (1) identify if there is a relationship between variations in commonly used contouring similarity metrics and resulting dosimetry and (2) identify the variation in clinical target volume (CTV) contouring that significantly impacts dosimetry.Approach.The study retrospectively analysed CT scans of 10 patients from the TROG 08.03 RAVES trial. The CTV, rectum, and bladder were contoured independently by three experienced observers. Using these contours reference simultaneous truth and performance level estimation (STAPLE) volumes were established. Additional CTVs were generated using an atlas algorithm based on a single benchmark case with 42 manual contours. Volumetric-modulated arc therapy (VMAT) treatment plans were generated for the observer, atlas, and reference volumes. The dosimetry was evaluated using radiobiological metrics. Correlations between contouring similarity and dosimetry metrics were calculated using Spearman coefficient (Γ). To access impact of variations in planning target volume (PTV) margin, the STAPLE PTV was uniformly contracted and expanded, with plans created for each PTV volume. STAPLE dose-volume histograms (DVHs) were exported for plans generated based on the contracted/expanded volumes, and dose-volume metrics assessed.Mainresults. The study found no strong correlations between the considered similarity metrics and modelled outcomes. Moderate correlations (0.5 <Γ< 0.7) were observed for Dice similarity coefficient, Jaccard, and mean distance to agreement metrics and rectum toxicities. The observations of this study indicate a tendency for variations in CTV contraction/expansion below 5 mm to result in minor dosimetric impacts.Significance. Contouring similarity metrics must be used with caution when interpreting them as indicators of treatment plan variation. For post-prostatectomy VMAT patients, this work showed variations in contours with an expansion/contraction of less than 5 mm did not lead to notable dosimetric differences, this should be explored in a larger dataset to assess generalisability.

Prostate Virtual High-dose-rate Brachytherapy Boost: 5-Year Results from the PROMETHEUS Prospective Multicentre Trial.

BACKGROUND AND OBJECTIVE: Despite the high efficacy of high-dose-rate brachytherapy boost (HDRB) in the management of prostate cancer (PC), use of this approach is declining. Similar dosimetry can be achieved using stereotactic body radiotherapy or "virtual HDRB" (vHDRB). The aim of the multicentre, single-arm, phase 2 PROMETHEUS trial (ACTRN12615000223538) was to evaluate the safety and efficacy of vHDRB in patients with PC. METHODS: Patients with intermediate-risk PC or selected patients with high-risk PC were eligible for inclusion. vHDRB was given as 19-20 Gy in two fractions, delivered 1 wk apart, followed by conventionally fractionated external beam radiotherapy (EBRT) at 46 Gy in 23 fractions or 36 Gy in 12 fractions. The primary endpoint was the biochemical/clinical relapse-free rate (bcRFR). Toxicity was graded using Common Terminology Criteria for Adverse Events version 4 and quality of life (QoL) data were collected used the Expanded Prostate Cancer Index Composite-26 questionnaire. KEY FINDINGS AND LIMITATIONS: From March 2014 to December 2018, 151 patients (74% intermediate risk, 26% high risk) with a median age of 69 yr were treated across five centres. Median follow-up was 60 mo. The 5-yr bcRFR was 94.1% (95% confidence interval [CI] 90-98%) and the local control rate was 98.7%. Acute grade 2 gastrointestinal (GI) and genitourinary (GU) toxicity occurred in 6.6% and 23.2% of patients, respectively, with no acute grade 3 toxicity. At 60 mo after treatment, the prevalence of late grade ≥2 GI toxicity was 1.7% (95% CI 0.3-6.5%) and the prevalence of late grade ≥2 GU toxicity was 3.3% (95% CI 1.1-8.8%). Between baseline and 60 mo, QoL improved for urinary obstructive and hormonal domains, was stable for the bowel domain, and deteriorated slightly for the sexual and urinary incontinence domains. CONCLUSIONS: Delivery of gantry-based vHDRB followed by conventionally fractionated EBRT is feasible in a multicentre setting, with high 5-yr bcRFR and low toxicity. This approach is being compared with prostate ultrahypofractionated radiotherapy in the TROG 18.01 NINJA randomised trial (ACTRN12618001806257). PATIENT SUMMARY: The PROMETHEUS trial investigated noninvasive high-dose precision radiotherapy combined with conventional radiotherapy in patients with prostate cancer. We found that this new technique was well tolerated and resulted in better cancer control outcomes than historically reported.

Association Between Serum Ferritin and the Duration of Type 2 Diabetes Mellitus in a Tertiary Care Hospital in Chennai.

BACKGROUND: Hyperinsulinemia has been linked to increased ferritin production and iron absorption in type 2 diabetes mellitus, ultimately leading to increased iron storage. Glucose intolerance is intimately linked to this issue. Increased oxidative stress from iron decreases insulin's ability to be taken into cells and used for energy. Researchers suggest that increased iron levels in the body play a role in the emergence of insulin resistance, glucose intolerance, and vascular repercussions associated with diabetes. OBJECTIVE: The aim of this study is to assess the levels of serum ferritin and fasting plasma glucose in both diabetic and nondiabetic individuals while establishing a relationship between the two. Exploring the connection between serum ferritin levels and the duration of diabetes mellitus in individuals diagnosed with diabetes is our objective. METHODOLOGY: In this study, 80 men diagnosed with type 2 diabetes mellitus were included, and they were compared with 70 male volunteers who were in good health. We took blood samples while the subjects fasted, and we analyzed the plasma glucose and serum ferritin levels. RESULTS: In the diabetic group, there were notably higher levels of serum ferritin and fasting plasma glucose compared to the nondiabetic subjects. Furthermore, a correlation was observed between the duration of diabetes among participants with diabetes and elevated serum ferritin levels. CONCLUSION: The findings suggest that low-grade inflammation and increased body iron stores are positively related to hyperglycemia in type 2 diabetes mellitus.

Assessment of interfraction dose variation in pancreas SBRT using daily simulation MR images.

Pancreatic Cancer is associated with poor treatment outcomes compared to other cancers. High local control rates have been achieved by using hypofractionated stereotactic body radiotherapy (SBRT) to treat pancreatic cancer. Challenges in delivering SBRT include close proximity of several organs at risk (OARs) and target volume inter and intra fraction positional variations. Magnetic resonance image (MRI) guided radiotherapy has shown potential for online adaptive radiotherapy for pancreatic cancer, with superior soft tissue contrast compared to CT. The aim of this study was to investigate the variability of target and OAR volumes for different treatment approaches for pancreatic cancer, and to assess the suitability of utilizing a treatment-day MRI for treatment planning purposes. Ten healthy volunteers were scanned on a Siemens Skyra 3 T MRI scanner over two sessions (approximately 3 h apart), per day over 5 days to simulate an SBRT daily simulation scan for treatment planning. A pretreatment scan was also done to simulate patient setup and treatment. A 4D MRI scan was taken at each session for internal target volume (ITV) generation and assessment. For each volunteer a treatment plan was generated in the Raystation treatment planning system (TPS) following departmental protocols on the day one, first session dataset (D1S1), with bulk density overrides applied to enable dose calculation. This treatment plan was propagated through other imaging sessions, and the dose calculated. An additional treatment plan was generated on each first session of each day (S1) to simulate a daily replan process, with this plan propagated to the second session of the day. These accumulated mock treatment doses were assessed against the original treatment plan through DVH comparison of the PTV and OAR volumes. The generated ITV showed large variations when compared to both the first session ITV and daily ITV, with an average magnitude of 22.44% ± 13.28% and 25.83% ± 37.48% respectively. The PTV D95 was reduced by approximately 23.3% for both plan comparisons considered. Surrounding OARs had large variations in dose, with the small bowel V30 increasing by 128.87% when compared to the D1S1 plan, and 43.11% when compared to each daily S1 plan. Daily online adaptive radiotherapy is required for accurate dose delivery for pancreas cancer in the absence of additional motion management and tumour tracking techniques.

Assessment of intrafraction motion and its dosimetric impact on prostate radiotherapy using an in-house developed position monitoring system.

Purpose: To implement an in-house developed position monitoring software, SeedTracker, for conventional fractionation prostate radiotherapy, and study the effect on dosimetric impact and intrafraction motion. Methods: Thirty definitive prostate radiotherapy patients with implanted fiducial markers were included in the study. All patients were treated with VMAT technique and plans were generated using the Pinnacle planning system using the 6MV beam model for Elekta linear accelerator. The target dose of 60 Gy in 20 fractions was prescribed for 29 of 30 patients, and one patient was treated with the target dose of 78 Gy in 39 fractions. The SeedTracker position monitoring system, which uses the x-ray images acquired during treatment delivery in the Elekta linear accelerator and associated XVI system, was used for online prostate position monitoring. The position tolerance for online verification was progressively reduced from 5 mm, 4 mm, and to 3 mm in 10 patient cohorts to effectively manage the treatment interruptions resulting from intrafraction motion in routine clinical practice. The delivered dose to target volumes and organs at risk in each of the treatment fractions was assessed by incorporating the observed target positions into the original treatment plan. Results: In 27 of 30 patients, at least one gating event was observed, with a total of 177 occurrences of position deviation detected in 146 of 619 treatment fractions. In 5 mm, 4 mm, and 3 mm position tolerance cohorts, the position deviations were observed in 13%, 24%, and 33% of treatment fractions, respectively. Overall, the mean (range) deviation of -0.4 (-7.2 to 5.3) mm, -0.9 (-6.1 to 15.6) mm, and -1.7 (-7.0 to 6.1) mm was observed in Left-Right, Anterior-Posterior, and Superior-Inferior directions, respectively. The prostate CTV D99 would have been reduced by a maximum value of 1.3 Gy compared to the planned dose if position deviations were uncorrected, but with corrections, it was 0.3 Gy. Similarly, PTV D98 would have been reduced by a maximum value of 7.6 Gy uncorrected, with this difference reduced to 2.2 Gy with correction. The V60 to the rectum increased by a maximum of 1.0% uncorrected, which was reduced to 0.5%. Conclusion: Online target position monitoring for conventional fractionation prostate radiotherapy was successfully implemented on a standard Linear accelerator using an in-house developed position monitoring software, with an improvement in resultant dose to prostate target volume.

Reducing the margin in prostate radiotherapy: optimizing radiotherapy with a general-purpose linear accelerator using an in-house position monitoring system.

Purpose: To study the feasibility of optimizing the Clinical Target Volume to Planning Target Volume (CTV-PTV) margin in prostate radiotherapy(RT) with a general-purpose linear accelerator using an in-house developed position monitoring system, SeedTracker. Methods: A cohort of 30 patients having definitive prostate radiotherapy treated within an ethics-approved prospective trial was considered for this study. The intrafraction prostate motion and the position deviations were measured using SeedTracker system during each treatment fraction. Using this data the CTV-PTV margin required to cover 90% of the patients with a minimum of 95% of the prescription dose to CTV was calculated using van Herk's formula. The margin calculations were performed for treatment scenarios both with and without applying the position corrections for observed position deviations. The feasibility of margin reduction with real-time monitoring was studied by assessing the delivered dose that incorporates the actual target position during treatment delivery and comparing it with the planned dose. This assessment was performed for plans generated with reduced CTV-PTV margin in the range of 7mm-3mm. Results: With real-time monitoring and position corrections applied the margin of 2.0mm, 2.1mm and 2.1mm in LR, AP and SI directions were required to meet the criteria of 90% population to receive 95% of the dose prescription to CTV. Without position corrections applied for observed position deviations a margin of 3.1mm, 4.0mm and 3.0mm was required in LR, AP and SI directions to meet the same criteria. A mean ± SD reduction of 0.5 ± 1.8% and 3 ± 7% of V60 for the rectum and bladder can be achieved for every 1mm reduction of PTV margin. With position corrections applied, the CTV D99 can be delivered within -0.2 ± 0.3 Gy of the planned dose for plans with a 3mm margin. Without applying corrections for position deviations the CTV D99 was reduced by a maximum of 1.1 ± 1.1 Gy for the 3mm margin plan and there was a statistically significant difference between planned and delivered dose for 3mm and 4mm margin plans. Conclusion: This study demonstrates the feasibility of reducing the margin in prostate radiotherapy with SeedTracker system without compromising the dose delivery accuracy to CTV while reducing dose to critical structures.

Implementing online position monitoring for prostate radiotherapy using an in-house position monitoring system: User experience and impact on workforce.

INTRODUCTION: To evaluate the feasibility of prostate intrafraction motion monitoring using the SeedTracker real-time image guidance system in order to improve targeting accuracy in prostate radiotherapy. METHODS: SeedTracker was used to monitor prostate gold fiducial seeds with kV x-ray imaging during radiotherapy in 30 patients. Feedback from radiation therapists was collected via the use of a user evaluation form. The impact on treatment time was established by using a record and verify system. The effective dose and a risk of exposure-induced cancer death (REID) were estimated for a 60-year-old patient when using the SeedTracker system. RESULTS: A total of 22 radiation therapists completed user evaluation forms. The time taken to prepare a reference data set for one patient varied with three (13.6%) radiation therapists taking less than 2 min, 10 (45.5%) between 2 and 4 min, eight (36.4%) between 4 and 6 min and one (4.5%) between 6 and 8 min. The useability of the SeedTracker system was reported as 'easy' by 21 (95.5%) radiation therapists and 'hard' by 1 (4.5%) radiation therapist. Mean treatment time changed from 6 to 7 min with prostate-only radiotherapy treatment and from 6.9 to 10.2 min with prostate and whole pelvis radiotherapy treatments. The maximum effective dose with the SeedTracker was 1.6276 mSv, and increase in REID was 0.007%. CONCLUSION: The SeedTracker real-time image guidance system is a feasible tool to use in radiotherapy departments to monitor and correct for prostate intrafraction motion.

The delivered dose assessment in pancreas SBRT with the target position determined using an in-house position monitoring system.

Purpose: This study assessed the delivered dose accuracy in pancreas SBRT by incorporating the real-time target position determined using an in-house position monitoring system. Methods and materials: An online image-based position monitoring system, SeedTracker, was developed to monitor radiopaque marker positions using monoscopic x-ray images, available from the Elekta XVI imaging system. This system was applied to patients receiving SBRT for pancreatic cancer on the MASTERPLAN Pilot trial (ACTRN 12617001642370). All patients were implanted pre-treatment with at least three peri-tumoral radiopaque markers for target localisation. During treatment delivery, marker positions were compared to expected positions delineated from the planning CT. The position tolerance of ±3mm from the expected position of the markers was set to trigger a gating event (GE) during treatment. The dosimetric impact of position deviations and actual dose delivered with position corrections was assessed by convolving the plan control point dose matrices with temporal target positions determined during treatment. Results: Eight patients were treated within this study. At least one GE was observed in 38% of the treatment fractions and more than one GE was observed in 10% of the fractions. The position deviations resulted in the mean(range) difference of -0.1(-1.1 - 0.4)Gy in minimum dose to tumour and 1.9(-0.1- 4.6)Gy increase to Dmax to duodenum compared to planned dose. In actual treatment delivery with the patient realignment, the mean difference of tumour min dose and duodenal Dmax was reduced to 0.1(-1.0 - 1.1)Gy and 1.1 (-0.7 - 3.3)Gy respectively compared to the planned dose. Conclusions: The in-house real-time position monitoring system improved the treatment accuracy of pancreatic SBRT in a general-purpose linac and enabled assessment of delivered dose by incorporating the temporal target position during delivery. The intrafraction motion impacts the dose to tumour even if target position is maintained within a 3mm position tolerance.

Correcting rotational error in rectal cancer radiation therapy: Can planning target volume margins be safely reduced?

INTRODUCTION: The magnitude and impact of rotational error is unclear in rectal cancer radiation therapy. This study evaluates rotational errors in rectal cancer patients, and investigates the feasibility of planning target volume (PTV) margin reduction to decrease organs at risk (OAR) irradiation. METHODS: In this study, 10 patients with rectal cancer were retrospectively selected. Rotational errors were assessed through image registration of daily cone beam computed tomography (CBCT) and planning CT scans. Two reference treatment plans (TPR ) with PTV margins of 5 mm and 10 mm were generated for each patient. Pre-determined rotational errors (±1°, ±3°, ±5°) were simulated to produce six manipulated treatment plans (TPM ) from each TPR . Differences in evaluated dose-volume metrics between TPR and TPM of each rotation were compared using Wilcoxon Signed-Rank Test. Clinical compliance was investigated for statistically significant dose-volume metrics. RESULTS: Mean rotational errors in pitch, roll and yaw were -0.72 ± 1.81°, -0.04 ± 1.36° and 0.38 ± 0.96° respectively. Pitch resulted in the largest potential circumferential displacement of clinical target volume (CTV) at 1.42 ± 1.06 mm. Pre-determined rotational errors resulted in statistically significant differences in CTV, small bowel, femoral heads and iliac crests (P < 0.05). Only small bowel and iliac crests failed clinical compliance, with majority in the PTV 10 mm margin group. CONCLUSION: Rotational errors affected clinical compliance for OAR dose but exerted minimal impact on CTV coverage even with reduced PTV margins. Both PTV margin reduction and rotational correction decreased irradiated volume of OAR. PTV margin reduction to 5 mm is feasible, and rotational corrections are recommended in rectal patients to further minimise OAR irradiation.

Evaluation of the ability of three commercially available dosimeters to detect systematic delivery errors in step-and-shoot IMRT plans.

BACKGROUND: There is limited data on error detectability for step-and-shoot intensity modulated radiotherapy (sIMRT) plans, despite significant work on dynamic methods. However, sIMRT treatments have an ongoing role in clinical practice. This study aimed to evaluate variations in the sensitivity of three patient-specific quality assurance (QA) devices to systematic delivery errors in sIMRT plans. MATERIALS AND METHODS: Four clinical sIMRT plans (prostate and head and neck) were edited to introduce errors in: Multi-Leaf Collimator (MLC) position (increasing field size, leaf pairs offset (1-3 mm) in opposite directions; and field shift, all leaves offset (1-3 mm) in one direction); collimator rotation (1-3 degrees) and gantry rotation (0.5-2 degrees). The total dose for each plan was measured using an ArcCHECK diode array. Each field, excluding those with gantry offsets, was also measured using an Electronic Portal Imager and a MatriXX Evolution 2D ionisation chamber array. 132 plans (858 fields) were delivered, producing 572 measured dose distributions. Measured doses were compared to calculated doses for the no-error plan using Gamma analysis with 3%/3 mm, 3%/2 mm, and 2%/2 mm criteria (1716 analyses). RESULTS: Generally, pass rates decreased with increasing errors and/or stricter gamma criteria. Pass rate variations with detector and plan type were also observed. For a 3%/3 mm gamma criteria, none of the devices could reliably detect 1 mm MLC position errors or 1 degree collimator rotation errors. CONCLUSIONS: This work has highlighted the need to adapt QA based on treatment plan type and the need for detector specific assessment criteria to detect clinically significant errors.

Quantifying and Assessing the Dosimetric Impact of Changing Gas Volumes Throughout the Course of VMAT Radiation Therapy of Upper Gastrointestinal Tumors.

PURPOSE: This retrospective patient study assessed the consistency of abdominal gas presence throughout radiation therapy for patients with upper gastrointestinal cancer and determined the impact of variations in gas volume on the calculated dose distribution of volumetric modulated arc therapy. METHODS AND MATERIALS: Eight patients with pancreatic cancer were included for analysis. A plan library consisting of 3 reference plans per patient (Ref0.0, Ref0.5, and Ref1.0) was created based on planning computed tomography (CT) with density overrides of 0.0, 0.5, and 1.0 applied to gas volumes, respectively. Corresponding cone beam CT (CBCT) data sets were obtained and density overrides were applied to enable fractional dose calculation. Variation in gas volume relative to initial volume determined from CT was assessed. Dose metrics for targets and organs at risk were compared between the accumulated CBCT dose and the planned dose of the 3 reference plans for each patient. RESULTS: There was a significant decrease in gas present from CT to treatment CBCT, with a mean decrease in volume of 48.6% for the entire cohort. Dosimetrically, all accumulated target and organ-at-risk parameters, aside from the kidneys, exhibited the smallest mean deviation from the Ref0.0 plan and largest mean deviation from the Ref1.0 plan. A statistically significant difference in mean accumulated dose to Ref0.0 and Ref1.0 was observed for the dose delivered to 95% of the planning target volume. CONCLUSIONS: Significant variation in gas volumes from CT to treatment can occur throughout volumetric modulated arc therapy for pancreatic cancer. Through the use of a plan library, it was determined that initial assessment of a patient's treatment plan with an assigned gas density of 0.0 provided the most accurate prediction of the accumulated dose.

The first real-time intrafraction target position monitoring in pancreas SBRT on an Elekta linear accelerator.

To perform implanted fiducial based real-time target position monitoring in pancreas stereotactic body radiotherapy (SBRT) using the x-ray imaging system available in a Elekta linear accelerator. An in-house system was developed and clinically utilised for real-time target position monitoring of pancreas SBRT delivery. The developed system was used for the target position monitoring of a pancreas cancer patient treated in free breathing treatment within the study entitled 'Mfolfirinox And STEreotactic Radiotherapy for Patients with Locally Advanced paNcreas cancer (MASTERPLAN): a feasibility study' (ACTRN 12617001642370) consisting of five treatment fractions. The clinical efficacy of the system was studied by performing a retrospective cumulative dose assessment of delivered dose using observed position deviations. The developed system identified two events of baseline shifts in target position that exceeded the accepted tolerance level of ± 3 mm from reference planned position. The retrospective dose assessment study showed that if the position deviations were not detected and corrected for, the maximum dose to duodenum would have increased from 34.6 to 38.8 Gy. The first real-time position monitoring in pancreas SBRT on an Elekta linear accelerator was successfully performed. The developed system was shown to improve the safety and accuracy of SBRT delivery.

An investigation of the IQM signal variation and error detection sensitivity for patient specific pre-treatment QA.

PURPOSE: To evaluate the Integral Quality Monitor (IQM) as a clinical dosimetry device for detecting photon beam delivery errors in clinically relevant conditions. MATERIALS AND METHODS: The IQM's ability to detect delivery errors introduced into clinical VMAT plans for two different treatment sites was assessed. This included measuring 103 nasopharynx VMAT plans and 78 lung SBRT VMAT plans with introduced errors in gantry angle (1-5°) and in MLC-defined field size and field shift (1-5 mm). The IQM sensitivity was compared to ArcCheck detector performance. Signal dependence on field position for on-axis and asymmetrically offset square field sizes from 1 × 1 cm2 to 30 × 30 cm2 was also investigated. RESULTS: The IQM detected almost all introduced clinically-significant MLC field size errors, but not some small gantry angle errors or most MLC field shift errors. The IQM sensitivity was comparable to the ArcCheck for lung SBRT, but worse for the nasopharynx plans. Differences between IQM calculated/predicted and measured signals were within ± 2% for all on-axis square fields, but up to 60% for the smallest asymmetrically offset fields at large offsets. CONCLUSION: The IQM performance was consistent and reproducible. It showed highest sensitivity to the field size errors for these plans, but did not detect some clinically-significant introduced gantry angle errors or most MLC field shift errors. The IQM calculation model is still being developed, which should improve small offset-field performance. Care is required in IQM use for plan verification or online monitoring, especially for small fields that are off-axis in the detector gradient direction.

Arecoline N-oxide initiates oral carcinogenesis and arecoline N-oxide mercapturic acid attenuates the cancer risk.

Arecoline N-oxide (ANO), an oxidative metabolite of the areca nut, is a predictable initiator in carcinogenesis. The mechanisms of arecoline metabolites in human cancer specimens is still limited. This present study aims to estimate the oral squamous cell carcinoma (OSCC) inductive activity between arecoline metabolites in human cancer specimens/OSCC cells. We have collected 22 pairs (tumor and non-tumor part) of patient's specimens and checked for clinical characteristics. The identification of arecoline and its metabolites levels by using LC-MS/MS. The NOD/SCID mice model was used to check the OSCC inductive activity. The tumor part of OSCC samples exhibited higher levels of arecoline and ANO. Besides, ANO treated mice accelerates the NOTCH1, IL-17a and IL-1ß expressions compared to the control mice. ANO exhibited higher cytotoxicity, intracellular ROS levels and decline in antioxidant enzyme levels in OC-3 cells. The protein expression of NOTCH1 and proliferation marker levels are significantly lower in NOM treated cells. Overall, ANO induced initial stage carcinogenesis in the oral cavity via inflammation, ROS and depletion of antioxidant enzymes. Arecoline N-oxide mercapturic acid (NOM) attenuates the initiation of oral carcinogenesis.

Real-Time Image Guided Ablative Prostate Cancer Radiation Therapy: Results From the TROG 15.01 SPARK Trial.

PURPOSE: Kilovoltage intrafraction monitoring (KIM) is a novel software platform implemented on standard radiation therapy systems and enabling real-time image guided radiation therapy (IGRT). In a multi-institutional prospective trial, we investigated whether real-time IGRT improved the accuracy of the dose patients with prostate cancer received during radiation therapy. METHODS AND MATERIALS: Forty-eight patients with prostate cancer were treated with KIM-guided SABR with 36.25 Gy in 5 fractions. During KIM-guided treatment, the prostate motion was corrected for by either beam gating with couch shifts or multileaf collimator tracking. A dose reconstruction method was used to evaluate the dose delivered to the target and organs at risk with and without real-time IGRT. Primary outcome was the effect of real-time IGRT on dose distributions. Secondary outcomes included patient-reported outcomes and toxicity. RESULTS: Motion correction occurred in ≥1 treatment for 88% of patients (42 of 48) and 51% of treatments (121 of 235). With real-time IGRT, no treatments had prostate clinical target volume (CTV) D98% dose 5% less than planned. Without real-time IGRT, 13 treatments (5.5%) had prostate CTV D98% doses 5% less than planned. The prostate CTV D98% dose with real-time IGRT was closer to the plan by an average of 1.0% (range, -2.8% to 20.3%). Patient outcomes showed no change in the 12-month patient-reported outcomes compared with baseline and no grade ≥3 genitourinary or gastrointestinal toxicities. CONCLUSIONS: Real-time IGRT is clinically effective for prostate cancer SABR.

EPID sensitivity to delivery errors for pre-treatment verification of lung SBRT VMAT plans.

PURPOSE: To study the sensitivity of an Electronic Portal Imaging Device (EPID) in detecting delivery errors for VMAT lung stereotactic body radiotherapy (SBRT) using the Collapsed Arc method. METHODS: Baseline VMAT plans and plans with errors intentionally introduced were generated for 15 lung SBRT patients. Three types of errors were introduced by modifying collimator angles and multi-leaf collimator (MLC) field sizes (MLCFS) and MLC shifts by ±5, ±2, and ±1° or millimeters. A total of 103 plans were measured with EPID on an Elekta Synergy Linear Accelerator (Agility MLC) and compared to both the original treatment planning system (TPS) Collapsed Arc dose matrix and the no-error plan baseline EPID measurements. Gamma analysis was performed using the OmniPro-I'mRT (IBA Dosimetry) software and gamma criteria of 1%/1 mm, 2%/1 mm, 2%/2 mm, and 3%/3. RESULTS: When the error-introduced EPID measured dose matrices were compared to the TPS matrices, the majority of simulated errors were detected with gamma tolerance of 2%/1 mm and 1%/1 mm. When the error-introduced EPID measured dose matrices were compared to the baseline EPID measurements, all the MLCFS and MLC shift errors, and ±5°collimator errors were detected using 2%/1 mm and 1%/1 mm gamma criteria. CONCLUSION: This work demonstrates the feasibility and effectiveness of the collapsed arc technique and EPID for pre-treatment verification of lung SBRT VMAT plans. The EPID was able to detect the majority of MLC and the larger collimator errors with sensitivity to errors depending on the gamma tolerances.

Phase 2 Multicenter Study of Gantry-Based Stereotactic Radiotherapy Boost for Intermediate and High Risk Prostate Cancer (PROMETHEUS).

Objectives: To report feasibility, early toxicity, and PSA kinetics following gantry-based, stereotactic radiotherapy (SBRT) boost within a prospective, phase 2, multicenter study (PROMETHEUS: ACTRN12615000223538). Methods: Patients were treated with gantry-based SBRT, 19-20 Gy in two fractions delivered 1 week apart, followed by conventionally fractionated IMRT (46 Gy in 23 fractions). The study mandated MRI fusion for RT planning, rectal displacement, and intrafraction image guidance. Toxicity was prospectively graded using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4). Results: Between March 2014 and July 2018, 135 patients (76% intermediate, 24% high-risk) with a median age of 70 years (range 53-81) were treated across five centers. Short course (≤6 months) androgen deprivation therapy (ADT) was used in 36% and long course in 18%. Rectal displacement method was SpaceOAR in 59% and Rectafix in 41%. Forty-two and ninety-three patients were treated at the 19 Gy and 20 Gy dose levels, respectively. Median follow-up was 24 months. Acute grade 2 gastrointestinal (GI) and urinary toxicity occurred in 4.4 and 26.6% with no acute grade 3 toxicity. At 6, 12, 18, 24, and 36 months post-treatment the prevalence of late grade ≥2 gastrointestinal toxicity was 1.6, 3.7, 2.2, 0, and 0%, respectively, and the prevalence of late grade ≥2 urinary toxicity was 0.8, 11, 12, 7.1, and 6.3%, respectively. Three patients experienced grade 3 late toxicity at 12 to 18 months which subsequently resolved to grade 2 or less. For patients not receiving ADT the median PSA value pre-treatment was 7.6 ug/L (1.1-20) and at 12, 24, and 36 months post-treatment was 0.86, 0.36, and 0.20 ug/L. Conclusions: Delivery of a gantry-based SBRT boost is feasible in a multicenter setting, is well-tolerated with low rates of early toxicity and is associated with promising PSA responses. A second transient peak in urinary toxicity was observed at 18 months which subsequently resolved. Follow-up is ongoing to document late toxicity, long-term patient reported outcomes, and tumor control with this approach.

Reduced motion and improved rectal dosimetry through endorectal immobilization for prostate stereotactic body radiotherapy.

OBJECTIVE: PROMETHEUS (ACTRN12615000223538) is a multicentre clinical trial investigating the feasibility of 19 Gy in 2 fractions of stereotactic body radiotherapy (SBRT) as a boost technique for prostate cancer. The objective of this substudy was to evaluate intrafraction motion using cine MRI and assess the dosimetric impact of using a rectal displacement device (RDD). METHODS: The initial 10 patients recruited underwent planning CT and MRI, with and without a RDD. Cine MRI images were captured using an interleaved T2 HASTE sequence in sagittal and axial planes with a temporal resolution of 5.2 s acquired over 4.3 min. Points of interest (POIs) were defined and a validated tracking algorithm measured displacement of these points over the 4.3 min in the anteroposterior, superior-inferior and left-right directions. Plans were generated with and without a RDD to examine the impact on dosimetry. RESULTS: There was an overall trend for increasing displacement in all directions as time progressed when no RDD was in situ . points of interest remained comparatively stable with the RDD. In the sagittal plane, the RDD resulted in statistically significant improvement in the range of anteroposterior displacement for the rectal wall, anterior prostate, prostate apex and base. Dosimetrically, the use of a RDD significantly reduced rectal V16, V14 and Dmax, as well as the percentage of posterior rectal wall receiving 8.5 Gy. CONCLUSION: The RDD used in stereotactic prostate radiotherapy leads to reduced intrafraction motion of the prostate and rectum, with increasing improvement with time. It also results in significant improvement in rectal wall dosimetry. ADVANCES IN KNOWLEDGE: It was found that the rectal displacement device improved prostate stabilization significantly, improved rectum stabilization and dosimetry significantly. The rectal displacement device did not improve target volume dosimetry.

PROstate Multicentre External beam radioTHErapy Using a Stereotactic boost: the PROMETHEUS study protocol.

BACKGROUND: High Dose Rate Brachytherapy (HDRB) boost is a well-established treatment for prostate cancer (PC). We describe the PROstate Multicentre External beam radioTHErapy Using Stereotactic boost (PROMETHEUS) study. Non-surgical stereotactic techniques are used to deliver similar doses to HDRB boost regimens with a dose escalation sub-study. METHODS: Eligible patients have intermediate or high risk PC. PROMETHEUS explores the safety, efficacy and feasibility of multiple Australian centres cooperating in the delivery of Prostate Stereotactic Body Radiotherapy (SBRT) technology. A SBRT boost component Target Dose (TD) of 19Gy in two fractions is to be delivered, followed by a subsequent EBRT component of 46Gy in 23 fractions. Once accrual triggers have been met, SBRT doses can be escalated in 1 Gy increments to a maximum of 22Gy in two fractions. Patient safety will also be measured with the rate of both acute and late moderate to severe Gastro-Intestinal (GI) and Genito-Urinary (GU) Common Terminology Criteria for Adverse Events (CTCAE) toxicities as well as patient reported quality of life. Efficacy will be assessed via biochemical control after 3 years. DISCUSSION: PROMETHEUS aims to generate evidence for a non-surgical possible future alternative to HDRB boost regimens, and introduce advanced radiotherapy techniques across multiple Australian cancer centres. TRIAL REGISTRATION: The study was retrospectively registered on the ANZCTR (Australian New Zealand Clinical Trials Registry) with trial ID: ACTRN12615000223538 .