Reduction of post-radiotherapy urinary toxicity via intrafractional MV-kV prostate location monitoring.

PURPOSE/OBJECTIVE(S): We hypothesized that an in-house developed system using MV and kV image guidance (MKIG) to ensure correct prostate positioning during SBRT could potentially avoid unwanted doses to non-target tissues, leading to reduced toxicities. MATERIALS/METHODS: We built a 3D MKIG platform that accurately tracks prostate implanted fiducials in real-time and clinically translated the system to replace a commercial approach, intrafraction motion review (IMR), which only tracks fiducials in the 2D kV views. From 2017 to 2019, 150 prostate cancer patients were treated with SBRT and monitored by MKIG. The motion trace of the fiducials alerts therapists to interrupt and reposition the prostate when displacement exceeds a 1.5 mm threshold. A comparison cohort of 121 patients was treated with the same dose regimen and treatment technique but managed by IMR. Statistics of intrafractional patient shifts and delivery time were collected to evaluate the workflow efficacy. The incidence of grade ≥2 urinary toxicities was analyzed to assess clinical complications. The median follow-up time was 3.7 years (0.2 to 8.2 years). RESULTS: MKIG treatments had more treatment shifts (1.09 vs. 0.28) and a longer average delivery time per fraction (579±205s vs. 357±117s) than IMR treatments. Three-quarters (75%) of shifts resulting from MKIG were ≤3mm, vs. 51% in IMR, indicating that MKIG detected and corrected smaller deviations. The incidence of grade ≥2 urinary toxicity was lower in the MKIG than IMR cohort: 10.7% vs. 19.8% (p=0.047). On multivariate analysis of late urinary toxicity, only high (>7) pre-RT IPSS (p<0.043) and the use of MKIG were selected (p< 0.029). CONCLUSIONS: Automated and quantitative MKIG introduced minimal workflow impact and was superior to IMR in localizing the prostate during SBRT, which correlated with a clinically significant reduction in late urinary toxicity. Further clinical testing via randomized trial will be required to validate the impact on outcomes.

Clinical Experience and Feasibility of Using 2D-kVimage Online Intervention in the Ultrafractionated Stereotactic Radiation Treatment of Prostate Cancer.

PURPOSE: This study reports clinical experience and feasibility of using a 2-dimensional (2D)-kV image system with online intervention in the ultrafractionated stereotactic body radiation treatment (UF-SBRT) of prostate cancer. METHODS AND MATERIALS: Fifteen patients with prostate cancer who had a low- to intermediate-risk marker implanted received UF-SBRT with online 2D-kV image tracking and a manual beam interruption strategy with a 2-mm motion threshold. A total of 180 kV paired setup images and 1272 intrabeam 2D-kV images were analyzed to evaluate the setup deviation and intratreatment target deviation. Correlation of expected treatment interruptions with a set of parameters (eg, image and treatment time; direction of deviation) was performed (Spearman test). A subset of the data from 22 fractions was re-evaluated to check the differences in analysis results between using the planning position and using the pretreatment setup position as a reference. Margins based on the derived system and random errors were calculated to evaluate the feasibility of the workflow in ensuring prostate coverage during treatment. RESULTS: Mean target motion in 3D propagated from 1.0 mm (setup at 0 minutes) to 2.0 mm (beam on at 7 minutes) to 2.4 mm (end at 13.5 minutes). Out of 75 fractions, 50 were found to require beam interruption. Interruption had a strong correlation with prostate motion along the longitudinal direction and had moderate correlation with prostate motion along the vertical direction and the prostate's treatment starting position along vertical and longitudinal directions. Using the pretreatment position as a reference for intrabeam monitoring, the magnitude of motion deviation from the reference position was reduced by 0.3 mm at a vertical direction and 0.4 mm at lateral and longitudinal directions. The calculated 3D margin to ensure target coverage was 3.7 mm, 4.6 mm, and 5.0 mm in lateral, vertical, and longitudinal directions, respectively. CONCLUSIONS: Prostate motion propagated over time. It is feasible to use a 2D-kV online intrabeam monitoring system with a proper intervention scheme to perform UF-SBRT for prostate cancer.

Retrospective analysis of MV-kV imaging-based fiducial tracking in prostate SBRT treatment.

PURPOSE: Motion management is critical for prostate stereotactic body radiotherapy (SBRT) due to its high fractional dose and proximity to organs at risk. This study seeks to quantify the advantages of MV-kV tracking over kV imaging alone through a retrospective analysis of over 300 patients who underwent prostate SBRT treatment using MV-kV tracking. METHODS: An MV-kV imaging-based fiducial tracking technique has been developed at our institute and become a standard clinical practice. This technique calculates three-dimensional (3D) fiducial displacement in real time from orthogonal kV and MV images acquired simultaneously. The patient will be repositioned if for two consecutive MV-kV data points, the motion is larger than a tolerance of 1.5 mm in any of the lateral, superior-inferior, and/or anterior-posterior directions. This study retrospectively analyzed detected 3D motions using an MV-kV approach of 324 patients who recently underwent prostate SBRT treatments. An algorithm was developed to recover the 2D motion components as if they were detected by kV or MV imaging alone. RESULTS: Our results indicated that out-of-tolerance motions were primarily limited to the range of 1.5-3 mm (>95%). The motions are primarily anterior-posterior and superior-inferior, with less than 14.8% of the occurrences in the lateral direction. Compared to out-of-tolerance occurrences detected by MV-kV approach, kV alone caught 46.6% of motions in all three directions, and MV alone caught 46.7%. kV alone shows an overall missing rate of 45.8% for superior-inferior motions and 38.6% for lateral motions. It is also demonstrated that the detectability of motion in specific directions greatly depends on gantry angles, as does the missing rate. CONCLUSIONS: Our study demonstrated that MV-kV imaging-based intrafraction motion tracking is superior to single kV imaging for prostate SBRT in clinical practice.

Predictors for post-treatment biopsy outcomes after prostate stereotactic body radiotherapy.

PURPOSE: To investigate predictors associated with post-treatment biopsy outcomes after stereotactic body radiotherapy (SBRT) for localized prostate cancer. MATERIALS AND METHODS: 257 patients treated with prostate SBRT to dose levels of 32.5 Gy to >40 Gy in 5-6 fractions underwent a post-treatment biopsy performed approximately two years after treatment to evaluate local control status. 73 had% intermediate-risk disease (n = 187) and the remaining 17% (n = 43) and 10% (n = 27) had low-risk and high-risk disease, respectively. RESULTS: The incidence of positive, negative, and treatment-effect post-treatment biopsies were 15.6%, 57.6%, and 26.8%, respectively. The incidence of a positive biopsy according to dose was 37.5% (n = 9/24), 21.4% (n = 6/28), 19.4% (n = 6/31), and 10.9% (n = 19/174) for 32.5 Gy, 35 Gy, 37.5 Gy, and >40 Gy, respectively. In a multivariable model, patients treated with SBRT doses of <40 Gy and those with unfavorable-intermediate-risk or high-risk disease had higher likelihood of a positive post-treatment biopsy. A positive post-SBRT biopsy was associated with a significantly higher likelihood of subsequent PSA relapse at five years (Positive biopsy: 57%, 95% CI: 29-77% compared to negative biopsy: 7%, 95% CI: 3-14%; p < 0.001). CONCLUSION: Based on two-year post-SBRT biopsies, excellent tumor control was achieved when dose levels of 40 Gy or higher were used. Standard SBRT dose levels of 35-37.5 Gy were associated with a higher likelihood of a positive post-treatment biopsy. Two-year positive post-treatment biopsies pre-dated the development of PSA failure in the majority of patients.

Clinical experience and workflow challenges with magnetic resonance-only radiation therapy simulation and planning for prostate cancer.

BACKGROUND AND PURPOSE: Magnetic Resonance (MR)-only planning has been implemented clinically for radiotherapy of prostate cancer. However, fewer studies exist regarding the overall success rate of MR-only workflows. We report on successes and challenges of implementing MR-only workflows for prostate. MATERIALS AND METHODS: A total of 585 patients with prostate cancer underwent an MR-only simulation and planning between 06/2016-06/2018. MR simulation included images for contouring, synthetic-CT generation and fiducial identification. Workflow interruptions occurred that required a backup CT, a re-simulation or an update to our current quality assurance (QA) process. The challenges were prospectively evaluated and classified into syn-CT generation, motion/artifacts in the MRs, fiducial QA and bowel preparation guidelines. RESULTS: MR-only simulation was successful in 544 (93.2 %) patients. . In seventeen patients (2.9%), reconstruction of synthetic-CT failed due to patient size, femur angulation, or failure to determine the body contour. Twenty-four patients (4.1%) underwent a repeat/backup CT scan because of artifacts on the MR such as image blur due to patient motion or biopsy/surgical artifacts that hampered identification of the implanted fiducial markers. In patients requiring large coverage due to nodal involvement, inhomogeneity artifacts were resolved by using a two-stack acquisition and adaptive inhomogeneity correction. Bowel preparation guidelines were modified to address frequent rectum/gas issues due to longer MR scan time. CONCLUSIONS: MR-only simulation has been successfully implemented for a majority of patients in the clinic. However, MR-CT or CT-only pathway may still be needed for patients where MR-only solution fails or patients with MR contraindications.

Strict bladder filling and rectal emptying during prostate SBRT: Does it make a dosimetric or clinical difference?

BACKGROUND: To evaluate inter-fractional variations in bladder and rectum during prostate stereotactic body radiation therapy (SBRT) and determine dosimetric and clinical consequences. METHODS: Eighty-five patients with 510 computed tomography (CT) images were analyzed. Median prescription dose was 40 Gy in 5 fractions. Patients were instructed to maintain a full bladder and empty rectum prior to simulation and each treatment. A single reviewer delineated organs at risk (OARs) on the simulation (Sim-CT) and Cone Beam CTs (CBCT) for analyses. RESULTS: Bladder and rectum volume reductions were observed throughout the course of SBRT, with largest mean reductions of 86.9 mL (19.0%) for bladder and 6.4 mL (8.7%) for rectum noted at fraction #5 compared to Sim-CT (P < 0.01). Higher initial Sim-CT bladder volumes were predictive for greater reduction in absolute bladder volume during treatment (ρ = - 0.69; P < 0.01). Over the course of SBRT, there was a small but significant increase in bladder mean dose (+ 4.5 ± 12.8%; P < 0.01) but no significant change in the D2cc (+ 0.8 ± 4.0%; P = 0.28). The mean bladder trigone displacement was in the anterior direction (+ 4.02 ± 6.59 mm) with a corresponding decrease in mean trigone dose (- 3.6 ± 9.6%; P < 0.01) and D2cc (- 6.2 ± 15.6%; P < 0.01). There was a small but significant increase in mean rectal dose (+ 7.0 ± 12.9%, P < 0.01) but a decrease in rectal D2cc (- 2.2 ± 10.1%; P = 0.04). No significant correlations were found between relative bladder volume changes, bladder trigone displacements, or rectum volume changes with rates of genitourinary or rectal toxicities. CONCLUSIONS: Despite smaller than expected bladder and rectal volumes at the time of treatment compared to the planning scans, dosimetric impact was minimal and not predictive of detrimental clinical outcomes. These results cast doubt on the need for excessively strict bladder filling and rectal emptying protocols in the context of image guided prostate SBRT and prospective studies are needed to determine its necessity.

Prostate SBRT With Intrafraction Motion Management Using a Novel Linear Accelerator-Based MV-kV Imaging Method.

PURPOSE: This study reports clinical experience using a linear accelerator-based MV-kV imaging system for intrafraction motion management during prostate stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: From June 2016 to August 2018, 193 prostate SBRT patients were treated using MV-kV motion management (median dose 40 Gy in 5 fractions). Patients had 3 fiducials implanted then simulated and treated with a full bladder and empty rectum. Pretreatment orthogonal kVs and cone beam computed tomography were used to position patients and evaluate internal anatomy. Motion was tracked during volumetric modulated arc therapy delivery using simultaneously acquired kV and MV images from standard on-board systems. Treatment was interrupted to reposition patients when motion >1.5-2 mm was detected. Motion traces were analyzed and compared with Calypso traces from a previously treated similar patient cohort. To evaluate "natural motion" (ie, if we had not interrupted treatment and repositioned), intrafraction couch corrections were removed from all traces. Clinical effectiveness of the MV-kV system was explored by evaluating toxicity (Common Terminology Criteria for Adverse Events v3.0) and biochemical recurrence rates (nadir + 2 ng/mL). RESULTS: Median number of interruptions for patient repositioning was 1 per fraction (range, 0-9). Median overall treatment time was 8.2 minutes (range, 4.2-44.8 minutes). Predominant motion was inferior and posterior, and probability of motion increased with time. Natural motion >3 mm and >5 mm in any direction was observed in 32.3% and 10.2% of fractions, respectively. Calypso monitoring (n = 50) demonstrated similar motion results. In the 151 MV-kV patients with ≥3-month follow-up (median, 9.5 months; range, 3-26.5 months), grade ≥2 acute genitourinary/gastrointestinal and late genitourinary/gastrointestinal toxicity was observed in 9.9%/2.0% and 11.9%/2.7%, respectively. Biochemical control was 99.3% with a single failure in a high-risk patient. CONCLUSIONS: The MV-kV system is an effective method to manage intrafraction prostate motion during SBRT, offering the opportunity to correct for prostate clinical target volume displacements that would have otherwise extended beyond typical planning target volume margins.

Early Tolerance and Tumor Control Outcomes with High-dose Ultrahypofractionated Radiation Therapy for Prostate Cancer.

BACKGROUND: Studies using stereotactic body radiotherapy (SBRT) dose escalation in in low- and intermediate-risk prostate cancer patients have indicated favorable outcomes. OBJECTIVE: To evaluate tolerance and tumor control outcomes in low- and intermediate-risk prostate cancer patients treated with high-dose SBRT following our phase 1 trial. DESIGN, SETTING, AND PARTICIPANTS: A total of 551 patients with low- or intermediate-risk prostate cancer were treated with SBRT. INTERVENTION: Treatment with 37.5-40Gy SBRT in five fractions directed to the prostate and seminal vesicles. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcome measurements included acute toxicities (<3 mo after radiotherapy [RT]) and late toxicities (>3 mo after RT) and tumor control evaluation (prostate-specific antigen [PSA] levels at 3-6-mo intervals and post-treatment prostate biopsy at 2yr). RESULTS AND LIMITATIONS: Acute grade 2 gastrointestinal (GI) toxicities occurred in 1.8% of patients, and late grade 2 and 3 GI toxicities were observed in 3.4% and 0.4% of patients, respectively. Acute grade 2 genitourinary (GU) toxicities occurred in 10% of patients, and grade 3 acute GU toxicities were observed in 0.7% of patients. Late grade 2 and 3 GU toxicities were observed in 21.1% and 2.5% of patients, respectively. The use of a hydrogel rectal spacer was significantly associated with reduced late GI toxicity and lower odds of developing late GU toxicity. The median follow-up was 17 mo, and 53% of those with at least 2yr of follow-up (103/193) had a biopsy performed. The 5-yr cumulative incidence of PSA failure was 2.1%, and the incidence of a positive 2-yr treatment biopsy was 12%. Limitations to this report include its retrospective nature and short follow-up time. CONCLUSIONS: Favorable short-term outcomes were achieved with high-dose SBRT for low- and intermediate-risk disease. Severe late toxicities were observed and favorable tumor control was found. PATIENT SUMMARY: We utilized stereotactic body radiotherapy, a form of external beam radiotherapy that delivers highly targeted high-dose treatment to the prostate, to treat over 500 localized prostate cancer patients in five sessions over 1.5 wk. Treatments were well tolerated without significant urinary or rectal side effects. Nearly 90% of those who underwent biopsies after treatment did not demonstrate residual active disease.

Developing a MLC modifier program to improve fiducial detection for MV/kV imaging during hypofractionated prostate volumetric modulated arc therapy.

PURPOSE: To develop an Eclipse plug-in (MLC_MODIFIER) that automatically modifies control points to expose fiducials obscured by MLC during VMAT, thereby facilitating tracking using periodic MV/kV imaging. METHOD: Three-dimensional fiducial tracking was performed during VMAT by pairing short-arc (3°) MV digital tomosynthesis (DTS) images to triggered kV images. To evaluate MLC_MODIFIER efficacy, two cohorts of patients were considered. For first 12 patients, plans were manually edited to expose one fiducial marker. Next for 15 patients, plans were modified using MLC_MODIFIER script. MLC_MODIFIER evaluated MLC apertures at appropriate angles for marker visibility. Angles subtended by control points were compressed and low-dose "imaging" control points were inserted and exposed one marker with 1 cm margin. Patient's images were retrospectively reviewed to determine rate of MV registration failures. Failure categories were poor DTS image quality, MLC blockage of fiducials, or unknown reasons. Dosimetric differences in rectum, bladder, and urethra D1 cc, PTV maximum dose, and PTV dose homogeneity (PTV HI) were evaluated. Statistical significance was evaluated using Fisher's exact and Student's t test. RESULT: Overall MV registration failures, failures due to poor image quality, MLC blockage, and unknown reasons were 33% versus 8.9% (P < 0.0001), 8% versus 6.4% (P < 0.05), 13.6% versus 0.1% (P < 0.0001), and 7.6% versus 2.4% (P < 0.0001) for manually edited and MLC_MODIFIER plans, respectively. PTV maximum and HI increased on average from unmodified plans by 2.1% and 0.3% (P < 0.004) and 22.0% and 3.3% (P < 0.004) for manually edited and MLC_MODIFIED plans, respectively. Changes in bladder, rectum, and urethra D1CC were similar for each method and less than 0.7%. CONCLUSION: Increasing fiducial visibility via an automated process comprised of angular compression of control points and insertion of additional "imaging" control points is feasible. Degradation of plan quality is minimal. Fiducial detection and registration success rates are significantly improved compared to manually edited apertures.

Early Tolerance Outcomes of Stereotactic Hypofractionated Accelerated Radiation Therapy Concomitant with Pelvic Node Irradiation in High-risk Prostate Cancer.

PURPOSE: This study aimed to evaluate the toxicity of prostate and pelvic lymph node stereotactic body radiation therapy (SBRT) for high-risk prostate cancer. METHODS AND MATERIALS: Twenty-three patients with high-risk or lymph node-positive prostate cancer were treated with SBRT that delivered 37.5 to 40 Gy in 5 fractions to the prostate and seminal vesicles, with concomitant treatment of the pelvic nodes to 25 Gy. In general, patients received neoadjuvant, concurrent, and adjuvant androgen deprivation therapy for a duration of 18 months. Toxicities were evaluated with the Common Terminology Criteria for Adverse Events, version 3.0. The median follow-up was 19 months (range, 3-48 months). RESULTS: Acute grade 1 gastrointestinal (GI) toxicities were noted in 2 patients (9.1%). No patient experienced acute grade ≥2 GI toxicity. Acute genitourinary (GU) grade 1, 2, and 3 toxicities were observed in 7 patients (31.8%), 8 patients (36.4%), and 1 patient (4.5%), respectively. Late grade 2 GI and GU toxicities were observed in 2 patients (9.1%) and 6 patients (27.3%), respectively. No late grade ≥3 GI toxicity was noted. Late grade ≥3 GU (hemorrhagic cystitis) was noted in 1 patient (4.5%), which responded to laser fulguration. CONCLUSIONS: SBRT with pelvic lymph node radiation therapy was feasible and well tolerated. The incidence of grade ≥3 GU and GI toxicities was uncommon. Continued follow-up will be required to determine the long-term safety and efficacy of this approach for high-risk patients.

Five-Year Outcomes of a Phase 1 Dose-Escalation Study Using Stereotactic Body Radiosurgery for Patients With Low-Risk and Intermediate-Risk Prostate Cancer.

PURPOSE: To report toxicity outcomes, prostate-specific antigen (PSA) relapse, and cumulative incidence posttreatment biopsy results among patients treated on a prospective dose escalation study using ultra-hypofractionated stereotactic body radiation therapy (SBRT) for patients with low- and intermediate-risk prostate cancer. METHODS AND MATERIALS: A total of 136 patients were enrolled in a phase 1 dose-escalation study to determine the tolerance of escalating radiation dose levels of SBRT for the treatment of localized prostate cancer. The initial dose level was 32.5 Gy in 5 fractions, and doses were then sequentially escalated to 35 Gy, 37.5 Gy, and 40 Gy. Eligibility criteria included only patients with low and intermediate risk, and the maximum prostate volume was 60 cm3. Patients treated with neoadjuvant androgen deprivation were excluded. The median follow-up in survivors for the 4 dose levels was 5.9, 5.4, 4.1, and 3.5 years, respectively. RESULTS: The incidence of acute grade 2 rectal toxicities for dose levels 1 to 4 were 0%, 2.9%, 2.8%, and 11.4% respectively. No grade 3 or 4 acute rectal toxicities were observed. The incidence of acute grade 2 urinary toxicities for dose levels 1 to 4 were 16.7%, 22.9%, 8.3%, and 17.1%, respectively. No grade 3 or 4 acute urinary toxicities were observed. No grade 2 or higher rectal toxicities were observed. The incidence of late grade 2 urinary toxicities for dose levels 1 to 4 was 23.3%, 25.7%, 27.8%, and 31.4%, respectively. Only 1 late grade 3 urinary toxicity (urethral stricture) developed in the 40-Gy dose arm; the stricture was corrected with transurethral resection. No grade 4 late urinary toxicity was observed. The 5-year cumulative incidence of prostate-specific antigen failure for dose levels 1 to 4 was 15%, 6%, 0%, and 0%. The incidence of a 2-year positive posttreatment biopsy was 47.6%, 19.2%, 16.7%, and 7.7%, respectively for the 4 dose arms (P = .013). CONCLUSIONS: SBRT doses ranging from 32.5 to 40 Gy in 5 fractions were well tolerated without severe urinary or rectal toxicities. Biopsy outcomes suggest improved rates of tumor clearance observed with higher doses.

Design and validation of a MV/kV imaging-based markerless tracking system for assessing real-time lung tumor motion.

PURPOSE: Localizing lung tumors during treatment delivery is critical for managing respiratory motion, ensuring tumor coverage, and reducing toxicities. The purpose of this project is to develop a real-time system that performs markerless tracking of lung tumors using simultaneously acquired MV and kV images during radiotherapy of lung cancer with volumetric modulated arc therapy. METHOD: Continuous MV/kV images were simultaneously acquired during dose delivery. In the subsequent analysis, a gantry angle-specific region of interest was defined according to the treatment aperture. After removing imaging artifacts, processed MV/kV images were directly registered to the corresponding daily setup cone-beam CT (CBCT) projections that served as reference images. The registration objective function consisted of a sum of normalized cross-correlation, weighted by the contrast-to-noise ratio of each MV and kV image. The calculated 3D shifts of the tumor were corrected by the displacements between the CBCT projections and the planning respiratory correlated CT (RCCT) to generate motion traces referred to a specific respiratory phase. The accuracy of the algorithm was evaluated on both anthropomorphic phantom and patient studies. The phantom consisted of localizing a 3D printed tumor, embedded in a thorax phantom, in an arc delivery. In an IRB-approved study, data were obtained from VMAT treatments of two lung cancer patients with three electromagnetic (Calypso) beacon transponders implanted in airways near the lung tumor. RESULT: In the phantom study, the root mean square error (RMSE) between the registered and actual (programmed couch movement) target position was 1.2 mm measured by the MV/kV imaging system, which was smaller compared to the MV or kV alone, of 4.1 and 1.3 mm, respectively. In the patient study, the mean and standard deviation discrepancy between electromagnetic-based tumor position and the MV/KV-markerless approach was -0.2 ± 0.6 mm, 0.2 ± 1.0 mm, and -1.2 ± 1.5 mm along the superior-inferior, anterior-posterior, and left-right directions, respectively; resulting in a 3D displacement discrepancy of 2.0 ± 1.1 mm. Poor contrast around the tumor was the main contribution to registration uncertainties. CONCLUSION: The combined MV/kV imaging system can provide real-time 3D localization of lung tumor, with comparable accuracy to the electromagnetic-based system when features of tumors are detectable. Careful design of a registration algorithm and a VMAT plan that maximizes the tumor visibility are key elements for a successful MV/KV localization strategy.

Review of Real-Time 3-Dimensional Image Guided Radiation Therapy on Standard-Equipped Cancer Radiation Therapy Systems: Are We at the Tipping Point for the Era of Real-Time Radiation Therapy?

PURPOSE: To review real-time 3-dimensional (3D) image guided radiation therapy (IGRT) on standard-equipped cancer radiation therapy systems, focusing on clinically implemented solutions. METHODS AND MATERIALS: Three groups in 3 continents have clinically implemented novel real-time 3D IGRT solutions on standard-equipped linear accelerators. These technologies encompass kilovoltage, combined megavoltage-kilovoltage, and combined kilovoltage-optical imaging. The cancer sites treated span pelvic and abdominal tumors for which respiratory motion is present. For each method the 3D-measured motion during treatment is reported. After treatment, dose reconstruction was used to assess the treatment quality in the presence of motion with and without real-time 3D IGRT. The geometric accuracy was quantified through phantom experiments. A literature search was conducted to identify additional real-time 3D IGRT methods that could be clinically implemented in the near future. RESULTS: The real-time 3D IGRT methods were successfully clinically implemented and have been used to treat more than 200 patients. Systematic target position shifts were observed using all 3 methods. Dose reconstruction demonstrated that the delivered dose is closer to the planned dose with real-time 3D IGRT than without real-time 3D IGRT. In addition, compromised target dose coverage and variable normal tissue doses were found without real-time 3D IGRT. The geometric accuracy results with real-time 3D IGRT had a mean error of <0.5 mm and a standard deviation of <1.1 mm. Numerous additional articles exist that describe real-time 3D IGRT methods using standard-equipped radiation therapy systems that could also be clinically implemented. CONCLUSIONS: Multiple clinical implementations of real-time 3D IGRT on standard-equipped cancer radiation therapy systems have been demonstrated. Many more approaches that could be implemented were identified. These solutions provide a pathway for the broader adoption of methods to make radiation therapy more accurate, impacting tumor and normal tissue dose, margins, and ultimately patient outcomes.

Institutional experience with SRS VMAT planning for multiple cranial metastases.

BACKGROUND AND PURPOSE: This study summarizes the cranial stereotactic radiosurgery (SRS) volumetric modulated arc therapy (VMAT) procedure at our institution. MATERIALS AND METHODS: Volumetric modulated arc therapy plans were generated for 40 patients with 188 lesions (range 2-8, median 5) in Eclipse and treated on a TrueBeam STx. Limitations of the custom beam model outside the central 2.5 mm leaves necessitated more than one isocenter pending the spatial distribution of lesions. Two to nine arcs were used per isocenter. Conformity index (CI), gradient index (GI) and target dose heterogeneity index (HI) were determined for each lesion. Dose to critical structures and treatment times are reported. RESULTS: Lesion size ranged 0.05-17.74 cm3 (median 0.77 cm3 ), and total tumor volume per case ranged 1.09-26.95 cm3 (median 7.11 cm3 ). For each lesion, HI ranged 1.2-1.5 (median 1.3), CI ranged 1.0-2.9 (median 1.2), and GI ranged 2.5-8.4 (median 4.4). By correlating GI to PTV volume a predicted GI = 4/PTV0.2 was determined and implemented in a script in Eclipse and used for plan evaluation. Brain volume receiving 7 Gy (V7 Gy ) ranged 10-136 cm3 (median 42 cm3 ). Total treatment time ranged 24-138 min (median 61 min). CONCLUSIONS: Volumetric modulated arc therapy provide plans with steep dose gradients around the targets and low dose to critical structures, and VMAT treatment is delivered in a shorter time than conventional methods using one isocenter per lesion. To further improve VMAT planning for multiple cranial metastases, better tools to shorten planning time are needed. The most significant improvement would come from better dose modeling in Eclipse, possibly by allowing for customizing the dynamic leaf gap (DLG) for a special SRS model and not limit to one DLG per energy per treatment machine and thereby remove the limitation on the Y-jaw and allow planning with a single isocenter.

Modeling Dose Response for Late Dysphagia in Patients With Head and Neck Cancer in the Modern Era of Definitive Chemoradiation.

PURPOSE: To develop personalized multivariate dose-response models for late dysphagia in patients with head and neck cancer treated in the modern era of combined chemotherapy with intensity-modulated radiation therapy. PATIENTS AND METHODS: The analysis included 424 patients (oropharyngeal cancer [n = 295] and nasopharyngeal, hypopharyngeal, or laryngeal cancer [n = 129]) who received definitive chemoradiation between January 2004 and April 2009. The superior, middle, and inferior pharyngeal constrictor muscles were contoured. We calculated generalized equivalent uniform dose (gEUD) for each and the total constrictor muscle volume, with the volume effect parameter a varying from log10 a = -1 to +1 in steps of 0.1. We used the National Cancer Institute Common Toxicity Criteria for Adverse Events (version 3.0) to grade late dysphagia and logistic regression to evaluate the correlation of gEUD( a) with grade 2 or higher (≥ G2) and grade 3 or higher (≥ G3) late dysphagia at each value of a. RESULTS: Median follow-up was 33.3 months (range, 6 to 69 months). There were 41 cases (10%) of ≥ G2 dysphagia and 22 cases (5%) of ≥ G3 dysphagia. Mean doses to the total constrictor ranged from 30.1 to 85.7 Gy (median, 61.2 Gy). The predicted rate of ≥ G2 dysphagia increased by approximately 3.4% per Gy at the mean dose, for which the probability of ≥ G2 dysphagia is 50%. The threshold mean total constrictor doses that limited rates of ≥ G2 and ≥ G3 dysphagia to < 5% were < 58 Gy and < 61 Gy, respectively. Other significant factors in the multivariate predictive model included disease site, mean dose to total constrictor muscle, and patient age. CONCLUSION: Incidences of both ≥ G2 and ≥ G3 dysphagia were dependent on the mean radiation dose to the total constrictor muscle volume, disease site, and patient age. Limiting the total volume of constrictor muscle to < 58 Gy could keep the predicted rate of ≥ G2 dysphagia to < 5%.

Hip-related toxicity after prostate radiotherapy: Treatment related or coincidental?

BACKGROUND AND PURPOSE: To evaluate the incidence and predictors of hip toxicity postradiotherapy for localized prostate cancer. METHODS AND MATERIALS: 4067 prostate cancer patients were treated with external beam radiotherapy (EBRT; n=2569; 63%) or brachytherapy with or without supplemental EBRT (n=1508; 27%). 43% (n=1738) were treated with neo-adjuvant and concurrent ADT and 57% (n=2329) with radiotherapy alone. Hip toxicity was defined as moderate or severe pain upon ambulation with or without the need for hip-revision surgery. Median follow-up was 7years (range, 3-21years). RESULTS: One hundred twenty-one (2.7%) patients developed moderate-to-severe hip pain after radiotherapy affecting ambulation. Of these, 73 (60%) required hip replacement secondary to persistent hip pain. Among patients with baseline degenerative joint disease (DJD) changes on scans, 10-year incidence of hip-related toxicity was 11% versus 3% for those without such changes (P<.001). The only variables on multivariate analysis associated with hip-related toxicity post-radiotherapy were baseline DJD on imaging (P<.0001) and prolonged ADT for salvage therapy (P<.0001). CONCLUSIONS: Prostate EBRT or brachytherapy is associated with low incidence of long-term hip-related toxicity. The only variables identified associated with hip toxicity posttherapy was the presence of baseline DJD and prolonged salvage ADT posttreatment for patients developing recurrence.

Optimizing fiducial visibility on periodically acquired megavoltage and kilovoltage image pairs during prostate volumetric modulated arc therapy.

PURPOSE: Robust detection of implanted fiducials is essential for monitoring intrafractional motion during hypofractionated treatment. The authors developed a plan optimization strategy to ensure clear visibility of implanted fiducials and facilitate 3D localization during volumetric modulated arc therapy (VMAT). METHODS: Periodic kilovoltage (kV) images were acquired at 20° gantry intervals and paired with simultaneously acquired 4.4° short arc megavoltage digital tomosynthesis (MV-DTS) to localize three fiducials during VMAT delivery for hypofractionated prostate cancer treatment. Beginning with the original optimized plan, control point segments where fiducials were consistently blocked by multileaf collimator (MLC) within each 4.4° MV-DTS interval were first identified. For each segment, MLC apertures were edited to expose the fiducial that led to the least increase in the cost function. Subsequently, MLC apertures of all control points not involved with fiducial visualization were reoptimized to compensate for plan quality losses and match the original dose-volume histogram. MV dose for each MV-DTS was also kept above 0.4 MU to ensure acceptable image quality. Different imaging (gantry) intervals and visibility margins around fiducials were also evaluated. RESULTS: Fiducials were consistently blocked by the MLC for, on average, 36% of the imaging control points for five hypofractionated prostate VMAT plans but properly exposed after reoptimization. Reoptimization resulted in negligible dosimetric differences compared with original plans and outperformed simple aperture editing: on average, PTV D98 recovered from 87% to 94% of prescription, and PTV dose homogeneity improved from 9% to 7%. Without violating plan objectives and compromising delivery efficiency, the highest imaging frequency and largest margin that can be achieved are a 10° gantry interval, and 15 mm, respectively. CONCLUSIONS: VMAT plans can be made to accommodate MV-kV imaging of fiducials. Fiducial visualization rate and workflow efficiency are significantly improved with an automatic modification and reoptimization approach.

Modeling positioning uncertainties of prostate cancer external beam radiation therapy using pre-treatment data.

PURPOSE: To investigate the influence of treatment plan data and image guidance (IG) on positioning uncertainty during prostate cancer (PCa) radiotherapy (RT). METHODS: Body mass index (BMI), planning target volume (PTV), bladder volume (BV), and rectal cross section area (RCS) were collected for 267 consecutive PCa patients undergoing daily IGRT. Radiographic isocenter corrections to intra-prostatic fiducials for 12,490 treatment fractions were used to derive random (RE) and systematic (SE) inter-fraction uncertainties for the cardinal axes. These data were used to simulate RE and SE for weekly IG and Action Level (AL)-IG treatment protocols. RESULTS: SE and RE were 2-5 and 3-4mm in the cardinal axes, respectively, during simulation of no IG. Without IG, positive correlations (p<0.01) were noted for (1) anterior-posterior RE vs. RCS and BV and (2) cranio-caudal RE vs. RCS, BV and BMI. The RE increase was 3mm for the highest quartile of RCS, BV and BMI. Daily IGRT eliminated this relationship. 3D IG corrections of 1cm or more occured in 27% of treatment fractions and in 97% of patients. CONCLUSION: PCa patients with elevated pre-treatment BV, RCS and BMI have increased inter-fractionation positioning uncertainty and appear the primary candidates for daily IGRT.

Impact of dose to the bladder trigone on long-term urinary function after high-dose intensity modulated radiation therapy for localized prostate cancer.

PURPOSE: To determine the potential association between genitourinary (GU) toxicity and planning dose-volume parameters for GU pelvic structures after high-dose intensity modulated radiation therapy in localized prostate cancer patients. METHODS AND MATERIALS: A total of 268 patients who underwent intensity modulated radiation therapy to a prescribed dose of 86.4 Gy in 48 fractions during June 2004-December 2008 were evaluated with the International Prostate Symptom Score (IPSS) questionnaire. Dose-volume histograms of the whole bladder, bladder wall, urethra, and bladder trigone were analyzed. The primary endpoint for GU toxicity was an IPSS sum increase ≥10 points over baseline. Univariate and multivariate analyses were done by the Kaplan-Meier method and Cox proportional hazard models, respectively. RESULTS: Median follow-up was 5 years (range, 3-7.7 years). Thirty-nine patients experienced an IPSS sum increase ≥10 during follow-up; 84% remained event free at 5 years. After univariate analysis, lower baseline IPSS sum (P=.006), the V90 of the trigone (P=.006), and the maximal dose to the trigone (P=.003) were significantly associated with an IPSS sum increase ≥10. After multivariate analysis, lower baseline IPSS sum (P=.009) and increased maximal dose to the trigone (P=.005) remained significantly associated. Seventy-two patients had both a lower baseline IPSS sum and a higher maximal dose to the trigone and were defined as high risk, and 68 patients had both a higher baseline IPSS sum and a lower maximal dose to the trigone and were defined as low risk for development of an IPSS sum increase ≥10. Twenty-one of 72 high-risk patients (29%) and 5 of 68 low-risk patients (7%) experienced an IPSS sum increase ≥10 (P=.001; odds ratio 5.19). CONCLUSIONS: The application of hot spots to the bladder trigone was significantly associated with relevant changes in IPSS during follow-up. Reduction of radiation dose to the lower bladder and specifically the bladder trigone seems to be associated with a reduction in late GU toxicity.

Robust plan optimization for electromagnetic transponder guided hypo-fractionated prostate treatment using volumetric modulated arc therapy.

To develop an optimization algorithm for volumetric modulated arc therapy which incorporates an electromagnetic tracking (EMT) guided gating strategy and is robust to residual intra-fractional motion uncertainties. In a computer simulation, intra-fractional motion traces from prior treatments with EMT were converted to a probability distribution function (PDF), truncated using a patient specific action volume that encloses allowed deviations from the planned position, and renormalized to yield a new PDF with EMT-gated interventions. In lieu of a conventional planning target volume (PTV), multiple instances of clinical target volume (CTV) and organs at risk (OARs) were replicated and displaced to extreme positions inside the action volume representing possible delivery scenarios. When optimizing the volumetric modulated arc therapy plan, doses to the CTV and OARs were calculated as a sum of doses to the replicas weighted by the PDF to account for motion. A treatment plan meeting the clinical constraints was produced and compared to the counterpart conventional margin (PTV) plan. EMT traces from a separate testing database served to simulate motion during gated delivery. Dosimetric end points extracted from dose accumulations for each motion trace were utilized to evaluate potential clinical benefit. Five prostate cases from a hypofractionated protocol (42.5 Gy in 5 fractions) were retrospectively investigated. The patient specific gating window resulted in tight anterior and inferior action levels (~1 mm) to protect rectal wall and bladder wall, and resulted in an average of four beam interruptions per fraction in the simulation. The robust-optimized plans achieved the same average CTV D95 coverage of 40.5 Gy as the PTV-optimized plans, but with reduced patient-averaged rectum wall D1cc by 2.2 Gy (range 0.7 to 4.7 Gy) and bladder wall mean dose by 2.9 Gy (range 2.0 to 3.4 Gy). Integration of an intra-fractional motion management strategy into the robust optimization process is feasible and may yield improved OAR sparing compared to the standard margin approach.