Investigation of autosegmentation techniques on T2-weighted MRI for off-line dose reconstruction in MR-linac workflow for head and neck cancers.

BACKGROUND: In order to accurately accumulate delivered dose for head and neck cancer patients treated with the Adapt to Position workflow on the 1.5T magnetic resonance imaging (MRI)-linear accelerator (MR-linac), the low-resolution T2-weighted MRIs used for daily setup must be segmented to enable reconstruction of the delivered dose at each fraction. PURPOSE: In this pilot study, we evaluate various autosegmentation methods for head and neck organs at risk (OARs) on on-board setup MRIs from the MR-linac for off-line reconstruction of delivered dose. METHODS: Seven OARs (parotid glands, submandibular glands, mandible, spinal cord, and brainstem) were contoured on 43 images by seven observers each. Ground truth contours were generated using a simultaneous truth and performance level estimation (STAPLE) algorithm. Twenty total autosegmentation methods were evaluated in ADMIRE: 1-9) atlas-based autosegmentation using a population atlas library (PAL) of 5/10/15 patients with STAPLE, patch fusion (PF), random forest (RF) for label fusion; 10-19) autosegmentation using images from a patient's 1-4 prior fractions (individualized patient prior [IPP]) using STAPLE/PF/RF; 20) deep learning (DL) (3D ResUNet trained on 43 ground truth structure sets plus 45 contoured by one observer). Execution time was measured for each method. Autosegmented structures were compared to ground truth structures using the Dice similarity coefficient, mean surface distance (MSD), Hausdorff distance (HD), and Jaccard index (JI). For each metric and OAR, performance was compared to the inter-observer variability using Dunn's test with control. Methods were compared pairwise using the Steel-Dwass test for each metric pooled across all OARs. Further dosimetric analysis was performed on three high-performing autosegmentation methods (DL, IPP with RF and 4 fractions [IPP_RF_4], IPP with 1 fraction [IPP_1]), and one low-performing (PAL with STAPLE and 5 atlases [PAL_ST_5]). For five patients, delivered doses from clinical plans were recalculated on setup images with ground truth and autosegmented structure sets. Differences in maximum and mean dose to each structure between the ground truth and autosegmented structures were calculated and correlated with geometric metrics. RESULTS: DL and IPP methods performed best overall, all significantly outperforming inter-observer variability and with no significant difference between methods in pairwise comparison. PAL methods performed worst overall; most were not significantly different from the inter-observer variability or from each other. DL was the fastest method (33 s per case) and PAL methods the slowest (3.7-13.8 min per case). Execution time increased with a number of prior fractions/atlases for IPP and PAL. For DL, IPP_1, and IPP_RF_4, the majority (95%) of dose differences were within ± 250 cGy from ground truth, but outlier differences up to 785 cGy occurred. Dose differences were much higher for PAL_ST_5, with outlier differences up to 1920 cGy. Dose differences showed weak but significant correlations with all geometric metrics (R2 between 0.030 and 0.314). CONCLUSIONS: The autosegmentation methods offering the best combination of performance and execution time are DL and IPP_1. Dose reconstruction on on-board T2-weighted MRIs is feasible with autosegmented structures with minimal dosimetric variation from ground truth, but contours should be visually inspected prior to dose reconstruction in an end-to-end dose accumulation workflow.

Radiotherapy reimagined: Integrating nanomedicines into radiotherapy clinical trials.

Radioenhancing nanoparticles (NPs) are being evaluated in ongoing clinical trials for various cancers including head and neck, lung, esophagus, pancreas, prostate, and soft tissue sarcoma. Supported by decades of preclinical investigation and recent randomized trial data establishing clinical activity, these agents are poised to influence future multimodality treatment paradigms involving radiotherapy. Although the physical interactions between NPs and ionizing radiation are well characterized, less is known about how these agents modify the tumor microenvironment, particularly regarding tumor immunogenicity. In this review, we describe the key multidisciplinary considerations related to radiation, surgery, immunology, and pathology for designing radioenhancing NP clinical trials. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

NBTXR3, a first-in-class radioenhancer for pancreatic ductal adenocarcinoma: Report of first patient experience.

BACKGROUND AND PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) remains one of the leading causes of cancer-related deaths in the world. For patients with PDAC who are not eligible for surgery, radiation therapy improves local disease control, yet safely delivering therapeutic doses of radiation remains challenging due to off-target toxicities in surrounding normal tissues. NBTXR3, a novel radioenhancer composed of functionalized hafnium oxide crystalline nanoparticles, has recently shown clinical activity in soft tissue sarcoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, and advanced solid malignancies with lung or liver metastases. Here we report the first patient with pancreatic cancer treated with NBTXR3. MATERIALS AND METHODS: A 66-year-old male with unresectable locally advanced PDAC was enrolled on our clinical trial to receive NBTXR3 activated by radiation therapy. Local endoscopic delivery of NBTXR3 was followed by intensity modulated radiation therapy (IMRT). Follow-up assessment consisted of physical examination, laboratory studies including CA19-9, and CT of the chest, abdomen, and pelvis. RESULTS: The patient received NBTXR3 by local endoscopic delivery without any acute adverse events. Radiation treatment consisted of 45 Gy in 15 daily fractions using IMRT. The patient began radiation twelve days after NBTXR3 injection. Daily CT-on-rails imaging demonstrated retention of NBTXR3 within the tumor for the duration of treatment. At initial follow-up evaluation, the lesion remained radiographically stable and the patient did not demonstrate treatment-related toxicity. CONCLUSION: This report demonstrates initial feasibility of local endoscopic delivery of NBTXR3 activated by radiation therapy for patients with pancreatic cancer who are not eligible for surgery.

Highly conformal reirradiation in patients with prior oropharyngeal radiation: Clinical efficacy and toxicity outcomes.

BACKGROUND: Reirradiation of head and neck cancer is associated with high rates of locoregional failure and potentially severe treatment-related toxicity. We report our institutional experience of reirradiation using modern highly conformal radiotherapy approaches in patients with prior oropharyngeal radiation. METHODS: We reviewed patients receiving curative-intent reirradiation with intensity-modulated radiation therapy, stereotactic body radiation therapy, and proton beam radiotherapy at our institution from 1999 to 2019. Disease control, survival, and toxicity rates following reirradiation were determined. RESULTS: Sixty-nine patients were evaluated. Local control (LC), progression-free survival, and overall survival at 2 years following reirradiation were 77%, 35%, and 51%, respectively. Grade 3 or greater (G3+) late toxicities occurred in 46% of patients and 41% required feeding tube placement during or after reirradiation. CONCLUSIONS: In select patients with prior oropharyngeal radiation, highly conformal reirradiation offers acceptable LC, but G3+ toxicity and out-of-field failure rates remain high. These findings warrant continued evaluation of new multimodality approaches to improve oncologic outcomes.

Augmenting the therapeutic window of radiotherapy: A perspective on molecularly targeted therapies and nanomaterials.

Radiation therapy is a cornerstone of modern cancer therapy alongside surgery, chemotherapy, and immunotherapy, with over half of all cancer patients receiving radiation therapy as part of their treatment regimen. Development of novel radiation sensitizers that can improve the therapeutic window of radiation therapy are sought after, particularly for tumors at an elevated risk of local and regional recurrence such as locally-advanced lung, head and neck, and gastrointestinal tumors. This review discusses clinical strategies to enhance radiotherapy efficacy and decrease toxicity, hence, increasing the overall therapeutic window. A focus is given to the molecular targets that have been identified and their associated mechanisms of action in enhancing radiotherapy. Examples include cell survival and proliferation signaling such as the EGFR and PI3K/AKT/mTOR pathways, DNA repair genes including PARP and ATM/ATR, angiogenic growth factors, epigenetic regulators, and immune checkpoint proteins. By manipulating various mechanisms of tumor resistance to ionizing radiation (IR), targeted therapies hold significant value to increase the therapeutic window of radiotherapy. Further, the use of novel nanoparticles to enhance radiotherapy is also reviewed, including nanoparticle delivery of chemotherapies, metallic (high-Z) nanoparticles, and nanoparticle delivery of targeted therapies - all of which may improve the therapeutic window of radiotherapy by enhancing the tumor response to IR or reducing normal tissue toxicity.

Roadmap for metal nanoparticles in radiation therapy: current status, translational challenges, and future directions.

This roadmap outlines the potential roles of metallic nanoparticles (MNPs) in the field of radiation therapy. MNPs made up of a wide range of materials (from Titanium, Z = 22, to Bismuth, Z = 83) and a similarly wide spectrum of potential clinical applications, including diagnostic, therapeutic (radiation dose enhancers, hyperthermia inducers, drug delivery vehicles, vaccine adjuvants, photosensitizers, enhancers of immunotherapy) and theranostic (combining both diagnostic and therapeutic), are being fabricated and evaluated. This roadmap covers contributions from experts in these topics summarizing their view of the current status and challenges, as well as expected advancements in technology to address these challenges.

Association of Sociodemographic and Health-Related Factors With Receipt of Nondefinitive Therapy Among Younger Men With High-Risk Prostate Cancer.

Importance: Multiple randomized clinical trials have shown that definitive therapy improves overall survival among patients with high-risk prostate cancer. However, many patients do not receive definitive therapy because of sociodemographic and health-related factors. Objective: To identify factors associated with receipt of nondefinitive therapy (NDT) among patients aged 70 years and younger with high-risk prostate cancer. Design, Setting, and Participants: This cohort study identified 72 036 patients aged 70 years and younger with high-risk prostate cancer and Charlson Comorbidity Index scores of 2 or less who were entered in the National Cancer Database between January 2004 and December 2014. Data analysis was conducted from November 2018 to December 2019. Exposure: Receipt of NDT as an initial treatment approach. Main Outcomes and Measures: Survival rates were compared based on receipt of definitive therapy or NDT, and sociodemographic and health-related factors were associated with the type of therapy received. Residual life expectancy was estimated from the National Center for Health Statistics to calculate person-years of life lost. Results: A total of 72 036 men with a median (range) age of 63 (30-70) years, Charlson Comorbidity Index scores of 2 or less, and high-risk prostate cancer without regional lymph node or distant metastatic disease were analyzed. Among eligible patients, 5252 (7.3%) received NDT as an initial therapeutic strategy. On univariate and multivariate analyses, NDT was associated with worse overall survival (univariate analysis hazard ratio, 2.54; 95% CI, 2.40-2.69; P < .001; multivariate analysis hazard ratio, 2.40; 95% CI, 2.26-2.56; P < .001). Compared with patients with private insurance or managed care, those with no insurance, Medicaid, or Medicare were more likely to receive systemic therapy only (no insurance: odds ratio [OR], 3.34; 95% CI, 2.81-3.98; P < .001; Medicaid: OR, 2.92; 95% CI, 2.48-3.43; P < .001; Medicare: OR, 1.36; 95% CI, 1.20-1.53; P < .001) or no treatment (no insurance: OR, 2.63; 95% CI, 2.24-3.08; P < .001; Medicaid: OR, 1.71; 95% CI, 1.45-2.01; P < .001; Medicare: OR, 1.14; 95% CI, 1.04-1.24; P = .004). Compared with white patients, black patients were more likely to receive systemic therapy only (OR, 1.93; 95% CI, 1.74-2.14; P < .001) or no treatment (OR, 1.46; 95% CI, 1.32-1.61; P < .001), and Hispanic patients were more likely to receive systemic therapy only (OR, 1.36; 95% CI, 1.13-1.64; P = .001) or no treatment (OR, 1.36; 95% CI, 1.14-1.60; P < .001). Between 2004 and 2014, patients without insurance or enrolled in Medicaid had 1.83-fold greater person-years of life lost compared with patients with private insurance (area under the curve, 77 600 vs 42 300 person-years of life lost). Conclusions and Relevance: In this study, receipt of NDT was associated with insurance status and race/ethnicity. While treatment decisions should be individualized for every patient, younger men with high-risk prostate cancer and minimal comorbidities should be encouraged to receive definitive local therapy regardless of other factors. These data suggest that significant barriers to life-extending treatment options for patients with prostate cancer remain.

Stereotactic ablative radiation therapy for pulmonary metastases: Improving overall survival and identifying subgroups at high risk of local failure.

BACKGROUND & PURPOSE: Stereotactic ablative radiation therapy (SABR) is an emerging treatment option for patients with pulmonary metastases; identifying patients who would benefit from SABR can improve outcomes. MATERIALS & METHODS: We retrospectively analyzed local failure (LF), distant failure (DF), overall survival (OS), and toxicity in 317 patients with 406 pulmonary metastases treated with SABR in January 2006-September 2017 at a tertiary cancer center. RESULTS: Median follow-up time was 23 months. Primary adrenal, colorectal, sarcoma, or pancreatic ("less responsive") tumors led to high rates of LF. LF rates for patients with less responsive vs. responsive tumors were 4.6% vs. 1.6% at 12 months and 12.8% vs. 3.9% at 24 months (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.11-0.73; Log-Rank P = 0.0087). A nomogram for 24-month local control was created using Cox multivariate factors (surgical history, planning target volume, primary disease site, lung lobe location). Treating patients with ≤3 pulmonary metastases vs. >3 pulmonary metastases was associated with improved 24-month (74.2% vs. 59.3%) and 48-month (47.7% vs. 35.1%) OS (HR 0.66, 95% CI 0.47-0.95; Log-Rank P = 0.043), and reduced 12-month (22.5% vs. 50.8%) and 24-month (31.8% vs. 61.4%) intrathoracic DF (HR 0.53, 95% CI 0.38-0.74; Log-Rank P < 0.0001). The most common toxicity was asymptomatic pneumonitis (14.8%). Six patients had grade 3 events (5 pneumonitis, 1 brachial plexus). CONCLUSIONS: SABR for pulmonary metastases was effective and well tolerated. Irradiating limited intrathoracic sites of disease led to improved OS and intrathoracic DM. Higher SABR doses or surgery could be considered for less radio-responsive primary tumors.

Xerostomia-related quality of life for patients with oropharyngeal carcinoma treated with proton therapy.

PURPOSE: We report longitudinal patient-reported quality-of-life (QoL) outcomes related to xerostomia in patients with oropharyngeal cancer treated with intensity-modulated proton therapy (IMPT). MATERIALS AND METHODS: Patients treated from May 2012 through December 2016 at a single institution for AJCC7 stage III-IV, M0 oropharyngeal cancer were given the 15-item Xerostomia-Related QoL Scale (XeQoLS) before, during, and for up to 2 years after treatment. We evaluated the evolution of xerostomia-related QoL over that time, and examined potential associations between those measures with clinical characteristics. RESULTS: Sixty-nine patients had XeQoLS scores at baseline and at least once either during or after treatment. The mean (±SD) XeQoLS score (0-4) was 0.24 ±â€¯0.57 at baseline. Subsequent scores were 2.00 ±â€¯1.01 at 6 weeks on treatment, and 1.03 ±â€¯0.76, 0.97 ±â€¯0.78, 0.82 ±â€¯0.69, and 0.70 ±â€¯0.75 at 10 weeks, 6 months, 1 year, and 2 years after treatment, respectively. All were statistically different from baseline (p < 0.001). Univariate analyses demonstrated associations between XeQoLS score and time (p < 0.0001 for each interval), baseline XeQoLS score (p < 0.0001), stage (p = 0.008), N status (p = 0.006), and mean oral cavity dose (p = 0.038), but not for age, sex, T status, receipt of chemotherapy, smoking history, disease site, laterality of neck irradiation, mean parotid dose, or mean submandibular dose. Multivariate analysis suggested that baseline XeQoLS scores, phase of treatment, and N status were associated with XeQoLS scores measured during treatment and recovery. CONCLUSIONS: Patients receiving IMPT reported the greatest xerostomia-related QoL impairment at 6 weeks on treatment, with a 49% improvement by 10 weeks after treatment; however, XeQoLS scores remained above baseline after 2 years. As we aim to establish the value of IMPT in oropharyngeal tumors to de-intensify treatment over conventional therapy, these data help inform discussions about xerostomia-related quality of life for patients with oropharyngeal cancer treated with IMPT.

Hydrogel Spacer Reduces Rectal Dose during Proton Therapy for Prostate Cancer: A Dosimetric Analysis.

PURPOSE: Proton therapy for prostate cancer may reduce bowel dose and risk of bowel symptoms relative to photon-based methods. Here, we determined the effect of using a biodegradable, injectable hydrogel spacer on rectal dose on plans for treating prostate cancer with intensity-modulated proton therapy (IMPT) or passive scattering proton therapy (PSPT). MATERIALS AND METHODS: Pairs of IMPT and PSPT plans for 9 patients were created from fused computed tomography/magnetic resonance imaging scans obtained before and after spacer injection. Calculated values of rectal V40, V60, V70, V80, and maximum dose (Dmax) were compared with Wilcoxon signed rank tests. Displacements at the base (BP), midgland (MP), and apex (AP) of the prostate relative to the anterior rectal wall with the spacer in place were averaged for each patient and correlated with V70 by using linear regression models. RESULTS: The presence of a spacer reduced all dosimetric parameters for both PSPT and IMPT, with the greatest difference in V70, which was 81.1% lower for PSPT-with-spacer than for IMPT-without-spacer. Median displacements at BP, MP, and AP were 12 mm (range 7-19), 2 mm (range 0-4), and 1 mm (range 0-5) without the spacer and 19 mm (range 12-23), 10 mm (range 8-16), and 7 mm (range 2-12) with the spacer. Modest linear trends were noted between rectal V70 and displacement for IMPT-with-spacer and PSPT-with-spacer. When displacement was ≥8 mm, V70 was ≤5.1% for IMPT-with-spacer and PSPT-with-spacer. CONCLUSION: Use of biodegradable hydrogel spacers for prostate cancer treatment provides a significant reduction of radiation dose to the rectum with proton therapy. Significant reductions in rectal dose occurred in both PSPT and IMPT plans, with the greatest reduction for IMPT-with-spacer relative to PSPT alone. Prospective studies are ongoing to assess the clinical impact of reducing rectal dose with hydrogel spacers.

Efficacy of proton therapy in children with high-risk and locally recurrent neuroblastoma.

PURPOSE: Proton therapy is currently used in the management of pediatric tumors to decrease late toxicities. However, one of the criticisms of proton therapy is the limited data regarding efficacy on disease control. The purpose of this study was to examine local and distant control rates after proton therapy for neuroblastoma. METHODS AND MATERIALS: Eighteen patients with high-risk (n = 16) and locally recurrent neuroblastoma (n = 2) were treated with curative intent and received proton therapy to the primary site and up to three post-induction MIBG-avid metastatic sites. Primary sites (n = 18) were treated to 21-36 Gy (relative biological effectiveness [RBE]), and metastatic sites (n = 16) were treated to 21-24 Gy (RBE). Local control and survival rates were calculated using the Kaplan-Meier method. RESULTS: With a median follow-up of 60.2 months, two- and five-year local control rates at the irradiated primary site were 94% and 87%, respectively. No failures at irradiated distant metastatic sites were observed. The five-year progression-free survival (PFS) was 64%, and the five-year overall survival (OS) was 94%. The extent of surgical resection was not associated with local control, PFS, or OS. No radiation-related nephropathy or hepatopathy was reported. CONCLUSIONS: Excellent local control was achieved using proton therapy to the primary and post-induction MIBG-positive distant sites. The predominant site of failure is progression in post-induction non-MIBG-avid distant sites. Although proton therapy provides high rates of local control with acceptable toxicity for neuroblastoma, further advances in systemic therapy are needed for the improved control of systemic disease.

Endothelial Thermotolerance Impairs Nanoparticle Transport in Tumors.

The delivery of diagnostic and therapeutic agents to solid tumors is limited by physical transport barriers within tumors, and such restrictions directly contribute to decreased therapeutic efficacy and the emergence of drug resistance. Nanomaterials designed to perturb the local tumor environment with precise spatiotemporal control have demonstrated potential to enhance drug delivery in preclinical models. Here, we investigated the ability of one class of heat-generating nanomaterials called plasmonic nanoantennae to enhance tumor transport in a xenograft model of ovarian cancer. We observed a temperature-dependent increase in the transport of diagnostic nanoparticles into tumors. However, a transient, reversible reduction in this enhanced transport was seen upon reexposure to heating, consistent with the development of vascular thermotolerance. Harnessing these observations, we designed an improved treatment protocol combining plasmonic nanoantennae with diffusion-limited chemotherapies. Using a microfluidic endothelial model and genetic tools to inhibit the heat-shock response, we found that the ability of thermal preconditioning to limit heat-induced cytoskeletal disruption is an important component of vascular thermotolerance. This work, therefore, highlights the clinical relevance of cellular adaptations to nanomaterials and identifies molecular pathways whose modulation could improve the exposure of tumors to therapeutic agents.

Deep, noninvasive imaging and surgical guidance of submillimeter tumors using targeted M13-stabilized single-walled carbon nanotubes.

Highly sensitive detection of small, deep tumors for early diagnosis and surgical interventions remains a challenge for conventional imaging modalities. Second-window near-infrared light (NIR2, 950-1,400 nm) is promising for in vivo fluorescence imaging due to deep tissue penetration and low tissue autofluorescence. With their intrinsic fluorescence in the NIR2 regime and lack of photobleaching, single-walled carbon nanotubes (SWNTs) are potentially attractive contrast agents to detect tumors. Here, targeted M13 virus-stabilized SWNTs are used to visualize deep, disseminated tumors in vivo. This targeted nanoprobe, which uses M13 to stably display both tumor-targeting peptides and an SWNT imaging probe, demonstrates excellent tumor-to-background uptake and exhibits higher signal-to-noise performance compared with visible and near-infrared (NIR1) dyes for delineating tumor nodules. Detection and excision of tumors by a gynecological surgeon improved with SWNT image guidance and led to the identification of submillimeter tumors. Collectively, these findings demonstrate the promise of targeted SWNT nanoprobes for noninvasive disease monitoring and guided surgery.

Plasmonic photothermal heating of intraperitoneal tumors through the use of an implanted near-infrared source.

Plasmonic nanomaterials including gold nanorods are effective agents for inducing heating in tumors. Because near-infrared (NIR) light has traditionally been delivered using extracorporeal sources, most applications of plasmonic photothermal therapy have focused on isolated subcutaneous tumors. For more complex models of disease such as advanced ovarian cancer, one of the primary barriers to gold nanorod-based strategies is the adequate delivery of NIR light to tumors located at varying depths within the body. To address this limitation, a series of implanted NIR illumination sources are described for the specific heating of gold nanorod-containing tissues. Through computational modeling and ex vivo studies, a candidate device is identified and validated in a model of orthotopic ovarian cancer. As the therapeutic, imaging, and diagnostic applications of plasmonic nanomaterials progress, effective methods for NIR light delivery to challenging anatomical regions will complement ongoing efforts to advance plasmonic photothermal therapy toward clinical use.

Effectiveness of the SLICE program for youth concussion education.

OBJECTIVE: To analyze the effectiveness of the Sports Legacy Institute Community Educators (SLICE) curriculum for student-athletes on recognition and appropriate responses to concussions. DESIGN: Prospective cohort study, level II. SETTING: The SLICE concussion workshop. PARTICIPANTS: All students ranging from 9 to 18 years (n = 636) taking the SLICE concussion education program. INTERVENTION: The SLICE concussion education program featuring interactive demonstrations, discussion, and case studies of athletes delivered by medical students and others in health-related fields. MAIN OUTCOME MEASURES: Evaluations assessing knowledge of concussion recognition and appropriate response were administered before and after participating in the SLICE concussion education program. RESULTS: Students displayed significant improvements in absolute mean score on the concussion knowledge quiz between prepresentation and postpresentation (P < 0.0001). Significant improvements in mean score were observed among both male and female students within each age group. The proportion of students who passed the quiz increased from 34% prepresentation to 80% postpresentation (P < 0.0001). However, the percentage who passed the quiz postpresentation was significantly higher among female students compared with male students (P < 0.0001) and among students 13 years of age or older compared with students less than 13 years (P < 0.0001). Using multivariable logistic regression, we identified age group and gender as the most significant factors associated with passing the quiz postpresentation. CONCLUSION: The SLICE program promotes effective learning and knowledge about concussion recognition and response among students ranging from 9 to 18 years. Lessons from the SLICE program may be broadly applicable to youth concussion education.