Wide-Scale Clinical Implementation of Knowledge-Based Planning: An Investigation of Workforce Efficiency, Need for Post-automation Refinement, and Data-Driven Model Maintenance.

PURPOSE: Our purpose was to investigate the effect of automated knowledge-based planning (KBP) on real-world clinical workflow efficiency, assess whether manual refinement of KBP plans improves plan quality across multiple disease sites, and develop a data-driven method to periodically improve KBP automated planning routines. METHODS AND MATERIALS: Using clinical knowledge-based automated planning routines for prostate, prostatic fossa, head and neck, and hypofractionated lung disease sites in a commercial KBP solution, workflow efficiency was compared in terms of planning time in a pre-KBP (n = 145 plans) and post-KBP (n = 503) patient cohort. Post-KBP, planning was initialized with KBP (KBP-only) and subsequently manually refined (KBP +human). Differences in planning time were tested for significance using a 2-tailed Mann-Whitney U test (P < .05, null hypothesis: planning time unchanged). Post-refinement plan quality was assessed using site-specific dosimetric parameters of the original KBP-only plan versus KBP +human; 2-tailed paired t test quantified statistical significance (Bonferroni-corrected P < .05, null hypothesis: no dosimetric difference after refinement). If KBP +human significantly improved plans across the cohort, optimization objectives were changed to create an updated KBP routine (KBP'). Patients were replanned with KBP' and plan quality was compared with KBP +human as described previously. RESULTS: KBP significantly reduced planning time in all disease sites: prostate (median: 7.6 hrs â†’ 2.1 hrs; P < .001), prostatic fossa (11.1 hrs â†’ 3.7 hrs; P = .001), lung (9.9 hrs â†’ 2.0 hrs; P < .001), and head and neck (12.9 hrs â†’ 3.5 hrs; P <.001). In prostate, prostatic fossa, and lung disease sites, organ-at-risk dose changes in KBP +human versus KBP-only were minimal (<1% prescription dose). In head and neck, KBP +human did achieve clinically relevant dose reductions in some parameters. The head and neck routine was updated (KBP'HN) to incorporate dose improvements from manual refinement. The only significant dosimetric differences to KBP +human after replanning with KBP'HN were in favor of the new routine. CONCLUSIONS: KBP increased clinical efficiency by significantly reducing planning time. On average, human refinement offered minimal dose improvements over KBP-only plans. In the single disease site where KBP +human was superior to KBP-only, differences were eliminated by adjusting optimization parameters in a revised KBP routine.

Radiation Recall Pneumonitis After Treatment With Checkpoint Blockade Immunotherapy: A Case Series and Review of Literature.

BACKGROUND: Radiation recall pneumonitis (RRP) is a poorly understood clinical syndrome in which patients develop radiation pneumonitis triggered by a systemic agent, often years after the completion of radiation therapy. Immune checkpoint blockade agents have only recently been posited as a trigger for RRP. Here, we present three cases of immunotherapy-induced RRP. CASE PRESENTATION: Our first patient was diagnosed with primary lung adenocarcinoma, and 4.5 years after completing radiation therapy developed symptomatic RRP immediately following a second dose of nivolumab-containing immunotherapy regimen. Our second patient was diagnosed with primary bladder cancer metastatic to the mediastinum, which was treated twice with radiation therapy. He developed RRP in the days following his second course of ipilimumab-pembrolizumab which was months after his second course of radiation that he received. Our final patient was diagnosed with metastatic small cell lung cancer and received local consolidative radiation therapy in addition to whole-brain radiation. He developed RRP on the 11th day after concluding his 4th cycle of nivolumab-ipilimumab, approximately 7 months after having had completed chest radiation therapy. CONCLUSIONS: Immunotherapy-induced RRP is a rare diagnosis which can present more focally than traditional immunotherapy pneumonitis and which must be clinically differentiated from other local processes such as pneumonia. Further research should explore the mechanisms underlying these radiation recall reactions as many patients receive radiation and immunotherapy during the course of their cancer treatment.

Automated contouring and planning pipeline for hippocampal-avoidant whole-brain radiotherapy.

BACKGROUND: Whole-brain radiotherapy (WBRT) remains an important treatment for over 200,000 cancer patients in the United States annually. Hippocampal-avoidant WBRT (HA-WBRT) reduces neurocognitive toxicity compared to standard WBRT, but HA-WBRT contouring and planning are more complex and time-consuming than standard WBRT. We designed and evaluated a workflow using commercially available artificial intelligence tools for automated hippocampal segmentation and treatment planning to efficiently generate clinically acceptable HA-WBRT radiotherapy plans. METHODS: We retrospectively identified 100 consecutive adult patients treated for brain metastases outside the hippocampal region. Each patient's T1 post-contrast brain MRI was processed using NeuroQuant, an FDA-approved software that provides segmentations of brain structures in less than 8 min. Automated hippocampal segmentations were reviewed for accuracy, then converted to files compatible with a commercial treatment planning system, where hippocampal avoidance regions and planning target volumes (PTV) were generated. Other organs-at-risk (OARs) were previously contoured per clinical routine. A RapidPlan knowledge-based planning routine was applied for a prescription of 30 Gy in 10 fractions using volumetric modulated arc therapy (VMAT) delivery. Plans were evaluated based on NRG CC001 dose-volume objectives (Brown et al. in J Clin Oncol, 2020). RESULTS: Of the 100 cases, 99 (99%) had acceptable automated hippocampi segmentations without manual intervention. Knowledge-based planning was applied to all cases; the median processing time was 9 min 59 s (range 6:53-13:31). All plans met per-protocol dose-volume objectives for PTV per the NRG CC001 protocol. For comparison, only 65.5% of plans on NRG CC001 met PTV goals per protocol, with 26.1% within acceptable variation. In this study, 43 plans (43%) met OAR constraints, and the remaining 57 (57%) were within acceptable variation, compared to 42.5% and 48.3% on NRG CC001, respectively. No plans in this study had unacceptable dose to OARs, compared to 0.8% of manually generated plans from NRG CC001. 8.4% of plans from NRG CC001 were not scored or unable to be evaluated. CONCLUSIONS: An automated pipeline harnessing the efficiency of commercially available artificial intelligence tools can generate clinically acceptable VMAT HA-WBRT plans with minimal manual intervention. This process could improve clinical efficiency for a treatment established to improve patient outcomes over standard WBRT.

Framework for Evaluation of Automated Knowledge-Based Planning Systems Using Multiple Publicly Available Prostate Routines.

PURPOSE: To establish a framework for the evaluation of knowledge-based planning routines that empowers new adopters to select systems that best match their clinical priorities. We demonstrate the power of this framework using 4 publicly available prostate routines. METHODS AND MATERIALS: Four publicly available prostate routines (CCMB, Miami, UCSD, WUSTL) were automatically applied across a 25-patient cohort using Eclipse scripting and a PTV prescription of V81 Gy = 95%. The institutions' routines differed in contouring guidelines for planning target volume (PTV) and organs at risk, beam arrangements, and optimization parameters. Model-estimated dose-volume histograms (DVHs) and deliverable postoptimization DVHs were extracted from plans to calculate average DVHs for each routine. Each routine's average calculated DVH was subtracted from the average DVH for all plans and from the model's average predicted DVH for comparison. DVH metrics for PTV (DMAX, D1%, D99%, DMIN), Rectum (DMAX, V70, V60, V40), Bladder (V75, V40), Femur (DMAX), and PenileBulb (DMEAN) were compared with the average using 2-sided paired t tests (Bonferroni-corrected P < .05). To control for contouring effects, the full analysis was conducted for 2 PTV margin schemas: 5 mm uniform and 3 mm or 7 mm posterior/else. RESULTS: Calculated plans generally aligned with their routine's DVH estimations, except CCMB organ-at-risk Dmaxes. Dosimetric parameter differences were not significant, with the exception of PTV DMAX (Miami = 111.1% [P < .001]), PTV D99% (Miami = 97.4% [P = .05]; UCSD = 97.4% [P = .03]; CCMB = 98.5% [P = .001]), Rectum V40 (Miami = 19.1% [P < .001]; UCSD = 22.7% [P = .003]; CCMB = 53.5% [P < .001]), and Femur DMAX (WUSTL = 48.6% [P = .001.]; CCMB = 37.9% [P < .001]). Overall, UCSD and Miami had lower rectum doses, and CCMB and WUSTL had higher PTV homogeneity. Conclusions were unchanged with different PTV margin schemas. CONCLUSIONS: Using publicly available knowledge-based planning routines spares clinicians substantial effort in developing new models. Our results allow clinicians to select the prostate routine that matches their clinical priorities, and our methodology sets the precedent for comparing routines for different treatment sites.

Noninferiority Study of Automated Knowledge-Based Planning Versus Human-Driven Optimization Across Multiple Disease Sites.

PURPOSE: To evaluate whether automated knowledge-based planning (KBP) (a) is noninferior to human-driven planning across multiple disease sites and (b) systematically affects dosimetric plan quality and variability. METHODS AND MATERIALS: Clinical KBP automated planning routines were developed for prostate, prostatic fossa, hypofractionated lung, and head and neck. Clinical implementation consisted of independent generation of human-generated and KBP plans (145 cases across all sites), followed by blinded plan selection. Reviewing physicians were prompted to select a single plan; when plan equivalence was volunteered, this scored as KBP selection. Plan selection analysis used a noninferiority framework testing the hypothesis that KBP is not worse than human-driven planning (threshold: lower 95% confidence interval [CI] > 0.45 = noninferiority; > 0.5 = superiority). Target and organ-at-risk metrics were compared by dose differencing: ΔDx = Dx, human-Dx, KBP (2-tailed paired t test, Bonferroni-corrected P < .05 significance threshold). To evaluate the aggregated effect of KBP on planning performance, we examined post-KBP dosimetric parameters against 183 plans generated just before KBP implementation (2-tailed unpaired t test, Bonferroni-corrected P < .05). RESULTS: Across all disease sites, the KBP success rate (physician preferred + equivalent) was noninferior compared with human-driven planning (83 of 145 = 57.2%; range, 49.2%-65.3%) but did not cross the threshold for superiority. The KBP success rate in respective disease sites was superior with head and neck ([22 + 2]/36 = 66.7%; 95% CI, 51%-82%) and noninferior for lung stereotactic body radiation therapy ([21 + 2]/36 = 63.9%; 95% CI, 48%-80%) but did not meet noninferiority criteria with prostate ([16 + 3]/41 = 46.3%; 95% CI, 31%-62%) or prostatic fossa ([17 + 0]/32 = 53.1%; 95% CI, 36%-70%). Prostate, prostatic fossa, and head and neck showed significant differences in KBP-selected plans versus human-selected plans, with KBP generally exhibiting greater organ-at-risk sparing and human plans exhibiting better target homogeneity. Analysis of plan quality pre- and post-KBP showed some reductions in organ doses and quality metric variability in prostate and head and neck. CONCLUSIONS: Fully automated KBP was noninferior to human-driven plan optimization across multiple disease sites. Dosimetric analysis of treatment plans before and after KBP implementation showed a systematic shift to higher plan quality and lower variability with the introduction of KBP.

An in vitro study for the dosimetric and radiobiological validation of respiratory gating in conventional and hypofractionated radiotherapy of the lung: effect of dose, dose rate, and breathing pattern.

Stereotactic body radiotherapy (SBRT) of the lung has become a standard of care for early-stage inoperable non-small cell lung cancer (NSCLC). A common strategy to manage respiratory motion is gating, which inevitably results in an increase in treatment time, especially in irregularly-breathing patients. Flattening-filter free (FFF) beams allow for delivery of the treatment at a higher dose rate, therefore counteracting the lengthened treatment time due to frequent interruption of the beam during gated radiotherapy. In this study, we perform our in vitro evaluation of the dosimetric and radiobiological effect of gated lung SBRT with simultaneous integrated boost (SIB) using both flattened and FFF beams. A moving thorax-shaped phantom with inserts and applicators was used for simulation, planning, gated treatment delivery measurements and in vitro tests. The effects of gating window, dose rate, and breathing pattern were evaluated. Planned doses represented a typical conventional fractionation, 200 cGy per fraction with SIB to 240 cGy, flattened beam only, and SBRT, 800 cGy with SIB to 900 cGy, flattened and FFF beams. Ideal, as well as regular and irregular patient-specific breathing patterns with and without gating were used. A survival assay for lung adenocarcinoma A549 cell line was performed. Delivered dose was within 6% for locations planned to receive 200 and 800 cGy and within 4% for SIB locations. Time between first beam-on and last beam-off varied from approximately 1.5 min for conventional fractionation, 200/240 cGy, to 10.5 min for gated SBRT, 800/900 cGy doses, flattened beam and irregular breathing motion pattern. With FFF beams dose delivery time was shorter by a factor of 2-3, depending on the gating window and breathing pattern. We have found that, for the most part, survival depended on dose and not on dose rate, gating window, or breathing regularity.

Automated Closed- and Open-Loop Validation of Knowledge-Based Planning Routines Across Multiple Disease Sites.

PURPOSE: Knowledge-based planning (KBP) clinical implementation necessitates significant upfront effort, even within a single disease site. The purpose of this study was to demonstrate an efficient method for clinicians to assess the noninferiority of KBP across multiple disease sites and estimate any systematic dosimetric differences after implementation. We sought to establish these endpoints in a plurality of previously treated patients (validation set) with both closed-loop (training set overlapping validation set) and open-loop (independent training set) KBP routines. METHODS AND MATERIALS: We identified 53 prostate, 24 prostatic fossa, 54 hypofractionated lung, and 52 head and neck patients treated with volumetric modulated arc therapy in the year directly preceding our clinic's broad adoption of RapidPlan (Varian Medical Systems, Palo Alto, CA). Using the Varian Eclipse Scripting API, our program takes as input a list of patients, then performs semiautomated structure matching, fully automated RapidPlan-driven optimization, and plan comparison. All plans were normalized to the planning target volume (PTV) D95% = 100%. Dose metric differences (ΔDx = Dx,clinical - Dx,KBP) were computed for standard PTV and organ-at-risk (OAR) dose-volume histogram parameters across disease sites. A 2-tailed paired t test quantified statistical significance (P < .001). RESULTS: Statistically significant organ dose-volume histogram improvements were observed in the KBP cohort: the rectum, bladder, and penile bulb in prostate/prostatic fossa; and the larynx, esophagus, cricopharyngeus, parotid glands, and cochlea in head and neck. No OAR dose metric was statistically worse in any KBP sample. PTV ΔD1% increases in prostatic fossa were deemed acceptable given organ-sparing gains. PTV ΔD1% and internal target volume ΔD99% increase for the lung was by design owing to the prescription normalization variance in the pre-KBP lung sample. CONCLUSIONS: Our automated method showed multiple disease sites' KBP routines to be noninferior to manual planning, with statistically significant superiority in some aspects of OAR sparing. This method is applicable to any institution implementing either closed-loop or open-loop KBP autoplanning routines.

A novel 3D-printed phantom insert for 4D PET/CT imaging and simultaneous integrated boost radiotherapy.

PURPOSE: To construct a 3D-printed phantom insert designed to mimic the variable PET tracer uptake seen in lung tumor volumes and a matching dosimetric insert to be used in simultaneous integrated boost (SIB) phantom studies, and to evaluate the design through end-to-end tests. METHODS: A set of phantom inserts was designed and manufactured for a realistic representation of gated radiotherapy steps from 4D PET/CT scanning to dose delivery. A cylindrical phantom (φ80 × 120 mm) holds inserts for PET/CT scanning. The novel 3D printed insert dedicated to 4D PET/CT mimics high PET tracer uptake in the core and low uptake in the periphery. This insert is a variable density porous cylinder (φ44.5 × 70.0 mm), ABS-P430 thermoplastic, 3D printed by fused deposition modeling an inner (φ11 × 42 mm) cylindrical void. The square pores (1.8 × 1.8 mm2 each) fill 50% of outer volume, resulting in a 2:1 PET tracer concentration ratio in the void volume with respect to porous volume. A matching cylindrical phantom insert is dedicated to validate gated radiotherapy. It contains eight peripheral holes and one central hole, matching the location of the porous part and the void part of the 3D printed insert, respectively. These holes accommodate adaptors for Farmer-type ion chamber and cells vials. End-to-end tests were designed for imaging, planning, and dose measurements. RESULTS: End-to-end test were performed from 4D PET/CT scanning to transferring data to the planning system, target volume delineation, and dose measurements. 4D PET/CT scans were acquired of the phantom at different respiratory motion patterns and gating windows. A measured 2:1 18F-FDG concentration ratio between inner void and outer porous volume matched the 3D printed design. Measured dose in the dosimetric insert agreed well with planned dose on the imaging insert, within 3% for the static phantom and within 5% for most breathing patterns. CONCLUSIONS: The novel 3D printed phantom insert mimics variable PET tracer uptake typical of tumors. Obtained 4D PET/CT scans are suitable for segmentation and treatment planning and delivery in SIB gated treatments. Our experiments demonstrate the feasibility of this set of phantom inserts serving as end-to-end quality-assurance phantoms of SIB radiotherapy.

Prospective study of functional bone marrow-sparing intensity modulated radiation therapy with concurrent chemotherapy for pelvic malignancies.

PURPOSE: To test the hypothesis that intensity modulated radiation therapy (IMRT) can reduce radiation dose to functional bone marrow (BM) in patients with pelvic malignancies (phase IA) and estimate the clinical feasibility and acute toxicity associated with this technique (phase IB). METHODS AND MATERIALS: We enrolled 31 subjects (19 with gynecologic cancer and 12 with anal cancer) in an institutional review board-approved prospective trial (6 in the pilot study, 10 in phase IA, and 15 in phase IB). The mean age was 52 years; 8 of 31 patients (26%) were men. Twenty-one subjects completed (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) simulation and magnetic resonance imaging by use of quantitative IDEAL (IDEAL IQ; GE Healthcare, Waukesha, WI). The PET/CT and IDEAL IQ were registered, and BM subvolumes were segmented above the mean standardized uptake value and below the mean fat fraction within the pelvis and lumbar spine; their intersection was designated as functional BM for IMRT planning. Functional BM-sparing vs total BM-sparing IMRT plans were compared in 12 subjects; 10 were treated with functional BM-sparing pelvic IMRT per protocol. RESULTS: In gynecologic cancer patients, the mean functional BM V(10) (volume receiving ≥10 Gy) and V(20) (volume receiving ≥20 Gy) were 85% vs 94% (P<.0001) and 70% vs 82% (P<.0001), respectively, for functional BM-sparing IMRT vs total BM-sparing IMRT. In anal cancer patients, the corresponding values were 75% vs 77% (P=.06) and 62% vs 67% (P=.002), respectively. Of 10 subjects treated with functional BM-sparing pelvic IMRT, 3 (30%) had acute grade 3 hematologic toxicity or greater. CONCLUSIONS: IMRT can reduce dose to BM subregions identified by (18)F-fluorodeoxyglucose-PET/CT and IDEAL IQ. The efficacy of BM-sparing IMRT is being tested in a phase II trial.

Patterns of imaging failures in glioblastoma patients treated with chemoradiation: a retrospective study.

Glioblastoma multiforme (GBM) is the most common primary brain tumor of adults and carries a poor prognosis. This study sought to investigate recurrence patterns of GBM treated with temozolomide-based chemoradiation. Records for 31 patients treated for newly diagnosed GBM between 2007 and 2009 were retrospectively analyzed. Ten patients received maximal surgical resection followed by conventionally fractionated radiation (CFR) to a median dose of 60 Gy with concurrent and planned adjuvant temozolomide. Twelve patients were treated with maximal surgical debulking, intracavitary brachytherapy (ICB), and external beam radiation therapy with concurrent and planned adjuvant temozolomide. The remaining 9 patients had unresectable disease and underwent biopsy followed by a hypofractionated course of radiation to a median dose of 60 Gy over 10 fractions. Tumor failure was classified as local, marginal, or distant according to whether the recurrence was completely inside, crossed, or completely outside the 100% isodose line. With a median follow-up of 12.6 months, 5 patients were lost to follow-up, while the remaining 26 patients (100%) developed recurrent disease. The first failures totaled 29 discrete lesions, of which 15 (52%), 6 (21%), and 8 (28%) were local, marginal, and distant failures at median times of 6.8, 10.1, and 7.9 months, respectively. Marginal or distant failure was more likely in ICB patients as compared to CFR patients. While local failure predominated, distant failures were not uncommon, particularly at later time points. As local control of GBM improves, further study is needed to identify and appropriately treat patients susceptible to distant failure.