Organs At Risk Constraints Research Articles

Radiation treatment planning study to investigate feasibility of delivering Immunotherapy in Combination with Ablative Radiosurgery to Ultra-High DoSes (ICARUS).

PurposeImmune checkpoint inhibitors improve survival in metastatic diseases for some cancers. Multisite SBRT with pembrolizumab (SBRT + Pembro) was shown to be safe with promising local control using biologically effective doses (BEDs) = 95–120 Gy. Increased BED may improve response rate; however, SBRT doses are limited by surrounding organs at risk (OARs). The purpose of this work was to develop and validate methods for safe delivery of ultra‐high doses of radiation (BED10 > 300) to be used in future clinical trials.Methods and MaterialsThe radiation plans from 15 patients enrolled on a phase I trial of SBRT + pembro were reanalyzed. Metastatic disease sites included liver (8/15), inguinal region (1/15), pelvis (2/15), lung (1/15), abdomen (1/15), spleen (1/15), and groin (1/15). Gross tumor volumes (GTVs) ranged from 80 to 708 cc. Following the same methodology used in the Phase I trial on which these patients were treated, GTVs > 65 cc were contracted to a 65 cc subvolume (SubGTV) resulting in only a portion of the GTV receiving prescription dose. Volumetric modulated arc therapy (VMAT) was used to plan treatments BED10 = 360 Gy. Plans utilizing both 6FFF and 10FFF beams were compared to clinical plans delivering BED10 = 112.50 Gy. The target primary goal was V100% > 95% with a secondary goal of V70% > 99% and OAR objectives per the trial. To demonstrate feasibility, plans were delivered to a diode array phantom and evaluated for fidelity using gamma analysis.ResultsAll 30 plans met the secondary coverage goal and satisfied all OAR constraints. The primary goal was achieved in 12/15 of the 6FFF plans and 13/15 of the 10FFF plans. Average gamma analysis passing rate using criteria of 3% dose difference and 3, 2, and 1 mm were 99.1 ± 1.0%, 98.5 ± 1.6%, and 95.1 ± 3.8%, respectively.ConclusionNovel VMAT planning approaches with clinical treatment planning software and linear accelerators prove capable of delivering radiation doses in excess of 360 Gy BED10 to tumor subvolumes, while maintaining safe OAR doses.

Dosimetric and radiobiological comparison of treatment plan between CyberKnife and EDGE in stereotactic body radiotherapy for pancreatic cancer

To perform a comparison of the different stereotactic body radiotherapy (SBRT) plans between the Varian EDGE and CyberKnife (CK) systems for locally advanced unresectable pancreatic cancer. Fifteen patients with pancreatic cancer were selected in this study. The median planning target volume (PTV) was 28.688 cm3 (5.736–49.246 cm3). The SBRT plans for the EDGE and CK were generated in the Eclipse and Multiplan systems respectively with the same contouring and dose constrains for PTV and organs at risk (OARs). Dose distributions in PTV were evaluated in terms of coverage, conformity index (CI), new conformity index (nCI), homogeneity index (HI), and gradient index (GI). OARs, including spinal cord, bowel, stomach, duodenum and kidneys were statistically evaluated by different dose-volume metrics and equivalent uniform dose (EUD). The volume covered by the different isodose lines (ISDL) ranging from 10 to 100% for normal tissue were also analyzed. All SBRT plans for EDGE and CK met the dose constraints for PTV and OARs. For the PTV, the dosimetric metrics in EDGE plans were lower than that in CK, except that D99 and GI were slightly higher. The EDGE plans with lower CI, nCI and HI were superior to generate more conformal and homogeneous dose distribution for PTV. For the normal tissue, the CK plans were better at OARs sparing. The radiobiological indices EUD of spinal cord, duodenum, stomach, and kidneys were lower for CK plans, except that liver were higher. The volumes of normal tissue covered by medium ISDLs (with range of 20–70%) were lower for CK plans while that covered by high and low ISDLs were lower for EDGE plans. This study indicated that both EDGE and CK generated equivalent plan quality, and both systems can be considered as beneficial techniques for SBRT of pancreatic cancer. EDGE plans offered more conformal and homogeneous dose distribution for PTV, while the CK plans could minimize the exposure of OARs.

A dosimetric comparison of volumetric modulated arc therapy with three-dimensional conformal radiotherapy in the treatment of cervical cancer

Background: External beam radiotherapy (EBRT) is essential in the management of locally advanced cervical cancer (LACC). Volumetric modulated arc therapy (VMAT) is thought to achieve higher conformity to the planned target volume (PTV) and better sparing of organs at risk (OAR) when compared to three-dimensional conformal radiotherapy (3D-CRT). This study focused on these principles as it applied to treatment and potential toxicity in the management of LACC. Aim: The aim of this study was to compare dosimetric parameters between VMAT and 3D-CRT in the management of LACC. Setting: The study analysed patients treated at Groote Schuur Hospital (GSH) between May and December 2017. Methods: This is a non-randomised comparative retrospective study. Three-dimensional conformal radiation and VMAT plans were generated, and data on treatment parameters for PTV D50%, Dmax, Dmean, conformity index (CI), homogeneity index (HI), treated volume (TV), irradiated volume (IV) and OAR constraints; femoral heads, bladder, bowel bag, rectum and bone marrow were collected. Results: Of the 45 patients assessed, VMAT showed statistically significant, lower treatment parameter values for CI (1.09 vs. 1.49) and TV (1613.1 cm 3 vs. 2230.3 cm 3 ), whereas 3D-CRT showed lower Dmax (48.1 Gy vs. 49.2 Gy) and IV (10652.2 cm 3 vs. 14618.1 cm 3 ). Volumetric modulated arc therapy OAR doses revealed a lower V45 for bowel bag (182.3 cm 3 vs. 411.3 cm 3 ; p < 0.001), lower V40 for bone marrow (19.1% vs. 38.7%; p < 0.001) and rectum (88.5% vs. 96%; p < 0.001). A reduced 3D-CRT dose was noted for bladder Dmax (47.4 Gy vs. 48.3 Gy; p < 0.001). Conclusion: Volumetric modulated arc therapy offered a superior dosimetric option, with better OAR dose sparing and optimal tumour dosimetry.

Ultra hypofractionated extended nodal irradiation using volumetric modulated arc therapy for oligorecurrent pelvic nodal prostate cancer.

Prostate cancer (PCa) may recur after primary treatment but no standard of care exists for patients with pelvic nodal relapse. Based on obervational data, Extended Nodal Irradiation (ENI) might be associated with fewer treatment failures than Stereotactic Ablative Radiotherapy (SABR) to the involved node(s) alone. Ultra hypofractionated ENI is yet to be evaluated in this setting, but it could provide a therapeutic advantage if PCa has a low α/β ratio in addition to patient convenience/resource benefits. This volumetric modulated arc therapy (VMAT) planning study developed a class solution for 5-fraction Extended Nodal Irradiation (ENI) plus a simultaneous integrated boost (SIB) to involved node(s). Ten patients with oligorecurrent nodal disease after radical prostatectomy/post-operative prostate bed radiotherapy were selected. Three plans were produced for each dataset to deliver 25 Gy in 5 fractions ENI plus SIBs of 40, 35 and 30 Gy. The biologically effective dose (BED) formula was used to determine the remaining dose in 5 fractions that could be delivered to re-irradiated segments of organs at risk (OARs). Tumour control probability (TCP) and normal tissue complication probability (NTCP) were calculated using the LQ-Poisson Marsden and Lyman-Kutcher-Burman models respectively. Six patients had an OAR positioned within planning target volume node (PTVn), which resulted in reduced target coverage to PTV node in six, five and four instances for 40, 35 and 30 Gy SIB plans respectively. In these instances, only 30 Gy SIB plans had a median PTV coverage >90% (inter-quartile range 90-95). No OAR constraint was exceeded for 30 Gy SIB plans, including where segments of OARs were re-irradiated. Gross tumour volume node (GTVn) median TCP was 95.7% (94.4-96), 90.7% (87.1-91.2) and 78.6% (75.8-81.1) for 40, 35 and 30 Gy SIB plans respectively, where an α/β ratio of 1.5 was assumed. SacralPlex median NTCP was 43.2% (0.7-61.2), 12.1% (0.6-29.7) and 2.5% (0.5-5.1) for 40, 35 and 30 Gy SIB plans respectively. NTCP for Bowel_Small was <0.3% and zero for other OARs for all three plan types. Ultra hypofractionated ENI planning for pelvic nodal relapsed PCa appears feasible with encouraging estimates of nodal TCP and low estimates of NTCP, especially where a low α/β ratio is assumed and a 30 Gy SIB is delivered. This solution should be further evaluated within a clinical trial and compared against SABR to involved node(s) alone.

RBE-weighted dose conversions for patients with recurrent nasopharyngeal carcinoma receiving carbon-ion radiotherapy from the local effect model to the microdosimetric kinetic model

BackgroundWe sought to establish a conversion curve to convert the RBE-weighted doses calculated by local effect model I (LEM) (LEM RBE-weighted doses) in patients with locally recurrent nasopharyngeal carcinoma (rNPC) to the RBE-weighted doses calculated by microdosimetric kinetic model (MKM) (MKM RBE-weighted doses). We also converted the LEM dose constraints (RBE-weighted dose constraints in LEM plans) for the brain stem, spinal cord, and optic nerve based on this curve.MethodsData from 20 patients with rNPC receiving carbon-ion radiotherapy (CIRT) in our hospital were collected. LEM in Raystation (V8A, Raystation, Sweden) was used to generate treatment plans. The clinical target volume CTV1 (GTV + 5 mm) was given 3 Gy (RBE) per fraction. Ninety-nine percent of target volumes should be covered by 95% of the prescriptions; the maximum doses of the brainstem and spinal cord were < 45 Gy (RBE) and < 30 Gy (RBE), respectively. The doses covering 20% volumes of optical nerves/chiasms D20 were < 30 Gy (RBE). Then physical doses of the LEM plans were recalculated by using MKM in Raystation to generate MKM plans. A series of conversion factors (i.e., the ratio of LEM RBE-weighted dose to MKM RBE-weighted dose) was then obtained by using an isovolumetric dose method. The LEM plan prescriptions (LEM prescription) and dose constraints of the organs at risk (OARs) (OAR constraints) were converted to the corresponding MKM prescriptions and dose constraints using this conversion curve.ResultsFor the CTV1 fractional RBE-weighted dose prescription of 3.00 Gy (RBE) and CTV2 of 2.70 Gy (RBE) in LEM plans, the conversion factors (LEM RBE-weighted dose/MKM RBE-weighted dose) were 1.37 (CI 95% 1.35–1.39) and 1.46 (1.41–1.51), respectively. The average conversion factors from 1.37 (CI 95% 1.33–1.41) to 3.09 (2.94–3.24) corresponded to the LEM fractionated doses from 2.86 Gy (RBE) to 0.24 Gy (RBE), including the doses constraining upon OARs. LEM RBE-weighted doses of 30 Gy (RBE) and 45 Gy (RBE) in 21 fractions were converted to MKM RBE-weighted doses of 16.64 Gy (RBE) and 30.72 Gy (RBE) in 16 fractions.ConclusionsThis conversion curve could be used to convert LEM RBE-weighted doses to MKM RBE-weighted doses for patients with rNPC receiving CIRT, providing dose references for re-irradiation therapy.

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.

Initial Outcomes And Treatment-Associated Toxicities Using Stereotactic MRI-Guided Adaptive Radiation Therapy For Pancreatic Cancer Patients Treated At A Single Institution

High dose stereotactic body radiotherapy (SBRT) may offer improved outcomes for pancreatic cancer patients, but treatment delivery remains a challenge due to tumor proximity to organs-at-risk (OAR) and daily anatomic variability. Stereotactic MRI-guided adaptive radiation therapy (SMART) with real-time tumor tracking allows for improved dose delivery and OAR sparing by accounting for anatomic changes with each treatment. This study reports initial outcomes, treatment-associated toxicities, and dosimetric outcomes in locally advanced, metastatic, and/or recurrent pancreatic cancer patients treated using SMART. We performed a retrospective analysis of locally advanced, metastatic, and/or recurrent pancreatic cancer patients who underwent adaptive planning with MRI-guided radiation treatments. Charts were reviewed for follow-up, imaging, and laboratory values, including CA19-9 and absolute lymphocyte count. A plan was generated for each patient after initial CT and MR-simulation. At each treatment, MR imaging was obtained for the daily anatomy and the initial (unadapted) plan was compared to obtain a predicted dose to target volumes and OARs using a prescribed dose ranging from 30-50 Gy in 3-5 fractions. If constraints were not met or coverage was inadequate, an adaptive plan was generated based on the anatomy imaged on the day of treatment. From June 2018 to February 2020, a total of 23 patients were analyzed. With a median follow up of 5 months, we observed 15/19 (79%) with local control, 12/19 (63%) distal metastatic control, and a median overall survival of 19 months from cancer diagnosis. We observed no grade 3 or higher treatment related toxicities. Two patients were found to have an absolute lymphocyte count less than 0.5 x 103 cells/μl within six months of radiation, and 11/17 (65%) had lower CA19-9 six months after radiation treatment compared to before treatment. Of the 23 patients treated, there were 71 adaptive plans available for analysis. Compared to unadapted plans, adaptive fractions had improved coverage of PTV (84.94% vs. 73.36% at 100% of prescribed dose) and CTV (94.62% vs 88.08% at 95% of prescribed dose). Unadapted plans were more likely to exceed OAR constraints with 63 of 71 (89%) unadapted fractions predicted to violate prescribed duodenal, stomach, or small bowel constraints. Moreover, 34/71 (48%) of unadapted fractions violated constraints for 2 of 3 abdominal OARs and 10/71 (14%) violated constraints for all 3 compared to none for adapted fractions. Stereotactic adaptive MRI-guided radiotherapy demonstrated minimal treatment-related toxicities, enhanced tumor volume coverage, and improved adherence to OAR constraints in pancreatic cancer patients. Additional follow up is needed to further assess outcomes of these patients.

Dose-Volume and Radiobiological Model-Based Comparative Evaluation of the Gastrointestinal Toxicity Risk of Photon and Proton Irradiation Plans in Localized Pancreatic Cancer Without Distant Metastasis.

Background: Radiobiological model-based studies of photon-modulated radiotherapy for pancreatic cancer have reported reduced gastrointestinal (GI) toxicity, although the risk is still high. The purpose of this study was to investigate the potential of 3D-passive scattering proton beam therapy (3D-PSPBT) in limiting GI organ at risk (OAR) toxicity in localized pancreatic cancer based on dosimetric data and the normal tissue complication probability (NTCP) model.Methods: The data of 24 pancreatic cancer patients were retrospectively analyzed, and these patients were planned with intensity-modulated radiotherapy (IMRT), volume-modulated arc therapy (VMAT), and 3D-PSPBT. The tumor was targeted without elective nodal coverage. All generated plans consisted of a 50.4-GyE (Gray equivalent) dose in 28 fractions with equivalent OAR constraints, and they were normalized to cover 50% of the planning treatment volume (PTV) with 100% of the prescription dose. Physical dose distributions were evaluated. GI-OAR toxicity risk for different endpoints was estimated by using published NTCP Lyman–Kutcher–Burman (LKB) models. Analysis of variance (ANOVA) was performed to compare the dosimetric data, and ΔNTCPIMRT−PSPBT and ΔNTCPVMAT−PSPBT were also computed.Results: Similar homogeneity and conformity for the clinical target volume (CTV) and PTV were exhibited by all three planning techniques (P > 0.05). 3D-PSPBT resulted in a significant dose reduction for GI-OARs in both the low-intermediate dose range (below 30 GyE) and the highest dose region (Dmax and V50 GyE) in comparison with IMRT and VMAT (P < 0.05). Based on the NTCP evaluation, the NTCP reduction for GI-OARs by 3D-PSPBT was minimal in comparison with IMRT and VMAT.Conclusion: 3D-PSPBT results in minimal NTCP reduction and has less potential to substantially reduce the toxicity risk of upper GI bleeding, ulceration, obstruction, and perforation endpoints compared to IMRT and VMAT. 3D-PSPBT may have the potential to reduce acute dose-limiting toxicity in the form of nausea, vomiting, and diarrhea by reducing the GI-OAR treated volume in the low-to-intermediate dose range. However, this result needs to be further evaluated in future clinical studies.

Assessment of online adaptive MR-guided stereotactic body radiotherapy of liver cancers.

Online Adaptive Radiotherapy (ART) with daily MR-imaging has the potential to improve dosimetric accuracy by accounting for inter-fractional anatomical changes. This study provides an assessment for the feasibility and potential benefits of online adaptive MRI-Guided Stereotactic Body Radiotherapy (SBRT) for treatment of liver cancer. Ten patients with liver cancer treated with MR-Guided SBRT were included. Prescription doses ranged between 27 and 50Gy in 3-5 fx. All SBRT fractions employed daily MR-guided setup while utilizing cine-MR gating. Organs-at-risk (OARs) included duodenum, bowel, stomach, kidneys and spinal cord. Daily MRIs and contours were utilized to create each adapted plan. Adapted plans used the beam-parameters and optimization-objectives from the initial plan. Planning target volume (PTV) coverage and OAR constraints were used to compare non-adaptive and adaptive plans. PTV coverage for non-adapted treatment plans was below the prescribed coverage for 32/47 fractions (68%), with 11 fractions failing by more than 10%. All 47 adapted fractions met prescribed coverage. OAR constraint violations were also compared for several organs. The duodenum exceeded tolerance for 5/23 non-adapted and 0/23 for adapted fractions. The bowel exceeded tolerance for 5/34 non-adaptive and 1/34 adaptive fractions. The stomach exceeded tolerance for 4/19 non-adapted and 1/19 for adaptive fractions. Accumulated dose volume histograms were also generated for each patient. Online adaptive MR-Guided SBRT of liver cancer using daily re-optimization resulted in better target conformality, coverage and OAR sparing compared with non-adaptive SBRT. Daily adaptive planning may allow for PTV dose escalation without compromising OAR sparing.

Clinical Effectiveness of an Adaptive Treatment Planning Algorithm for Intensity Modulated Radiation Therapy Versus 3D Conformal Radiation Therapy for Node-Positive Breast Cancer Patients Undergoing Regional Nodal Irradiation/Postmastectomy Radiation Therapy

Clinical trials support adjuvant regional nodal irradiation (RNI) after breast-conserving surgery or mastectomy for patients with lymph node-positive breast cancer. Advanced treatment planning techniques (eg, intensity modulated radiation therapy [IMRT]) can reduce dose to organs at risk (OARs) in this situation. However, uncertainty persists about when IMRT is clinically indicated (vs 3-dimensional conformal radiation therapy [3DCRT]) for RNI. We hypothesized that an adaptive treatment planning algorithm (TPA) for IMRT adoption would allow OAR constraints for RNI to be met when 3DCRT could not without significantly changing toxicity and locoregional recurrence (LRR) patterns. Since 2013, all RNI patients also underwent an adaptive TPA that began with 3DCRT and then changed to IMRT when OAR constraints (mean heart dose ≤500 cGy; ipsilateral lung V20 ≤35%) could not be met. Patients received 2 Gy/d to the prospectively contoured target volumes (including internal mammary nodes). We retrospectively evaluated the dosimetry and clinical outcomes of the treatment groups (IMRT vs 3DCRT). The primary endpoint was the cumulative incidence of LRR as the site of first recurrence, and we specifically address patterns of failure based on dose to the posterior supraclavicular nodal region (SCL-post). Two hundred forty patients (60% stage III; mean 4.0 + nodes) underwent an adaptive-TPA for RNI after mastectomy (74%) or breast-conserving surgery (26%), resulting in 168 patients treated with 3DCRT and 72 patients treated with IMRT. There were 7 LRRs (2 IMRT, 5 3DCRT) resulting in 4-year LRR of 2.8% for IMRT versus 1.8% for 3DCRT (P = .99). Three patients (2 IMRT, 1 3DCRT) had SCL nodal failures (1 in the SCL-post). An adaptive TPA for use of IMRT when 3DCRT does not meet critical OAR constraints resulted in rare high-grade toxicity and no difference in failure patterns between patients treated with IMRT and 3DCRT. These data should provide reassurance that IMRT maintains the therapeutic ratio by preserving cancer control outcomes without excess toxicity when 3DCRT fails to meet OAR constraints.

Ablative Five-Fraction Stereotactic Body Radiation Therapy for Inoperable Pancreatic Cancer Using Online MR-Guided Adaptation

PurposePatients with inoperable pancreatic adenocarcinoma have limited options, with traditional chemoradiation providing modest clinical benefit and an otherwise poor prognosis. Stereotactic body radiation therapy for pancreatic cancer is limited by proximity to organs-at-risk (OAR). However, stereotactic magnetic resonance-guided adaptive radiation therapy (SMART) has shown promise in delivering ablative doses safely. We sought to demonstrate the benefits of SMART using a 5-fraction approach with daily on-table adaptation. Methods and MaterialsPatients with locally advanced, nonmetastatic pancreatic adenocarcinoma were treated with 50 Gy in 5 fractions (biologically effective dose10 100 Gy) with a prescribed goal of 95% planning target volume coverage by 95% of prescription, prioritizing hard OAR constraints. Daily online adaptation was performed using magnetic resonance-guidance and on-table reoptimization. Patient outcomes, treatment factors, and daily adaptation were evaluated. ResultsForty-four patients were treated with SMART at our institution from 2014 to 2019. Median follow-up from date of diagnosis was 16 months (range, 6.7-51.6). Late toxicity was limited to 2 (4.6%) grade 3 (gastrointestinal ulcers) and 3 (6.8%) grade 2 toxicities (duodenal perforation, antral ulcer, and gastric bleed). Tumor abutted OARs in 35 patients (79.5%) and tumor invaded OARs in 5 patients (11.1%). Reoptimization was performed for 93% of all fractions. Median overall survival was 15.7 months (95% confidence interval, 10.2-21.2), while 1-year and 2-year overall survival rates were 68.2% and 37.9%, respectively. One-year local control was 84.3%. ConclusionsThis is the first reported experience using 50 Gy in 5 fractions for inoperable pancreatic cancer. SMART allows this ablative dose with promising outcomes while minimizing toxicity. Additional prospective trials evaluating efficacy and safety are warranted.

Can polymetastatic disease be arrested using SABR? A dosimetric analysis to inform development of a phase I trial.

e21567 Background: Phase II randomized trials suggest that stereotactic ablative radiotherapy (SABR) improves progression-free and overall survival in patients with oligometastatic cancer, with phase III trials currently testing SABR in up to 10 metastases. Whether SABR could provide similar benefits in polymetastatic disease ( &gt; 10 metastases) is unknown. A critical first step is to determine the feasibility of planning SABR for a large number of metastases throughout the body while maintaining acceptable organ at risk (OAR) doses. Therefore, we sought to evaluate the dosimetric feasibility of using SABR in polymetastatic disease ( &gt; 10 sites) while adhering to OAR constraints to be used in a phase I trial (ARREST). Methods: Five craniospinal CT simulations were utilized to retrospectively contour 24 (n = 2), 30 (n = 2) and 50 (n = 1) tumour targets not present on the initial scan. Standard PTV margins were added based on institutional immobilization practices. OAR constraints from published clinical trial protocols were used. Radiotherapy plans for the highest dose level in our planned phase I trial (30Gy in 5 fractions) were created utilizing a minimum number of isocentres. Plans were created using Raystation (RaySearch Laboratories, Stockholm, Sweden) for delivery on linear accelerators using volumetric modulated arc therapy. Results: The gross tumour volumes (GTVs) ranged from 134.8– 184.2cm3 in our five test cases. The first two cases with 24 GTVs have been planned and were deemed to be clinically acceptable. PTV volumes were 483.0cm3 and 417.4cm3, utilizing five and six isocentres for treatment respectively. Median PTV D95 was 29.7Gy and 29.0Gy, whole body V10 was 21.2% and 17.4%, and V5 was 41.8% and 44.8%. All OAR goals were met, though low-dose conformality was less than traditional SABR treatment plans (R100 of 1.04 and 0.93; R50 of 9.90 and 6.98, respectively). The remainder of the test cases will be presented. Conclusions: In our test cases, planning SABR in polymetastatic disease appears dosimetrically feasible. Our phase I clinical trial (ARREST) is under development, which will evaluate the feasibility and toxicity of delivering SABR in polymetastatic disease in a 3+3 dose escalation study. The starting dose level will be 12Gy in 2 weekly fractions, escalating the dose by adding 6Gy weekly until our target dose of 30Gy in 5 weekly fractions. Our study population will include &gt; 10 sites of disease, all tumour types, and patients must have exhausted standard lines of systemic therapy.

Technical Note: A step-by-step guide to Temporally Feathered Radiation Therapy planning for head and neck cancer.

PurposePrior in silico simulations propose that Temporally Feathered Radiation Therapy (TFRT) may reduce toxicity related to head and neck radiation therapy. In this study we demonstrate a step‐by‐step guide to TFRT planning with modern treatment planning systems.MethodsOne patient with oropharyngeal cancer planned for definitive radiation therapy using intensity‐modulated radiation therapy (IMRT) techniques was replanned using the TFRT technique. Five organs at risk (OAR) were identified to be feathered. A “base plan” was first created based on desired planning target volumes (PTV) coverage, plan conformality, and OAR constraints. The base plan was then re‐optimized by modifying planning objectives, to generate five subplans. All beams from each subplan were imported onto one trial to create the composite TFRT plan. The composite TFRT plan was directly compared with the non‐TFRT IMRT plan. During plan assessment, the composite TFRT was first evaluated followed by each subplan to meet preset compliance criteria.ResultsThe following organs were feathered: oral cavity, right submandibular gland, left submandibular gland, supraglottis, and OAR Pharynx. Prescription dose PTV coverage (>95%) was met in each subplan and the composite TFRT plan. Expected small variations in dose were observed among the plans. The percent variation between the high fractional dose and average low fractional dose was 29%, 28%, 24%, 19%, and 10% for the oral cavity, right submandibular, left submandibular, supraglottis, and OAR pharynx nonoverlapping with the PTV.ConclusionsTemporally Feathered Radiation Therapy planning is possible with modern treatment planning systems. Modest dosimetric changes are observed with TFRT planning compared with non‐TFRT IMRT planning. We await the results of the current prospective trial to seeking to demonstrate the feasibility of TFRT in the modern clinical workflow (NCT03768856). Further studies will be required to demonstrate the potential benefit of TFRT over non‐TFRT IMRT Planning.

The addition of interstitial needles to intracavitary applicators in the treatment of locally advanced cervical cancer: Why is this important and how to implement in low- and middle-income countries?

PurposeCervical cancer is the leading cause of cancer mortality of women in low-/middle-income countries. Interstitial needles improve outcomes but require resources beyond those available in endemic regions. We conducted a retrospective review of the use of interstitial needles in locally advanced cervical cancer and simulated both 3D planning without needles and 2D planning to explore the benefit of interstitial needles. Methods and Materials57 brachytherapy plans of 17 patients who had intracavitary tandem and ring plus interstitial brachytherapy were reviewed. Prescribed dose was 7 Gy × four fractions. 2D plans prescribed to point A were generated to represent a standard Manchester loading. Dosimetric outcomes to clinical target volume and organs at risk (OARs) were compared with those of 3D-based plans. ResultsHigh-risk clinical target volume coverage was excellent: 93.2% for 2D plans, 93.9% for 3D plans without needles, and 96.2% for 3D with needles. The mean dose to 90% of target was 8.5 Gy/fraction for 2D plans, 7.5 for 3D without needles, and 7.9 Gy/fraction for 3D with needles. However, the 2D plans delivered 12% above recommended dose constraints for OARs (except rectum). Dosimetric differences were found between 3D planning and 3D with needles for target coverage (p = 0.002). Dose to OARs was significantly lower when 3D plans with needles were compared with 2D plans. ConclusionsInterstitial needles provide an optimal therapeutic ratio for patients with high-volume disease or/and unfavorable topography. This justifies additional capital investment in resources for implementation to provide optimal treatment for locally advanced cervical cancer globally.

Outcomes of stereotactic body radiotherapy 60\u2009Gy in 8 fractions when prioritizing organs at risk for central and ultracentral lung tumors

BackgroundFor stereotactic body radiotherapy (SBRT) to central (C) and ultracentral (UC) lung tumors, our provincial practice has been to prioritize organs at risk (OARs) constraints by compromising target volume coverage if needed. The objectives are to report the treatment’s efficacy and safety.MethodsWe conducted a retrospective analysis of all provincial patients who underwent SBRT at 60Gy in 8 fractions to C and UC lung tumors, from 2013 to 2017.ResultsNinety-eight lesions were treated, 57 (58.2%) C and 41 (41.8%) UC. The median follow-up was 22.9 months (range 2.5–64.8 months). The 1- and 3-year local control (LC) was 97.8 and 84.5% respectively, with no differences between C and UC groups (p = 0.662). Fifty-three (54.1%) cases had optimal dose coverage (V60Gy ITV&PTV > 95%), 29 (29.6%) had compromised PTV coverage (V60Gy ITV > 95%/PTV < 95%), and 16 (16.3%) had both compromised ITV and PTV coverage (V60Gy ITV&PTV < 95%). No significant difference in LC was detected at 2 years between the 3 groups (95.6, 91.8 and 90.9%, p = 0.717). There were 3 episodes of grade 3 toxicity in the C group (2 dyspnea, 1 pneumonitis) and 2 in the UC group (1 dyspnea, 1 hemoptysis). There were no gr4/5 toxicities. On multivariable Cox regression analysis, ITV size was found to be a predictor for LC (p = 0.001).ConclusionsSBRT at 60Gy in 8 fractions achieves high rates of LC with low risks of significant toxicities, even if target volume coverage is reduced to meet OARs constraints.

A planning study of focal dose escalations to multiparametric MRI-defined dominant intraprostatic lesions in prostate proton radiation therapy.

The purpose of this study is to investigate the dosimetric effect and clinical impact of delivering a focal radiotherapy boost dose to multiparametric MRI (mp-MRI)-defined dominant intraprostatic lesions (DILs) in prostate cancer using proton therapy. We retrospectively investigated 36 patients with pre-treatment mp-MRI and CT images who were treated using pencil beam scanning (PBS) proton radiation therapy to the whole prostate. DILs were contoured on co-registered mp-MRIs. Simultaneous integrated boost (SIB) plans using intensity-modulated proton therapy (IMPT) were created based on conventional whole-prostate-irradiation for each patient and optimized with additional DIL coverage goals and urethral constraints. DIL dose coverage and organ-at-risk (OAR) sparing were compared between conventional and SIB plans. Tumor control probability (TCP) and normal tissue complication probability (NTCP) were estimated to evaluate the clinical impact of the SIB plans. Optimized SIB plans significantly escalated the dose to DILs while meeting OAR constraints. SIB plans were able to achieve 125, 150 and 175% of prescription dose coverage in 74, 54 and 17% of 36 patients, respectively. This was modeled to result in an increase in DIL TCP by 7.3-13.3% depending on and DIL risk level. The proposed mp-MRI-guided DIL boost using proton radiation therapy is feasible without violating OAR constraints and demonstrates a potential clinical benefit by improving DIL TCP. This retrospective study suggested the use of IMPT-based DIL SIB may represent a strategy to improve tumor control. This study investigated the planning of mp-MRI-guided DIL boost in prostate proton radiation therapy and estimated its clinical impact with respect to TCP and NTCP.

Quantification of plan robustness against different uncertainty sources for classical and anatomical robust optimized treatment plans in head and neck cancer proton therapy.

Classical robust optimization (cRO) in intensity-modulated proton therapy (IMPT) considers isocenter position and particle range uncertainties; anatomical robust optimization (aRO) aims to consider additional non-rigid positioning variations. This work compares the influence of different uncertainty sources on the robustness of cRO and aRO IMPT plans for head and neck squamous cell carcinoma (HNSCC). Two IMPT plans were optimized for 20 HNSCC patients who received weekly control CTs (cCT): cRO, using solely the planning CT, and aRO, including 2 additional cCTs. The robustness of the plans in terms of clinical target volume (CTV) coverage and organ at risk (OAR) sparing was analyzed considering stepwise the influence of (1) non-rigid anatomical variations given by the weekly cCT, (2) with fraction-wise added rigid random setup errors and (3) additional systematic proton range uncertainties. cRO plans presented significantly higher nominal CTV coverage but are outperformed by aRO plans when considering non-rigid anatomical variations only, as cRO and aRO plans presented a median target coverage (D98%) decrease for the low-risk/high-risk CTV of 1.8/1.1 percentage points (pp) and -0.2 pp/-0.3 pp, respectively. Setup and range uncertainties had larger influence on cRO CTV coverage, but led to similar OAR dose changes in both plans. Considering all error sources, 10/2 cRO/aRO patients missed the CTV coverage and a limited number exceeded some OAR constraints in both plans. Non-rigid anatomical variations are mainly responsible for critical target coverage loss of cRO plans, whereas the aRO approach was robust against such variations. Both plans provide similar robustness of OAR parameters. The influence of different uncertainty sources was quantified for robust IMPT HNSCC plans.

Initial Dosimetric Outcomes and Treatment Related Toxicities Using Stereotactic MRI-Guided Radiation Therapy (SMART) for Unresectable Pancreatic Cancer at a Single Institution

High dose stereotactic body radiotherapy (SBRT) may offer improved disease outcomes for locally advanced pancreatic cancer but treatment delivery remains a challenge due to tumor proximity to organs-at-risk (OAR) and daily, anatomic variability. Stereotactic MRI-guided adaptive radiation therapy (SMART) with real-time tumor tracking allows for improved dose delivery to disease targets and OAR sparing by accounting for anatomic changes with each treatment. This study reports initial dosimetric outcomes and treatment related toxicities in unresectable pancreatic cancer patients treated using SMART. Ten patients with unresectable, locally advanced pancreatic cancer were treated on a MR-guided linear accelerator using real-time tumor tracking and motion management. A plan was generated for each patient after initial CT and MR-simulation. At each treatment, MR imaging was obtained for the daily anatomy and the initial (unadapted) plan was compared to obtain a predicted dose coverage of tumor volumes and OAR constraints using a prescribed dose of 50 Gy in 5 fractions. If OAR constraints were not met or PTV coverage was inadequate, an adaptive plan was generated based on the anatomy imaged on the day of treatment. Goal PTV coverage was 95% of the volume at 100% of prescription dose, however, this was subject to hard OAR constraints and plans were optimized for best PTV coverage within an acceptable OAR dose. For each adaptive plan generated, the delivered dose for that fraction was compared to the predicted dose from the initial plan. Only toxicities grade 3 or higher were considered for inclusion. At time of analysis, from June 2018 to February 2019, a total of 46 fractions were delivered to ten patients. Of the 46 treatments, 5 were with the initial, unadapted plan and 41 were adaptive. Due to intra-fraction adjustments that occurred during 6 treatments, only 35 adaptive plans were included for analysis. When comparing the performance of the initial plan on the daily updated MR anatomy, adaptive planning led to improved coverage of both PTV (86.36% vs. 73.15% at 100% of prescribed dose) and CTV (95.97% vs 89.59% at 95% of prescribed dose). Unadapted plans were much more likely to exceed OAR constraints, with 27 of 35 (77%) unadapted fractions predicted to violate prescribed duodenal, stomach, or small bowel constraints compared to 2 of 35 (6%) of adapted fractions. Moreover, 16/35 (46%) of unadapted fractions violated constraints for 2 of 3 abdominal OARs and 5/35 (14%) violated constraints for all 3 compared to none for adapted fractions. No grade 3 toxicities were reported in any of the treated patients. Stereotactic adaptive MRI-guided radiotherapy led to improved tumor volume coverage and reduced dose to abdominal OARs in patients with locally advanced pancreatic cancer with no grade 3 or higher toxicities. Prospective studies examining disease outcomes and treatment related toxicities are ongoing.

The impact of proton LET/RBE modeling and robustness analysis on base-of-skull and pediatric craniopharyngioma proton plans relative to VMAT

Purpose: Pediatric craniopharyngioma, adult base-of-skull sarcoma and chordoma cases are all regarded as priority candidates for proton therapy. In this study, a dosimetric comparison between volumetric modulated arc therapy (VMAT) and intensity modulated proton therapy (IMPT) was first performed. We then investigated the impact of physical and biological uncertainties. We assessed whether IMPT plans remained dosimetrically superior when such uncertainty estimates were considered, especially with regards to sparing organs at risk (OARs).Methodology: We studied 10 cases: four chondrosarcoma, two chordoma and four pediatric craniopharyngioma. VMAT and IMPT plans were created according to modality-specific protocols. For IMPT, we considered (i) variable RBE modeling using the McNamara model for different values of (α/β)x, and (ii) robustness analysis with ±3 mm set-up and 3.5% range uncertainties.Results: When comparing the VMAT and IMPT plans, the dosimetric advantages of IMPT were clear: IMPT led to reduced integral dose and, typically, improved CTV coverage given our OAR constraints. When physical robustness analysis was performed for IMPT, some uncertainty scenarios worsened the CTV coverage but not usually beyond that achieved by VMAT. Certain scenarios caused OAR constraints to be exceeded, particularly for the brainstem and optical chiasm. However, variable RBE modeling predicted even more substantial hotspots, especially for low values of (α/β)x. Variable RBE modeling often prompted dose constraints to be exceeded for critical structures.Conclusion: For base-of-skull and pediatric craniopharyngioma cases, both physical and biological robustness analyses should be considered for IMPT: these analyses can substantially affect the sparing of OARs and comparisons against VMAT. All proton RBE modeling is subject to high levels of uncertainty, but the clinical community should remain cognizant possible RBE effects. Careful clinical and imaging follow-up, plus further research on end-of-range RBE mitigation strategies such as LET optimization, should be prioritized for these cohorts of proton patients.

Individualized Dose-Escalation of HDR Prostate Brachytherapy Implant to Decrease Required External Beam Radiation Dose: A Retrospective Feasibility Study

PurposeHigh-dose-rate brachytherapy (HDR-BT) is commonly combined with external beam radiation therapy (EBRT) for the treatment of localized prostate cancer. Escalating the HDR-BT dose as far as organ-at-risk (OAR) constraints allow, on a personalized basis, would allow for a reduction in EBRT dose while achieving similar total biologic equivalence. The primary objective of this study was to determine the dosimetric feasibility of escalating the HDR-BT dose from 15 Gy to 16 or 17 Gy while continuing to meet OAR constraints from the original 15 Gy plan on an individualized basis. Methods and materialsA total of 53 consecutive HDR-BT plans were retrospectively assessed to determine what percentage of plans could be reoptimized to deliver a dose of 16 Gy or 17 Gy, while meeting defined 15-Gy OAR constraints. Factors independently associated with dose escalation were examined. ResultsThirty-nine plans (74%) and 2 plans (4%) were successfully escalated to a dose of 16 Gy and 17 Gy, respectively. Rectum V80 and urethra Dmax were independently predictive of the ability to dose escalate to 16 Gy. ConclusionsIndividualized HDR-BT dose escalation beyond 15 Gy without compromising OAR constraints is dosimetrically feasible. This approach could allow for a corresponding reduction of EBRT fractions (ie, from 15 to 12 fractions) and would be beneficial in terms of resource savings for departments, convenience for patients, and potentially better tolerance of treatment with the expected reduction in biologically equivalent doses to OARs. A clinical trial is being developed to investigate the efficacy and tolerance of personalized HDR-BT/EBRT dose fractionation for localized intracapsular prostate cancer.