Improved Target Coverage Research Articles

Image-guided Adaptive Radiotherapy for Bladder Cancer

Technological advancement has facilitated patient-specific radiotherapy in bladder cancer. This has been made possible by developments in image-guided radiotherapy (IGRT). Particularly transformative has been the integration of volumetric imaging into the workflow. The ability to visualise the bladder target using cone beam computed tomography and magnetic resonance imaging initially assisted with determining the magnitude of inter- and intra-fraction target change. It has led to greater confidence in ascertaining true anatomy at each fraction. The increased certainty of dose delivered to the bladder has permitted the safe reduction of planning target volume margins. IGRT has therefore improved target coverage with a reduction in integral dose to the surrounding tissue. Use of IGRT to feed back into plan and dose delivery optimisation according to the anatomy of the day has enabled adaptive radiotherapy bladder solutions. Here we undertake a review of the stepwise developments underpinning IGRT and adaptive radiotherapy strategies for external beam bladder cancer radiotherapy. We present the evidence in accordance with the framework for systematic clinical evaluation of technical innovations in radiation oncology (R-IDEAL).

Benefit of replanning in MR-guided online adaptive radiation therapy in the treatment of liver metastasis

PurposeTo assess the effects of daily adaptive MR-guided replanning in stereotactic body radiation therapy (SBRT) of liver metastases based on a patient individual longitudinal dosimetric analysis.MethodsFifteen patients assigned to SBRT for oligometastatic liver metastases underwent daily MR-guided target localization and on-table treatment plan re-optimization. Gross tumor volume (GTV) and organs at risk (OARs) were adapted to the anatomy-of-the-day. A reoptimized plan (RP) and a rigidly shifted baseline plan (sBP) without re-optimization were generated for each fraction. After extraction of DVH parameters for GTV, planning target volume (PTV), and OARs (stomach, duodenum, bowel, liver, heart) plans were compared on a per-patient basis.ResultsMedian pre-treatment GTV and PTV were 14.9 cc (interquartile range (IQR): 7.7–32.9) and 62.7 cc (IQR: 42.4–105.5) respectively. SBRT with RP improved PTV coverage (V100%) for 47/75 of the fractions and reduced doses to the most proximal OARs (D1cc, Dmean) in 33/75 fractions compared to sBP. RP significantly improved PTV coverage (V100%) for metastases within close proximity to an OAR by 4.0% (≤ 0.2 cm distance from the edge of the PTV to the edge of the OAR; n = 7; p = 0.01), but only by 0.2% for metastases farther away from OAR (> 2 cm distance; n = 7; p = 0.37). No acute grade 3 treatment-related toxicities were observed.ConclusionsMR-guided online replanning SBRT improved target coverage and OAR sparing for liver metastases with a distance from the edge of the PTV to the nearest luminal OAR < 2 cm. Only marginal improvements in target coverage were observed for target distant to critical OARs, indicating that these patients do not benefit from daily adaptive replanning.

PP06 Presentation Time: 10:50 AM: Needles in T.A.R.G.I.T.: "Tandem Anchored Radially Guiding Interstitial Template" Enabling Simplified Needle Insertion for Optimized Dosimetry

Purpose: It is well established in cervical brachytherapy that the addition of interstitial (IS) needles to intra-cavitary (IC) applicators can significantly enhance dosimetry by improving target coverage without increasing normal tissues doses. Accurate placement of interstitial needles requires significant skill and imaging guidance proficiency, thereby limiting the benefits to a subset of practitioners and patients. Available commercial combined IC/IS applicators restrict the available needle positions to often unsatisfactory locations for optimized dosimetry.

Adaptive sequential plan-on-plan optimization during prostate-specific antigen response guided radiotherapy of recurrent prostate cancer.

BackgroundTreatment adaptation based on tumour biomarker response during radiotherapy of prostate cancer, could be used for both escalation and de-escalation of radiation doses and volumes. To execute an adaptation involving extension of treatment volumes during radiation can however be restricted by the doses already delivered. The aim of this work was to develop a treatment planning method that addresses this challenge.Material and methodsA volumetric-modulated-arc-therapy (VMAT) planning method with sequential plan-on-plan optimization was developed for a prospective phase II trial including 100 patients on salvage radiotherapy (SRT) for prostate cancer recurrence. A treatment adaptation was performed after five weeks of SRT based on prostate-specific antigen response during this phase of the treatment. This involved extension of treatment volumes for non-responders (n = 64) to include pelvic lymph nodes and boost to 68Gallium-Prostate-Specific-Membrane-Antigen-Positron-Emission-Tomography positive lesions. This method was evolved by introducing an EQD2 (equivalent dose in 2.0 Gy fractions) correction of the base plan for improved dose coverage.ResultsAll dose-volume criteria for target coverage were met for the non-responders when based on physical dose. An EQD2 correction of the base plan for non-responders, implemented for the final 29 patients, led to a statistically significant improvement in dose coverage as compared to the 35 patients treated without EQD2 correction.ConclusionsThis is to our knowledge the only study presented on biomarker-guided sequential VMAT radiotherapy using a plan-on-plan technique in the pelvis. By using a biologically adapted technique an improved target coverage was achieved without compromising doses to organs at risk.

Dosimetric evaluation of MRI-guided multi-leaf collimator tracking and trailing for lung stereotactic body radiation therapy.

PurposeThe treatment margins for lung stereotactic body radiotherapy (SBRT) are often large to cover the tumor excursions resulting from respiration, such that underdosage of the tumor can be avoided. Magnetic resonance imaging (MRI)‐guided multi‐leaf collimator (MLC) tracking can potentially reduce the influence of respiration to allow for smaller treatment margins. However, tracking is accompanied by system latency that may induce residual tracking errors. Alternatively, a simpler mid‐position delivery combined with trailing can be used. Trailing reduces influences of respiration by compensating for baseline motion, to potentially improve target coverage. In this study, we aim to show the feasibility of MRI‐guided tracking and trailing to reduce influences of respiration during lung SBRT.MethodsWe implemented MRI‐guided tracking on the MR‐linac using an Elekta research tracking interface to track tumor motion during intensity modulated radiotherapy (IMRT). A Quasar MRI4D phantom was used to generate Lujan motion (cos4, 4 s period, 20 mm peak‐to‐peak amplitude) with and without 1.0 mm/min cranial drift. Phantom tumor positions were estimated from sagittal 2D cine‐MRI (4 or 8 Hz) using cross‐correlation‐based template matching. To compensate the anticipated system latency, a linear ridge regression predictor was optimized for online MRI by comparing two predictor training approaches: training on multiple traces and training on a single trace. We created 15‐beam clinical‐grade lung SBRT plans for central targets (8 × 7.5 Gy) and peripheral targets (3 × 18 Gy) with different PTV margins for mid‐position based motion management (3–5 mm) and for MLC tracking (3 mm). We used a film insert with a 3 cm spherical target to measure the spatial distribution and quantity of the delivered dose. A 1%/1 mm local gamma‐analysis quantified dose differences between motion management strategies and reference cases. Additionally, a dose area histogram (DAH) revealed the target coverage relative to the reference scenario.ResultsThe prediction filter gain was on average 25% when trained on multiple traces and 44% when trained on a single trace. The filter reduced system latency from 313 ± 2 ms to 0 ± 5 ms for 4 Hz imaging and from 215 ± 3 ms to 3 ± 3 ms for 8 Hz. The local gamma analysis for the central delivery showed that tracking improved the gamma pass‐rate from 23% to 96% for periodic motion and from 14% to 93% when baseline drift was applied. For the peripheral delivery during periodic motion, delivery pass‐rates improved from 22% to 93%. Comparing mid‐position delivery to trailing for periodic+drift motion increased the local gamma pass rate from 15% to 98% for a central delivery and from 8% to 98% for a peripheral delivery. Furthermore, the DAHs revealed a relative D98% GTV coverage of 101% and 97% compared to the reference scenario for, respectively, central and peripheral tracking of periodic+drift motion. For trailing, a relative D98% of 99% for central and 98% for peripheral trailing was found.ConclusionsWe provided a first experimental demonstration of the technical feasibility of MRI‐guided MLC tracking and trailing for central and peripheral lung SBRT. Tracking maximizes the sparing of healthy tissue, while trailing is highly effective in mitigating baseline motion.

Anatomically robust proton therapy using multiple planning computed tomography scans for locally advanced prostate cancer

Background Proton therapy (PT) is sensitive towards anatomical changes that may occur during a treatment course. The aim of this study was to investigate if anatomically robust PT (ARPT) plans incorporating patient-specific target motion improved target coverage while still sparing normal tissues, when applied on locally advanced prostate cancer patients where pelvic irradiation is indicated. Material and methods A planning computed tomography (CT) scan used for dose calculation and two additional CTs (acquired on different days) were used to make patient-specific targets for the ARPT plans on the eight included patients. The plans were compared to a conventional robust PT plan and a volumetric modulated arc therapy (VMAT) photon plan, which were derived from the planning CT (pCT). Worst-case robust optimisation was used for all proton plans with a setup uncertainty of 5 mm and a range uncertainty of 3.5%. Target coverage (V95% and D95%) and normal tissue doses (V5–75 Gy) were evaluated on 6–8 rCTs per patient. Results The ARPT plans improved the prostate target coverage for the most challenging patient compared to conventional robust PT plans (20% point increase for V95% and 31 Gy increase for D95%). Across the whole cohort the estimated mean value for V95% was 97% for the ARPT plans and 95% for the conventional robust PT plans. The ARPT plans had a slight, statistically insignificant increase in normal tissue doses compared to the conventional robust proton plans. Compared to VMAT, the ARPT plans significantly reduced the normal tissue doses in the low-to-intermediate dose range. Conclusions While both proton plans reduced the low-to-intermediate normal tissue doses compared to VMAT, ARPT plans improved the target coverage for the most challenging patient without significantly increasing the normal tissue doses compared to conventional robust PT plans.

Inverse planning in Gamma Knife radiosurgery: A comparative planning study.

To determine the advantages of inverse planning using a prerelease version of Leksell Gamma Knife® (LGK) Lightning (Elekta AB, Sweden) compared to manual forward planning. Thirty-eight patients with metastases (MET, n=15), vestibular schwannomas (VS, n=11) and meningiomas (MEN, n=12), treated with LGK Icon™ at our institution, were analyzed retrospectively. For each case, an inverse (inv) and inverse full coverage (fc) treatment plan was generated using LGK Lightning and compared to the clinical plans. Several dosimetry and efficiency characteristics were compared for each indication. The mean, median difference and interquartile range were reported and the significance was assessed with a paired-sample Wilcoxon test (significance level<0.05). Further, the inter operator variability was analyzed for multiple users. Inv and fc treatment plans show improved target coverage (up to 3.6%) for all analyzed paradigms. For inv plans, the selectivity is enhanced (MET: 2.9%; VS: 1.8%; MEN: 1%) and the organ at risk doses are significantly reduced (VS: up to 4.5%; MEN: up to 17.5%). For inv and fc plans, the beam on time (BOT) is shortened (MET: up to 7.9%; benign tumors: 49.5%). The inter operator variability analysis shows similar treatment plan quality with small differences in plan efficiency (difference in BOT: 1-3.3min). LGK Lightning allows to generate improved LGK treatment plans regarding plan quality with reduced BOT compared to manual forward plans. The inter operator variability showed that multiple users with different experiences can generate similar treatment plan quality using LGK Lightning.

Optimisation of user-selectable volumetric modulated arc therapy (VMAT) planning parameters: VMAT arcs for prostate and head-and-neck cancers.

To evaluate different VMAT planning techniques for a multi-leaf collimator (MLC)providing maximum aperture of 21 × 16 cm². A VMAT planning study of nine prostate and nine head-and-neck cancer patients was carried out. The patients were previously treated with Intensity Modulated Radiotherapy (IMRT) technique during 2014-15, at radiation oncology SanBortolo Hospital, Vicenza, Italy. Three VMAT plans for each of prostate and head-and-neck cancer patient were optimized using Pinnacle treatment planning system for 6MV photon beam from ElektaSynergyS®Linac system. Single arc, dual arc and combined two independent-single-arcs were optimized for collimator angle 45°. VMAT treatment planning comparison was made among single-arc dual-arc and combined two independent-single-arcs. The student's t-test (two-sided) with p ≤ 0.05 was applied for significant difference between dose volume indices of plans. All VMAT techniques produced clinically acceptable plans for prostate, while for head-and-neck, DA and ISAs significantly improved target coverage compared to SA. Single arc is sufficient for prostate, while inefficient in case of head-and-neck dose-planning. In spite of having different VMAT optimization approach dual arc and two combined independent-single-arcs provided very similar target coverage, while dual arc improved sparing of organs-at-risk. Similar treatment delivery times were observed for DA and ISAs VMAT techniques. Single arc is sufficient for prostate, while inefficient in case of head-and-neck dose-planning. Dual arc and two combined independent-single-arcs provided similar PTV coverage, while DA provided better sparing of organs at risk.

Daily online adaptive magnetic resonance image (MRI) guided stereotactic body radiation therapy for primary renal cell cancer

Stereotactic body radiotherapy (SBRT) has demonstrated promising outcomes for patients with early-stage, medically inoperable, primary renal cell carcinoma (RCC) in large multi-institutional studies and prospective clinical trials. The traditional approach used in these studies consisted of a CT-based planning approach for target and organ-at-risk (OAR) volume delineation, treatment planning, and daily treatment delivery. Alternatively, MRI-based approaches using daily online adaptive radiotherapy have multiple advantages to improve treatment outcomes: (1) more accurate delineation of the target volume and OAR volumes with improved soft tissue visualization; (2) gated beam delivery with biofeedback from the patient; and (3) potential for daily plan adaptation due to changes in anatomy to improve target coverage, reduce dose to OARs, or both. The workflow, treatment planning principles, and aspects of treatment delivery specific to this technology are outlined using a case example of a patient with an early-stage RCC of the right kidney treated with MRI-guided SBRT using daily adaptive treatment to a dose of 42 Gy in 3 fractions.

Proof-of-Concept Comparative Dosimetric Analysis of Coplaner Horizontal-Port Carbon-Ion Radiotherapy in the Head and Neck

Carbon-ion radiotherapy (CIRT) may offer improved treatment of radioresistant disease in complex anatomy, such as in head and neck (H&N) cancer. Nonetheless, center cost remains prohibitive. A compact center implementing only horizontal ports has been theorized; coplaner irradiation may improve target coverage. As proof of concept, horizontal+coplaner (H+C) treatment was dosimetrically compared in variously located, complex H&N cases, to evaluate feasibility of this approach. 3 previously-treated patients with adenoid cystic carcinoma (ACC) (L. maxillary sinus, R. parotid, upper R. sinus), 1 with R. nasal angiosarcoma, and 1 with R. parotid adenocarcinoma, were selected. A H+C plan was developed on identical CIRT software per standard. Prescription dose was maintained (64-70.4 Gy (RBE)). Bed roll of +/-30 degrees and off-medial transcranial irradiation were employed to improve targeting and organ at risk (OAR) protection. OAR limits included a Dmax 40 Gy (RBE) with V40 20% for optic nerves and chiasm and Dmax 30 Gy (RBE) for brain stem. Individual dose-volume histograms (DVH) were qualitatively compared. PTV and GTV coverage varied <1% in all cases, with comparable DVHs. Stem dose was below Dmax 30 Gy (RBE) in all patients, with reduced H+C dose noted in the upper R. sinus and L maxillary sinus ACC patients (Dmax 6.8 vs 14.7 Gy (RBE) and 1.3 vs 17.8 Gy (RBE), respectively). H+C unilateral optic nerve dose was above the Dmax limit of 40 Gy (RBE) in the upper R sinus and L maxillary sinus ACC cases as well (40.4 vs 37.0 Gy (RBE) and 45.7 vs 46.2 Gy (RBE), respectively). In the latter case, left H+C optic nerve V40 dose exceeded the 20% limit, at 21.6% vs 3.6% standard. In the former, the upper sinus location increased bilateral eye irradiation: V10 rose from 57% and 0% to 100% each, with Dmax increased to 51.7 from 47 Gy (RBE) in the right, and 30.9 from 8 Gy (RBE) in the left. The sarcoma case experienced increased H+C chiasm Dmax to 28.7 from 1.8 Gy (RBE), below the 40 Gy (RBE) limit. H+C irradiation raised all V5, V10, and V20 brain dosages, with averages of 16.2 vs 2.2%, 10.9 vs 1.5%, and 2.8 vs 0.8%, respectively. Maximums of 25%, 20%, and 7% were noted in the right parotid ACC. Adequate CIRT dose delivery with protection of key OARs in complex H&N cancer appears feasible using only a horizontal port with coplaner approach. Dose increase could be seen in optic nerves and eyes when near or obstructing tumor from the port, highlighting disease location and anatomical limitations of treating solely within the horizontal plane. Increased brain dosage was noted in all cases. The impact of low-dose high-LET CIRT on neural tissue requires further exploration prior to deployment of a coplaner approach. Potentials such as sitting-up immobilization for anteroposterior delivery may mitigate the limitations seen here. A larger cohort analysis is in progress.

Volumetric Modulated Arc Therapy Versus Three-Dimensional Conformal Radiotherapy for Breast Cancer Patients Treated with Regional Nodal Irradiation

Locally advanced breast cancer is often treated with adjuvant radiotherapy to the chest wall or breast and the regional nodes following surgery. Intensity-modulated radiotherapy (IMRT) can improve target coverage and spare organ at risk, but the efficacy and safety of IMRT for locally advanced breast cancer have not been clarified. We aimed to compare the dosimetric parameters and clinical outcomes between 3D-CRT and volumetric modulated arc therapy (VMAT) for breast cancer. The hypothesis is that VMAT has better target coverage without increasing toxicities. Breast cancer patients who received adjuvant radiotherapy with regional nodes irradiation between July 2016 and December 2019 were included. Patients with a right-sided disease were treated with three-dimensional conformal radiotherapy (3D-CRT), whereas patients with a left-sided disease were treated with VMAT to reduce heart dose. Patients who received bilateral radiotherapy were excluded. Radiotherapy was delivered to the chest wall or breast, and supraclavicular region with or without internal mammary nodes. A dose of 50 Gy in 25 fractions was prescribed to the reference point for 3D-CRT, and to cover 75% of the PTV for VMAT. Single full or two partial arcs with 6MV were used for VMAT. Clinical outcome and dosimetric data were collected retrospectively from medical records. Toxicities were assessed by CTCAE ver.4.0. A total of 74 consecutive patients were included in this study. Thirty-five left-sided breast cancer patients received VMAT, and 39 right-sided breast cancer patients received 3D-CRT. The median follow-up was 591 days. The median age was 50 years. Grade 2 or higher acute dermatitis were observed in 10 patients (29%) with VMAT versus 17 patients (44%) with 3D-CRT (P = 0.18). Grade 3 acute dermatitis occurred in one patient in the 3D-CRT group. Grade 2 radiation pneumonitis occurred in one patient in each group (P = 1.0). Acute radiation esophagitis occurred in 25 patients only in the VMAT group. CTV coverage (CTV V47.5Gy, D95%, D75%) was significantly better for VMAT (86%, 42 Gy, 49 Gy) compared to 3D-CRT (72%, 29 Gy, 46 Gy) (all P < 0.01). Total lung V20 Gy was lower for VMAT versus 3D-CRT (11Gy versus 13 Gy, P < 0.01), whereas total lung V5 Gy and mean dose were higher for VMAT (34 Gy and 7.8 Gy) compared to 3D-CRT (22 Gy and 6.9 Gy) (P < 0.01, 0.01). Because of the laterality, the dose to the heart and esophagus was higher in the VMAT group (P < 0.01, 0.01). Five patients experienced recurrence (two distant metastases in the VMAT group and two distant and one local and distant metastases in the 3D-CRT group). VMAT for breast radiotherapy with regional nodal irradiation had better target coverage and lower lung V20 Gy at the expense of a small increase in the lung mean dose and V5 Gy. VMAT can be safely administered with similar toxicity to 3D-CRT.

Co-60 MR Guided Adaptive Radiation Treatment Improves Target Coverage and Organs-At-Risk Sparing: Dosimetric Analysis of 1185 Adaptive Fractions and 5 Years’ Experience

Early data indicate MRI guided online adaptive radiotherapy (MRGRT) spares organs-at-risk (OARs) when inter-fractional motion of tumor targets and critical GI organs is significant. However, these studies were limited in patient numbers. This study systematically assesses all previously adapted treatment fractions of the MR imaging system Co-60 machine at the authors’ institution. The dosimetry metrics on patients’ treatment day anatomy between the adapted plans vs the un-adapted plans are compared. The aims are to determine the reasons (and corresponding rates) necessitating plan adaptations and quantifying improvement in target coverage. All abdominal cancer patients (N = 137) previously treated with MRGRT on the VR Co-60 machine from 2015 to 2019 are included. Treatment sites were pancreas (98), adrenal (11) and not otherwise specified abdomen (28). A total 961 (81.1%) out of 1185 fractions were adapted. Plan adaptation conditions were 1) the target was edited, or 2) any critical OAR constraints were violated, or 3) target coverage was significantly worse (V95%Rx reduction >10% for PTV-PRV) than the one achieved with the previous plan. For each adapted fraction, dose was calculated using a Monte Carlo dose calculation engine previously developed by authors for both 1) the plan before adaptation and 2) the adapted new plan. A suite of computer algorithm programs were developed to 1) process the treatment plan data files exported from TPS, 2) recognize the case-specific target structure and critical OARs, 3) compute treatment-day DVH metrics (V95%Rx and D95% for the targets, and V>constraint for OARs) on the calculated dose volumes, and 4) analyze the results arithmetically and statistically. Data of 961 adapted treatment fractions were processed and analyzed. The analysis shows that 1) critical OARs were edited for 100% cases, 2) tumor targets were edited for 90 (9.4%) cases, 3) critical OAR constraints were violated for 870 (90.5%) cases by the un-adapted plans, 4) plan optimization objectives were edited for 33 (3.4%) cases and 5) all critical OAR constraints were met in all (100%) adapted plans, 6) target coverages were improved for 888 (92.4%) cases with the adapted plans compared to un-adapted plans that were normalized to meet OAR constraints. After more than 5 years and 1100 fractions of experience, results continue to confirm that adapted plans provided significantly better target coverage while preventing violation of critical OAR constraints. Future work is necessary to establish the clinical significance of these data and validate these findings in the VR MRI Linac.

A Single Institution Experience On High Dose MRI-Guided Stereotactic Body Radiotherapy For Pancreatic Cancer: Early Outcomes, Safety And Feasibility

Accumulating evidence has shown a benefit for dose-escalation and stereotactic body radiotherapy (SBRT) in the treatment of unresectable pancreatic cancer. To this end, MR-guided radiotherapy (MRgRT) allows for reduction of dose to organs at risk while accounting for intra- and inter-fraction motion with online treatment plan adaptation to improve target coverage. We sought to report on our early experience in MRgSBRT for pancreatic cancer. This study was a retrospective cohort of biopsy-proven, pancreatic cancer patients that were recommended to undergo high biological equivalent dose (BED) SBRT to their primary disease and were treated on the MR-Linac in 5 fractions. Acute toxicity measured by Common Terminology Criteria for Adverse Events (v5) by a provider during the weekly on-treatment visit, at 1 month following completion of treatment, and at regular 3-month follow-up intervals thereafter. Toxicity occurring greater than 3 months after completion of radiotherapy was deemed late. From April, 2019 until January, 2020 a total of 35 consecutively treated patients (48% borderline resectable, 37% locally advanced; 80% cN0) with a median follow up from diagnosis of 8.3 months were treated to median 45 Gy (Range: 35-50 Gy) on our MRI-Linac. At least three months of induction chemotherapy was given in 88.5% of patients, most commonly FOLFIRINOX (71%) or gemcitabine/abraxane (26%). Twenty-three patients (66%) were treated with online adaptive planning and 4 patients (11%) were treated for locally recurrent, unresectable disease with history of prior radiotherapy (n = 3 prior adjuvant chemoradiation, n = 1 prior definitive SBRT in the lateral decubitus position). Overall, nine patients (25%) experienced any toxicity, predominantly grade 1 fatigue (55%) and nausea (44%). A single patient (2.8%) experienced grade 3 abdominal pain 1.5 weeks after completion of SBRT presumed to be duodenitis from CT imaging. No grade 4/5 or any late toxicity from SBRT has been observed in this cohort to date. At the time of analysis, 9 patients (55% borderline resectable, 22% locally advanced) successfully underwent resection of their primary tumor (100% R0 resection) without perioperative mortality and with 2 reported pathological complete response (TRG 0; 22%), 2 patients with TRG 1 response and 5 patients with TRG 2 response (55%). Overall, no patients had experienced local recurrence based on CT pancreas protocol RECIST criteria and eight patients (22.8%) had distant progression with one reported death (OS: 97%). MRgSBRT for pancreatic cancer appears to be well-tolerated with encouraging early local control and without significant morbidity or increased perioperative mortality. Adaptive treatment parameters and tissue constraints for adaptive and non-adaptive treatment plans minimize toxicity for this increasingly utilized treatment.

A novel minimally invasive dynamic-shield, intensity-modulated brachytherapy system for the treatment of cervical cancer.

To present a novel, MRI-compatible dynamicshield intensity modulated brachytherapy (IMBT) applicator and delivery system using 192 Ir, 75 Se, and 169 Yb radioisotopes for the treatment of locally advanced cervical cancer. Needle-free IMBT is a promising technique for improving target coverage and organs at risk (OAR) sparing. The IMBT delivery system dynamically controls the rotation of a novel tungsten shield placed inside an MRI-compatible, 6-mm wide intrauterine tandem. Using 36 cervical cancer cases, conventional intracavitary brachytherapy (IC-BT) and intracavitary/interstitial brachytherapy (IC/IS-BT) (10Ci 192 Ir) plans were compared to IMBT (10Ci 192 Ir; 11.5Ci 75 Se; 44Ci 169 Yb). All plans were generated using the Geant4-based Monte Carlo dose calculation engine, RapidBrachyMC. Treatment plans were optimized then normalized to the same high-risk clinical target volume (HR-CTV) D90 and the D2cc for bladder, rectum, and sigmoid in the research brachytherapy planning system, RapidBrachyMCTPS. Plans were renormalized until either of the three OAR reached dose limits to calculate the maximum achievable HR-CTV D90 and D98 . Compared to IC-BT, IMBT with either of the three radionuclides significantly improves the HR-CTV D90 and D98 by up to 5.2%±0.3% (P<0.001) and 6.7%±0.5% (P<0.001), respectively, with the largest dosimetric enhancement when using 169 Yb followed by 75 Se and then 192 Ir. Similarly, D2cc for all OAR improved with IMBT by up to 7.7%±0.6% (P<0.001). For IC/IS-BT cases, needle-free IMBT achieved clinically acceptable plans with 169 Yb-based IMBT further improving HR-CTV D98 by 1.5%±0.2% (P=0.034) and decreasing sigmoid D2cc by 1.9%±0.4% (P=0.048). Delivery times for IMBT are increased by a factor of 1.7, 3.3, and 2.3 for 192 Ir, 75 Se, and 169 Yb, respectively, relative to conventional 192 Ir BT. Dynamic shield IMBT provides a promising alternative to conventional IC- and IC/IS-BT techniques with significant dosimetric enhancements and even greater improvements with intermediate energy radionuclides. The ability to deliver a highly conformal, OAR-sparing dose without IS needles provides a simplified method for improving the therapeutic ratio less invasively and in a less resource intensive manner.

Monte Carlo evaluation of target dose coverage in lung stereotactic body radiation therapy with flattening filter-free beams.

Previous studies showed that replacing conventional flattened beams (FF) with flattening filter-free (FFF) beams improves the therapeutic ratio in lung stereotactic body radiation therapy (SBRT), but these findings could have been impacted by dose calculation uncertainties caused by the heterogeneity of the thoracic anatomy and by respiratory motion, which were particularly high for target coverage. In this study, we minimized such uncertainties by calculating doses using high-spatial-resolution Monte Carlo and four-dimensional computed tomography (4DCT) images. We aimed to evaluate more reliably the benefits of using FFF beams for lung SBRT. For a cohort of 15 patients with early stage lung cancer that we investigated in a previous treatment planning study, we recalculated dose distributions with Monte Carlo using 4DCT images. This included fifteen FF and fifteen FFF treatment plans. Compared to Monte Carlo, the treatment planning system (TPS) over-predicted doses in low-dose regions of the planning target volume. For most patients, replacing FF beams with FFF beams improved target coverage, tumor control, and uncomplicated tumor control probabilities. Monte Carlo tends to reveal deficiencies in target coverage compared to coverage predicted by the TPS. Our data support previously reported benefits of using FFF beams for lung SBRT.

Early outcomes after definitive chemoradiation therapy with Vienna/Venezia hybrid high-dose rate brachytherapy applicators for cervical cancer: A single-institution experience

PURPOSEThe Vienna and Venezia (Elekta) are hybrid intracavitary/interstitial brachytherapy (BT) applicators for cervical cancers unsuitable for intracavitary BT alone to improve target coverage or reduce critical organ dose. There is limited outcome data with the use of these applicators outside published experience of the EMBRACE group. We report feasibility and early outcomes with the use of these hybrid applicators at our institution. METHODS AND MATERIALSHybrid applicators were used to treat 61 patients with cervical cancer from November 2011 to December 2019. Indications for hybrid applicator use were involvement of the vagina in 10 patients (16%), residual central or parametrial disease in 46 patients (75%), and a narrow introitus in 5 patients (9%). Toxicities were graded using the CTCAE v4.0. Outcomes were assessed with the Kaplan–Meier method. ResultsMedian follow-up was 16 months (IQR 9–32 mos). Median HRCTV volume was 31.6 cm3 (IQR 25–48 cm3). Median HRCTV D90 was 86.1 Gy (IQR 84.3–88.0 Gy). In 54 patients with follow-up PET/CT at 3 months, complete initial imaging response locally was seen in 46 patients.Estimated 12-month Kaplan–Meier overall survival, locoregional control, distant control, and recurrence-free survival estimates were 86.9%, 80.6%, 73.8%, and 65.9%, respectively. The 12-month incidence of Grade 3+ GI/GU chronic toxicities was 5.7%, consisting of vesicovaginal fistula, rectovaginal fistula, and ureterovesical fistula. ConclusionsOur single-institution data support the use of the hybrid applicators, as an alternative to traditional BT applicators when clinically warranted. Use of hybrid applicators is feasible with adequate coverage of disease in the vagina and parametrium.

A Physiologically‐Based Pharmacokinetic Model for the Prediction of “Half‐Life Extension” and “Catch and Release” Monoclonal Antibody Pharmacokinetics

Monoclonal antibodies (mAbs) can be engineered to have “extended half‐life” and “catch and release” properties to improve target coverage. We have developed a mAb physiologically‐based pharmacokinetic model that describes intracellular trafficking, neonatal Fc receptor (FcRn) recycling, and nonspecific clearance of mAbs. We extended this model to capture target binding as a function of target affinity, expression, and turnover. For mAbs engineered to have an extended half‐life, the model was able to accurately predict the terminal half‐life (82% within 2‐fold error of the observed value) in the human FcRn transgenic (Tg32) homozygous mouse and human. The model also accurately captures the trend in pharmacokinetic and target coverage data for a set of mAbs with differing catch and release properties in the Tg32 mouse. The mechanistic nature of this model allows us to explore different engineering techniques early in drug discovery, potentially expanding the number of “druggable” targets.

On adaptation cost and tractability in robust adaptive radiation therapy optimization.

In this paper, a framework for online robust adaptive radiation therapy (ART) is discussed and evaluated. The purpose of the presented approach to ART is to: (a) handle interfractional geometric variations following a probability distribution different from the a priori hypothesis, (b) address adaptation cost, and (c) address computational tractability. A novel framework for online robust ART using the concept of Bayesian inference and scenario reduction is introduced and evaluated in a series of simulated cases on a one-dimensional phantom geometry. The initial robust plan is generated from a robust optimization problem based on either expected-value or worst-case optimization approach using the a priori hypothesis of the probability distribution governing the interfractional geometric variations. Throughout the course of treatment, the simulated interfractional variations are evaluated in terms of their likelihood with respect to the a priori hypothesis of their distribution and violation of user-specified tolerance limits by the accumulated dose. If an adaptation is considered, the a posteriori distribution is computed from the actual variations using Bayesian inference. Then, the adapted plan is optimized to better suit the actual interfractional variations of the individual case. This adapted plan is used until the next adaptation is triggered. To address adaptation cost, the proposed framework provides an option for increased adaptation frequency. Computational tractability in robust planning and ART is addressed by an approximation algorithm to reduce the size of the optimization problem. According to the simulations, the proposed framework may improve target coverage compared to the corresponding nonadaptive robust approach. In particular, Bayesian inference may be useful to individualize plans to the actual interfractional variations. Concerning adaptation cost, the results indicate that mathematical methods like Bayesian inference may have a greater impact on improving individual treatment quality than increased adaptation frequency. In addition, the simulations suggest that the concept of scenario reduction may be useful to address computational tractability in ART and robust planning in general. The simulations indicate that the adapted plans may improve target coverage and OAR protection at manageable adaptation and computational cost within the novel framework. In particular, adaptive strategies using Bayesian inference appear to perform best among all strategies. This proof-of-concept study provides insights into the mathematical aspects of robustness, tractability, and ART, which are a useful guide for further development of frameworks for online robust ART.

MR-guided focused ultrasound cerebellothalamic tractotomy for chronic therapy-resistant essential tremor: anatomical target reappraisal and clinical results.

In addition to the well-recognized ventral intermediate nucleus (Vim) thalamotomy for the treatment of chronic therapy-resistant essential tremor (ET), an alternative approach targeting the posterior part of the subthalamus was proposed in the 1960s and early 1970s and then was reactualized as cerebellothalamic tractotomy (CTT) with the advent of MR-guided focused ultrasound (MRgFUS) surgery. The goal of this study was to improve target coverage and thus efficacy (i.e., tremor control and its consistency). The authors undertook a histological reappraisal of the CTT target and proposed a targeting strategy of the MRgFUS CTT based on 1) the MR visualization of the center of the red nucleus and 2) the application of preplanned target subunits realized with short sonications under thermal dose control. This study was aimed at demonstrating the efficacy and risk profile of this approach against chronic therapy-resistant ET. Ten consecutive patients suffering from chronic therapy-resistant ET benefited from a unilateral MRgFUS CTT and were followed over the course of 1 year. Primary endpoints were subjective tremor relief, Clinical Rating Scale for Tremor (CRST) score, activities of daily living (ADL) score, and the hand function (HF) scores HF16 and HF32. Histological reappraisal of the target led the authors to propose a standardized targeting protocol for MRgFUS CTT. Thermal doses for 18 and 240 cumulative equivalent minutes at 43°C were calculated and correlated with intraoperative and 2 days postoperative T2-weighted MR images. The mean ± SD for the baseline CRST score was 48 ± 12; the score was 16 ± 7 at 3 months, and 17 ± 8 at 1 year. The mean tremor relief rated by the patients for the operated side was 95% after 2 days, 96% at 3 months, and 93% at 1 year. The mean HF16 was 11.0 ± 2.1 at baseline, 0.7 ± 0.7 at 3 months, and 0.8 ± 0.9 at 1 year (93% mean reduction). The minimum reduction for the HF16 at 1 year was 78%. There was a 51% reduction of the mean ADL score at 1 year. There was no bleeding or infection. Gait difficulties, only detectable on tandem gait, were increased in 3 patients and reduced in 2 patients at 1 year. There was no dysarthria. The authors' results suggest that MRgFUS CTT is a very effective treatment option for therapy-resistant ET.

Development and clinical implementation of semi-automated treatment planning including 3D printable applicator holders in complex skin brachytherapy.

High-dose-rate brachytherapy (HDR-BT) is a treatment option for malignant skin diseases compared to external beam radiation therapy, HDR-BT provides improved target coverage, better organ sparing, and has comparable treatment times. This is especially true for large clinical targets with complex topologies. To standardize and improve the quality and efficacy of the treatments, a novel streamlined treatment approach in complex skin HDR-BT was developed and implemented. This approach consists of auto generated treatment plans and a 3D printable applicator holder (3D-AH). The in-house developed planning system automatically segments computed tomography simulation images (a), optimizes a treatment plan (b), and generates a model of the 3D-AH (c). The 3D-AH is used as an immobilization device for the flexible Freiburg flap applicator used to deliver treatment. The developed, automated planning is compared against the standard clinical plan generation process for a flat 10×10cm2 field, curved fields with radii of 4, 6, and 8cm, and a representative clinical case. The quality of the 3D print is verified via an additional CT of the flap applicator latched into the holder, followed by an automated rigid registration with the original planning CT. Finally, the methodology is implemented and tested clinically under an IRB approval. All automatically generated plans were reviewed and accepted for clinical use. For the clinical workflow, the coverage achieved at a prescription depth for the flat 4, 6, and 8cm applicator was (100.0±4.9)%, (100.0±4.9)%, (96.0±0.3)%, and (98.4±0.3)%, respectively. For auto planning, the coverage was (99.9±0.3)%, (100.0±0.2)%, (100.0±0.3)%, and (100.1±0.2)%. For the clinical test case, the D90 for the clinical workflow and auto planning was found to be 93.5% and 100.29% of the prescribed dose, respectively. Processing of the patient's CT to generate trajectories and positions as well as the 3D model of the applicator took <5min. This workflow automates time intensive catheter digitizing and treatment planning. Compared to printing full applicators, the use of 3D-AH reduces the complexity of the 3D prints, the amount of the material to be used, the time of 3D printing, and amount of quality assurance required. The proposed methodology improves the overall treatment plan quality in complex HDR-BT and impact patient treatment outcomes potentially.