Technical feasibility of novel immunostimulatory low-dose radiation for polymetastatic disease with CBCT-based online adaptive and conventional approaches.

PURPOSE: A workflow/planning strategy delivering low-dose radiation therapy (LDRT) (1 Gy) to all polymetastatic diseases using conventional planning/delivery (Raystation/Halcyon = "conventional") and the AI-based Ethos online adaptive RT (oART) platform is developed/evaluated. METHODS: Using retrospective data for ten polymetastatic non-small cell lung cancer patients (5-52 lesions each) with PET/CTs, gross tumor volumes (GTVs) were delineated using PET standardized-uptake-value (SUV) thresholding. A 1 cm uniform expansion of GTVs to account for setup/contour uncertainty and organ motion-generated planning target volumes (PTVs). Dose optimization/calculation used the diagnostic CT from PET/CT. Dosimetric objectives were: Dmin,0.03cc ≥ 95% (acceptable variation (Δ) ≥ 90%), V100% ≥ 95% (Δ ≥ 90%), and D0.03cc ≤ 120% (Δ ≤ 125%). Additionally, online adaptation was simulated. When available, subsequent diagnostic CT was used to represent on-treatment CBCT. Otherwise, the CT from PET/CT used for initial planning was deformed to simulate clinically representative changes. RESULTS: All initial plans generated, both for Raystation and Ethos, achieved clinical goals within acceptable variation. For all patients, Dmin,0.03cc ≥ 95%, V100% ≥ 95%, and D0.03cc ≤ 120% goals were achieved for 84.8%/99.5%, 97.7%/98.7%, 97.4%/92.3%, in conventional/Ethos plans, respectively. The ratio of 50% isodose volume to PTV volume (R50%), maximum dose at 2 cm from PTV (D2cm), and the ratio of the 100% isodose volume to PTV volume (conformity index) in Raystation/Ethos plans were 7.9/5.9; 102.3%/88.44%; and 0.99/1.01, respectively. In Ethos, online adapted plans maintained PTV coverage whereas scheduled plans often resulted in geographic misses due to changes in tumor size, patient position, and body habitus. The average total duration of the oART workflow was 26:15 (min:sec) ranging from 6:43 to 57:30. The duration of each oART workflow step as a function of a number of targets showed a low correlation coefficient for influencer generation and editing (R2 = 0.04 and 0.02, respectively) and high correlation coefficient for target generation, target editing and plan generation (R2 = 0.68, 0.63 and 0.69, respectively). CONCLUSIONS: This study demonstrates feasibility of conventional planning/treatment with Raystation/Halcyon and highlights efficiency gains when utilizing semi-automated planning/online-adaptive treatment with Ethos for immunostimulatory LDRT conformally delivered to all sites of polymetastatic disease.

Cluster model incorporating heterogeneous dose distribution of partial parotid irradiation for radiotherapy induced xerostomia prediction with machine learning methods.

PURPOSE: A cluster model incorporating heterogeneous dose distribution within the parotid gland was developed and validated retrospectively for radiotherapy (RT) induced xerostomia prediction with machine learning (ML) techniques. METHODS: Sixty clusters were obtained at 1 Gy step size with threshold doses ranging from 1 to 60 Gy, for each of the enrolled 155 patients with HNC from three institutions. Feature clusters were selected with the neighborhood component analysis (NCA) and subsequently fed into four supervised ML models for xerostomia prediction comparison: support vector machines (SVM), k-nearest neighbor (kNN), naïve Bayes (NB), and random forest (RF). The predictive performance of each model was evaluated using cross validation resampling with the area-under-the-curves (AUC) of the receiver-operating-characteristic (ROC). The xerostomia predicting capacity using testing data was assessed with accuracy, sensitivity, and specificity for these models and three cluster connectivity choices. Mean dose based logistic regression served as the benchmark for evaluation. RESULTS: Feature clusters identified by NCA fell in three threshold dose ranges: 5-15Gy, 25-35Gy, and 45-50Gy. Mean dose predictive power was 15% lower than that of the cluster model using the logistic regression classifier. Model validation demonstrated that kNN model outperformed slightly other three models but no substantial difference was observed. Applying the fine-tuned models to testing data yielded that the mean accuracy from SVM, kNN and NB models were between 0.68 and 0.7 while that of RF was ∼0.6. SVM model yielded the best sensitivity (0.76) and kNN model delivered consistent sensitivity and specificity. This is consistent with cross validation. Clusters calculated with three connectivity choices exhibited minimally different predictions. CONCLUSION: Compared to mean dose, the proposed cluster model has shown its improvement as the xerostomia predictor. When combining with ML techniques, it could provide a clinically useful tool for xerostomia prediction and facilitate decision making during radiotherapy planning for patients with HNC.

Gonadal-sparing total body irradiation with the use of helical tomotherapy for nonmalignant indications.

BACKGROUND: The aim was to demonstrate the feasibility and technique of gonadal sparing total body irradiation (TBI) with helical tomotherapy. Total body irradiation is a common part of the conditioning regimen prior to allogeneic stem cell transplantation. Shielding or dose-reduction to the gonads is often desired to preserve fertility, particularly in young patients undergoing transplant for non-malignant indications. Helical tomotherapy (HT) has been shown to be superior to traditional TBI delivery for organ at risk (OA R) doses and dose homogeneity. MATERIALS AND METHODS: We present two representative cases (one male and one female) to illustrate the feasibility of this technique, each of whom received 3Gy in a single fraction prior to allogeneic stem cell transplant for benign indications. The planning target volume (PTV) included the whole body with a subtraction of OA Rs including the lungs, heart, and brain (each contracted by 1cm) as well as the gonads (testicles expanded by 5 cm and ovaries expanded by 0.5 cm). RESULTS: For the male patient we achieved a homogeneity index of 1.35 with a maximum and median planned dose to the testes of 0.53 Gy and 0.35 Gy, respectively. In-vivo dosimetry demonstrated an actual received dose of 0.48 Gy. For the female patient we achieved a homogeneity index of 1.13 with a maximum and median planned dose to the ovaries of 1.66 Gy and 0.86 Gy, respectively. CONCLUSION: Gonadal sparing TBI is feasible and deliverable using HT in patients with non-malignant diseases requiring TBI as part of a pre-stem cell transplant conditioning regimen.

Neurosurgical management of perineural metastases: A case series and review of the literature.

BACKGROUND: Perineural invasion (PNI) and spread are one of the grimmest prognostic factors associated with primary skin and head-and-neck cancers, yet remain an often confused, and underreported, phenomenon. Adding complexity to reaching a diagnosis and treating perineural spread (PNS) is the finding that patients may have no known primary tumor, history of skin cancer, and/or incidental PNI in the primary tumor. These delays in diagnosis and treatment are further compounded by an already slow disease process and often require multidisciplinary care with combinations of stereotactic radiosurgery, surgical resection, and novel treatments such as checkpoint inhibitors. METHODS: Six patients with metastatic cancer to the cranial nerves who underwent Gamma Knife radiosurgery (GKRS) treatment were chosen for retrospective analysis. This information included age, gender, any past surgeries (both stereotactic and regular surgery), dose of radiation and volume of the tumor treated in the GKRS, date of PNS, comorbidities, the patient follow-up, and pre- and post-GKRS imaging. The goal of the follow-up with radiographing imaging was to assess the efficacy of GKSS. RESULTS: The clinical course of six patients with PNS is presented. Patients followed variable courses with mixed outcomes: two patients remain living, one was lost to follow-up, and three expired with a median survival of 12 months from date of diagnosis. Patients at our institution are ideally followed for life. CONCLUSION: Given the morbidity and mortality of PNS of cancer, time is limited, and further understanding is required to improve outcomes. Here, we provide a case series of patients with PNS treated with stereotactic radiosurgery, discuss their clinical courses, and review the known literature.

Dose cluster model parameterization of the parotid gland in irradiation of head and neck cancer.

To explore the parotid normal tissue complication probability (NTCP) modeling with percolation-based dose clusters for head-and-neck patients receiving concomitant chemotherapy and radiation therapy. Cluster models incorporating the spatial dose distribution in the parotid gland were developed to evaluate the radiation induced complication. Cluster metrics including the mean cluster size (NMCS) and the largest cluster size both normalized by the gland volume (NSLC) were evaluated and scrutinized against the benchmark NTCP. Two fitting strategies to the Lyman-Kutcher-Burman (LKB) model using the maximum likelihood method were devised: the volume parameter n fixed at 1.0 (mean dose model) and unrestricted (full LKB model). The fitted parameters TD50 and m were assessed with the LKB NTCP models with the available xerostomia data. NSLC was a better metric than NMCS with reference to the LKB model and strong correlation (r ~ 0.95) was observed between NTCP and NSLC. The mean dose model returned the parameter TD50 (39.9 Gy) and m (0.4) from the NSLC of threshold dose at around 40 Gy. Drastically different TD50 and m values were obtained from the fittings via the full LKB model, where the threshold dose would be near 27 Gy. Bootstrapping analyses further confirmed the fitting outcomes. Strong correlation with the traditional NTCP models revealed that the cluster model could achieve what NTCP models attain and may offer additional information. Parameterization of the model indicated that the model could have different predictions from current clinical recommendations. Further investigation using toxicity data is under way to validate the cluster model.

Three-dimensional cluster formation and structure in heterogeneous dose distribution of intensity modulated radiation therapy.

PURPOSE: To investigate three-dimensional cluster structure and its correlation to clinical endpoint in heterogeneous dose distributions from intensity modulated radiation therapy. METHODS: Twenty-five clinical plans from twenty-one head and neck (HN) patients were used for a phenomenological study of the cluster structure formed from the dose distributions of organs at risks (OARs) close to the planning target volumes (PTVs). Initially, OAR clusters were searched to examine the pattern consistence among ten HN patients and five clinically similar plans from another HN patient. Second, clusters of the esophagus from another ten HN patients were scrutinized to correlate their sizes to radiobiological parameters. Finally, an extensive Monte Carlo (MC) procedure was implemented to gain deeper insights into the behavioral properties of the cluster formation. RESULTS: Clinical studies showed that OAR clusters had drastic differences despite similar PTV coverage among different patients, and the radiobiological parameters failed to positively correlate with the cluster sizes. MC study demonstrated the inverse relationship between the cluster size and the cluster connectivity, and the nonlinear changes in cluster size with dose thresholds. In addition, the clusters were insensitive to the shape of OARs. CONCLUSION: The results demonstrated that the cluster size could serve as an insightful index of normal tissue damage. The clinical outcome of the same dose-volume might be potentially different.

Multi-institutional feasibility study of a fast patient localization method in total marrow irradiation with helical tomotherapy: a global health initiative by the international consortium of total marrow irradiation.

PURPOSE: To develop, characterize, and implement a fast patient localization method for total marrow irradiation. METHODS AND MATERIALS: Topographic images were acquired using megavoltage computed tomography (MVCT) detector data by delivering static orthogonal beams while the couch traversed through the gantry. Geometric and detector response corrections were performed to generate a megavoltage topogram (MVtopo). We also generated kilovoltage topograms (kVtopo) from the projection data of 3-dimensional CT images to reproduce the same geometry as helical tomotherapy. The MVtopo imaging dose and the optimal image acquisition parameters were investigated. A multi-institutional phantom study was performed to verify the image registration uncertainty. Forty-five MVtopo images were acquired and analyzed with in-house image registration software. RESULTS: The smallest jaw size (front and backup jaws of 0) provided the best image contrast and longitudinal resolution. Couch velocity did not affect the image quality or geometric accuracy. The MVtopo dose was less than the MVCT dose. The image registration uncertainty from the multi-institutional study was within 2.8 mm. In patient localization, the differences in calculated couch shift between the registration with MVtopo-kVtopo and MVCT-kVCT images in lateral, cranial-caudal, and vertical directions were 2.2 ± 1.7 mm, 2.6 ± 1.4 mm, and 2.7 ± 1.1 mm, respectively. The imaging time in MVtopo acquisition at the couch speed of 3 cm/s was <1 minute, compared with ≥15 minutes in MVCT for all patients. CONCLUSION: Whole-body MVtopo imaging could be an effective alternative to time-consuming MVCT for total marrow irradiation patient localization.

High dose bystander effects in spatially fractionated radiation therapy.

Traditional radiotherapy of bulky tumors has certain limitations. Spatially fractionated radiation therapy (GRID) and intensity modulated radiotherapy (IMRT) are examples of advanced modulated beam therapies that help in significant reductions in normal tissue damage. GRID refers to the delivery of a single high dose of radiation to a large treatment area that is divided into several smaller fields, while IMRT allows improved dose conformity to the tumor target compared to conventional three-dimensional conformal radiotherapy. In this review, we consider spatially fractionated radiotherapy approaches focusing on GRID and IMRT, and present complementary evidence from different studies which support the role of radiation induced signaling effects in the overall radiobiological rationale for these treatments.

Functional outcomes of chemoradiation in patients with head and neck cancer.

OBJECTIVE: Concurrent chemoradiotherapy (CCRT) has become the treatment of choice for oropharyngeal and hypopharyngolaryngeal cancers in many centers. Although it has increased the rates of organ preservation, there has also been an increase in treatment-related complications. We aimed to evaluate the functional outcomes of CCRT in head and neck cancer. STUDY DESIGN: Case series with chart review. SETTING: Tertiary cancer center. SUBJECTS AND METHODS: A retrospective study of patients treated with CCRT at the University of Arkansas for Medical Sciences was performed. Demographic data and treatment outcomes were extracted, specifically feeding tube and tracheotomy dependence and number of esophageal dilatations. RESULTS: Of the 243 patients treated with concurrent chemoradiotherapy (5-fluorouracil + cysplatin and radiotherapy), 152 patients received a feeding tube. The median percutaneous gastrostomy tube (PEG) use was 9 months (range, 1-96 months). More than 70% of the patients who had a PEG more than 6 months had a T3 or T4 tumor. Thirty-seven patients underwent esophageal dilatations, (median, 1; range, 1-7). The median use of a tracheotomy was 7 months, and 77% of these patients were treated for hypopharyngolaryngeal cancer. CONCLUSIONS: Despite major improvement in locoregional control rates, CCRT has a significant negative impact on the functional outcomes of head and neck cancer patients, with a high number of patients remaining PEG and tracheotomy dependent.

SonoKnife: feasibility of a line-focused ultrasound device for thermal ablation therapy.

PURPOSE: To evaluate the feasibility of line-focused ultrasound for thermal ablation of superficially located tumors. METHODS: A SonoKnife is a cylindrical-section ultrasound transducer designed to radiate from its concave surface. This geometry generates a line-focus or acoustic edge. The motivation for this approach was the noninvasive thermal ablation of advanced head and neck tumors and positive neck nodes in reasonable treatment times. Line-focusing may offer advantages over the common point-focusing of spherically curved radiators such as faster coverage of a target volume by scanning of the acoustic edge. In this paper, The authors report studies using numerical models and phantom and ex vivo experiments using a SonoKnife prototype. RESULTS: Acoustic edges were generated by cylindrical-section single-element ultrasound transducers numerically, and by the prototype experimentally. Numerically, simulations were performed to characterize the acoustic edge for basic design parameters: transducer dimensions, line-focus depth, frequency, and coupling thickness. The dimensions of the acoustic edge as a function of these parameters were determined. In addition, a step-scanning simulation produced a large thermal lesion in a reasonable treatment time. Experimentally, pressure distributions measured in degassed water agreed well with acoustic simulations, and sonication experiments in gel phantoms and ex vivo porcine liver samples produced lesions similar to those predicted with acoustic and thermal models. CONCLUSIONS: Results support the feasibility of noninvasive thermal ablation with a SonoKnife.

Evaluation of spatially fractionated radiotherapy (GRID) and definitive chemoradiotherapy with curative intent for locally advanced squamous cell carcinoma of the head and neck: initial response rates and toxicity.

PURPOSE: To present results and acute toxicity in 14 patients with bulky (>or=6 cm) tumors from locally advanced squamous cell carcinoma of the head and neck who received spatially fractionated radiotherapy (GRID) therapy to the bulky mass followed by concomitant chemoradiotherapy using simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT). METHODS AND MATERIALS: GRID therapy to the GTV was delivered by creating one treatment field with a checkerboard pattern composed of open-closed areas using a multileaf collimator. The GRID prescription was 20 Gy in one fraction. Chemotherapy started the day of GRID therapy and continued throughout the course of SIB-IMRT. The SIB-IMRT prescription was 66, 60, and 54 Gy to the planning target volume (PTV), intermediate-risk PTV, and low-risk PTV, respectively, in 30 fractions. RESULTS: With a median follow-up of 19.5 months (range, 2-38 months), the overall control rate of the GRID gross tumor volume was 79% (11 of 14). The most common acute skin and mucosal toxicities were Grade 3 and 2, respectively. CONCLUSION: For the treatment of locally advanced neck squamous cell carcinoma of the head and neck, GRID followed by chemotherapy and SIB-IMRT is well tolerated and yields encouraging clinical and pathologic responses, with similar acute toxicity profiles as in patients receiving chemoradiotherapy without GRID.

Spatially fractionated (GRID) therapy for large and bulky tumors.

Avanced bulky tumors warrant aggressive therapy to attempt to maximize local control of the disease. Spatially fractionated radiation therapy (GRID) delivers a single-fraction of high dose radiation to these tumors with a curative or palliative goal. GRID therapy may be combined with fractionated radiation therapy or used in a therapeutic multi-modality setting to achieve control of the bulky disease. Current clinical data confirms the value of GRID therapy in the management of large volume of disease with an acceptable toxicity profile. GRID therapy has broad systemic effects leading to increases in a variety of cytokines that correlate with clinical outcome.

Feasibility of concurrent treatment with the scanning ultrasound reflector linear array system (SURLAS) and the helical tomotherapy system.

PURPOSE: To evaluate the feasibility of concurrent treatment with the scanning ultrasound reflector linear array system (SURLAS) and helical tomotherapy (HT) intensity modulated radiation therapy (IMRT). METHODS: The SURLAS was placed on a RANDO phantom simulating a patient with superficial or deep recurrent breast cancer. A megavoltage CT (MVCT) of the phantom with and without the SURLAS was obtained in the HT system. MVCT images with the SURLAS were obtained for two configurations: (1) with the SURLAS's long axis parallel and (2) perpendicular to the longitudinal axis of the phantom. The MVCT simulation data set was then transferred to a radiation therapy planning station. Organs at risk (OAR) were contoured including the lungs, heart, abdomen and spinal cord. The metallic parts of the SURLAS were contoured as well and constraints were assigned to completely or directionally block radiation through them. The MVCT simulation data set and regions of interest (ROI) files were subsequently transferred to the HT planning station. Several HT plans were obtained with optimization parameters that are usually used in the clinic. For comparison purposes, planning was also performed without the SURLAS on the phantom. RESULTS: All plans with the SURLAS on the phantom showed adequate dose covering 95% of the planning target volume (PTV D95%), average dose and coefficient of variation of the planning target volume (PTV) dose distribution regardless of the SURLAS's orientation with respect to the RANDO phantom. Likewise, all OAR showed clinically acceptable dose values. Spatial dose distributions and dose-volume histogram (DVH) evaluation showed negligible plan degradation due to the presence of the SURLAS. Beam-on time varied depending on the selected optimization parameters. CONCLUSION: From the perspective of the radiation dosage, concurrent treatment with the SURLAS and HT IMRT is feasible as demonstrated by the obtained clinically acceptable treatment plans. In addition, proper orientation of the SURLAS may be of benefit in reducing dose to organs at risk in some cases.

Influence of the SURLAS applicator on radiation dose distributions during simultaneous thermoradiotherapy with helical tomotherapy.

Simultaneous thermoradiotherapy has been shown to maximize the effect of hyperthermia as a radiation sensitizer in cancer treatment. Here we follow our previous work on feasibility of thermoradiotherapy with the scanning ultrasound reflector linear array system (SURLAS) and TomoTherapy HiArt treatment system, and investigate the influence of the SURLAS hyperthermia applicator on delivered radiation dose with the TomoTherapy. A radiation treatment plan was calculated and the treatment was delivered to a phantom with SURLAS on top simulating the likely clinical setup. Proper positioning of the SURLAS was assisted with a magnetic position-and-orientation tracking device (POTD) and was verified with megavoltage-computed tomography. The delivered dose was measured with an ionization chamber (point measurement) and a radiographic film (2D dose distributions). The planned and delivered point dose data agreed within 0.61% +/- 0.63%. Planar dose data agreed within a dose difference of < or =3% of the maximum dose, and a distance-to-dose-agreement of < or =1 mm. The susceptibility of the delivered radiation dose on correct SURLAS positioning was studied as well. The largest dose discrepancy was measured for a position for which a maximum number of radiation beams intersected the incorrectly positioned SURLAS within one TomoTherapy gantry rotation. The point dose disagreed by 6.14% +/- 0.52%, and 2.25% of pixels of the 2D dose distribution did not pass the 3% dose difference/1 mm distance-to-dose-agreement criteria. Our study showed that correct positioning of the SURLAS applicator had an influence on the delivered radiation dose. Delivered and planned dose distributions were in an excellent agreement when SURLAS was positioned according to the treatment plan. Moving the applicator from its planned position was found to cause a modification of delivered dose distributions. A precise and reproducible positioning of the applicator was assured with a POTD.

Retrospective evaluation of pediatric cranio-spinal axis irradiation plans with the Hi-ART tomotherapy system.

Helical tomotherapy (HT) can be used for the delivery of cranio-spinal axis irradiation (CSAI) without the need for beam matching of conventional linac-based external beam irradiation. The aim of this study is to retrospectively evaluate HT plans used for treatment in nine patients treated with CSAI. Helical tomotherapy cranio-spinal axis irradiation (HT-CSAI) plans were created for each patient. Average length along the cranio-spinal axis of the PTV was 65.6 cm with a range between 53 and 74 cm. Treatment planning optimization and plan evaluation parameters were obtained from the HT planning station for each of the nine patients. PTV coverage by the 95% isodose surface ranged between 98.0 to 100.0% for all nine patients. The clinically acceptable dose variation within the PTV or tolerance range was between 0.7 and 2.5% for all nine patients. Doses to the organs at risk were clinically acceptable. An increasing length along the longitudinal axis of the PTV did not consistently increase the beam-on time indicating that using a larger jaw width had a greater impact on treatment time. With a larger jaw width it is possible to substantially reduce the normalized beam-on treatment time without compromising plan quality and sparing of organs at risk. By using a larger jaw width or lower modulation factor or both, normalized beam-on times were decreased by up to 61% as compared to the other evaluated treatment plans. From the nine cases reported in this study the minimum beam-on time was achieved with a jaw width of 5.0 cm, pitch of 0.287 and a modulation factor of 2.0. Large and long cylindrical volumes can be effectively treated with helical tomotherapy with both clinically acceptable dose distribution and beam-on time.

Dosimetric comparison of helical tomotherapy and Gamma Knife stereotactic radiosurgery for single brain metastasis.

BACKGROUND: Helical Tomotherapy (HT) integrates linear accelerator and computerized tomography (CT) technology to deliver IMRT. Targets are localized (i.e. outlined as gross tumor volume [GTV] and planning target volume [PTV]) on the planning kVCT study while daily MVCT is used for correction of patient's set-up and assessment of inter-fraction anatomy changes. Based on dosimetric comparisons, this study aims to find dosimetric equivalency between single fraction HT and Gamma Knife stereotactic radiosurgery (GKSRS) for the treatment of single brain metastasis. METHODS: The targeting MRI data set from the GKSRS were used for tomotherapy planning. Five patients with single brain metastasis treated with GKSRS were re-planned in the HT planning station using the same prescribed doses. There was no expansion of the GTV to create the PTV. Sub-volumes were created within the PTV and prescribed to the maximum dose seen in the GKSRS plans to imitate the hot spot normally seen in GKSRS. The PTV objective was set as a region at risk in HT planning using the same prescribed dose to the PTV periphery as seen in the corresponding GKSRS plan. The tumor volumes ranged from 437-1840 mm(3). RESULTS: Conformality indices are inconsistent between HT and GKSRS. HT generally shows larger lower isodose line volumes, has longer treatment time than GKSRS and can treat a much larger lesion than GKSRS. Both HT and GKSRS single fraction dose-volume toxicity may be prohibitive in treating single or multiple lesions depending on the number and the sizes of the lesions. CONCLUSION: Based on the trend for larger lower dose volumes and more constricted higher dose volumes in HT as compared to GKSRS, dosimetric equivalency was not reached between HT and GKSRS.