Clinical Outcome in Patients With Early-Stage Small Cell Lung Cancer Treated With Surgery or Radiation in the Absence of Prophylactic Cranial Irradiation: A Single-Center Retrospective Study.

Purpose: As screening chest computed tomography for patients at high risk for cancer has become more widely accepted, increasing numbers of patients with early-stage small cell lung cancer (SCLC) are being diagnosed. Although surgery is an accepted option for patients with early-stage SCLC, for patients who decline or cannot undergo surgery, stereotactic body radiation treatment (SBRT) is an alternative. Although prophylactic cranial irradiation (PCI) improves survival in patients with limited-stage SCLC, PCI for early-stage SCLC (stage T1-T2) has not been explored. This study defines survival and recurrence patterns in patients with early-stage SCLC who were treated with surgery or SBRT in the absence of PCI. Methods and Materials: In this single-institution retrospective study, 14 patients diagnosed with early-stage SCLC (stage T1-T2) between July 2015 and May 2021 at a single tertiary care hospital were treated with SBRT or surgery with no PCI. Primary outcomes were locoregional cancer recurrence, distant recurrence, recurrence-free survival, and overall survival. The secondary outcome was development of brain metastasis. Analyses included Cox regression, Kaplan-Meier survival, and log-rank tests. Results: A total of 14 patients (5 women and 9 men) were included in the study: 9 with stage T1 and 5 with stage T2 SCLC. Six patients (43%) received SBRT and 8 (57%) had surgical treatment. All patients except 1 received adjuvant chemotherapy. Median follow-up was 14.3 months (range, 2.4-64.4 months), and the median age at diagnosis was 71.5 years (range, 54-81 years). Cox regression and log-rank tests showed no significant differences in any outcomes between the surgery and SBRT groups, and no patients developed brain metastases during the study period. Conclusions: Data are lacking regarding the benefit of PCI in early-stage SCLC. Although the sample size in this study was too small to draw any conclusions, the findings add to the ongoing dialogue regarding the importance of PCI in this patient population. No difference was identified in survival and cancer recurrence in patients who received either surgery or SBRT in the absence of PCI.

An Analysis of Clinical Toxic Effects and Quality of Life as a Function of Radiation Dose and Volume After Lung Stereotactic Body Radiation Therapy.

PURPOSE: To analyze clinical toxicity and quality-of-life (QOL) outcomes among patients with stage I non-small cell lung cancer (NSCLC) after stereotactic body radiation therapy (SBRT) as a function of radiation dose and volume parameters. METHODS AND MATERIALS: In this institutional review board-approved study, 55 patients with stage I NSCLC who received SBRT (12 Gy × 4) and completed QOL forms were analyzed. Clinical symptoms and QOL outcomes were measured at baseline and at 3, 6, 12, 18, 24, and 36 months after SBRT. Clinical toxicity was graded using the Common Terminology Criteria for Adverse Events, version 4.0. Quality of life was followed using the validated Functional Assessment of Cancer Therapy-Lung-Trial Outcome Index (FACT-L-TOI) instrument. Dosimetric parameters including the mean lung radiation dose and the volume of normal lung receiving greater than 5, 10, 13, or 20 Gy (V5, V10, V13, and V20) were measured from the radiation treatment plan. Student t tests and Pearson correlation analyses were used to examine the relationships between radiation lung metrics and clinically meaningful changes in QOL and/or clinical toxic effects. The Kaplan-Meier method was used to estimate rates of local control (LC), disease-free survival (DFS), and overall survival (OS). RESULTS: With a median follow-up of 24 months, the 3-year LC, DFS, and OS were 93%, 65%, and 84%, respectively, with a 5.5% rate of grade-3 toxic effects and no grade 4 or 5 toxic effects. Clinically meaningful declines in patient-reported QOL (FACT-L-TOI, lung cancer subscale, physical well-being, and/or functional well-being) posttreatment significantly correlated with increased dosimetric parameters such as V10, V13, and V20. CONCLUSION: Although lung SBRT was associated with excellent LC and minimal clinical toxic effects for early-stage NSCLC, clinically meaningful declines in QOL were significantly correlated with increasing lung dose and volume parameters.

Phase I trial of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for the treatment of metastatic pancreatic cancer.

The safety of oncolytic adenovirus-mediated suicide and interleukin-12 (IL 12) gene therapy was evaluated in metastatic pancreatic cancer patients. In this phase I study, a replication-competent adenovirus (Ad5-yCD/mutTKSR39 rep-hIL-12) expressing yCD/mutTKSR39 (yeast cytidine deaminase/mutant S39R HSV-1 thymidine kinase) and human IL-12 (IL 12) was injected into tumors of 12 subjects with metastatic pancreatic cancer (T2N0M1-T4N1M1) at escalating doses (1 × 1011, 3 × 1011, or 1 × 1012 viral particles). Subjects received 5-fluorocytosine (5-FC) therapy for 7 days followed by chemotherapy (FOLFIRINOX or gemcitabine/albumin-bound paclitaxel) starting 21 days after adenovirus injection. The study endpoint was toxicity through day 21. Experimental endpoints included measurements of serum IL 12, interferon gamma (IFNG), and CXCL10 to assess immune system activation. Peripheral blood mononuclear cells and proliferation markers were analyzed by flow cytometry. Twelve patients received Ad5-yCD/mutTKSR39 rep-hIL-12 and oral 5-FC. Approximately 94% of the 121 adverse events observed were grade 1/2 requiring no medical intervention. Ad5-yCD/mutTKSR39 rep-hIL-12 DNA was detected in the blood of two patients. Elevated serum IL 12, IFNG, and CXCL10 levels were detected in 42%, 75%, and 92% of subjects, respectively. Analysis of immune cell populations indicated activation after Ad5-yCD/mutTKSR39 rep-hIL-12 administration. The median survival of patients in the third cohort is 18.1 (range, 3.5-20.0) months. The study maximum tolerated dose (MTD) was not reached.

Technical Note: Comparison of the internal target volume (ITV) contours and dose calculations on 4DCT, average CBCT, and 4DCBCT imaging for lung stereotactic body radiation therapy (SBRT).

PURPOSE: To investigate the differences between internal target volumes (ITVs) contoured on the simulation 4DCT and daily 4DCBCT images for lung cancer patients treated with stereotactic body radiotherapy (SBRT) and determine the dose delivered on 4D planning technique. METHODS: For nine patients, 4DCBCTs were acquired before each fraction to assess tumor motion. An ITV was contoured on each phase of the 4DCBCT and a union of the 10 ITVs was used to create a composite ITV. Another ITV was drawn on the average 3DCBCT (avgCBCT) to compare with current clinical practice. The Dice coefficient, Hausdorff distance, and center of mass (COM) were averaged over four fractions to compare the ITVs contoured on the 4DCT, avgCBCT, and 4DCBCT for each patient. Planning was done on the average CT, and using the online registration, plans were calculated on each phase of the 4DCBCT and on the avgCBCT. Plan dose calculations were tested by measuring ion chamber dose in the CIRS lung phantom. RESULTS: The Dice coefficients were similar for all three comparisons: avgCBCT-to-4DCBCT (0.7 ± 0.1), 4DCT-to-avgCBCT (0.7 ± 0.1), and 4DCT-to-4DCBCT (0.7 ± 0.1); while the mean COM differences were also comparable (2.6 ± 2.2mm, 2.3 ± 1.4mm, and 3.1 ± 1.1mm, respectively). The Hausdorff distances for the comparisons with 4DCBCT (8.2 ± 2.9mm and 8.1 ± 3.2mm) were larger than the comparison without (6.5 ± 2.5mm). The differences in ITV D95% between the treatment plan and avgCBCT calculations were 4.3 ± 3.0% and -0.5 ± 4.6%, between treatment plan and 4DCBCT plans, respectively, while the ITV V100% coverages were 99.0 ± 1.9% and 93.1 ± 8.0% for avgCBCT and 4DCBCT, respectively. CONCLUSION: There is great potential for 4DCBCT to evaluate the extent of tumor motion before treatment, but image quality challenges the clinician to consistently delineate lung target volumes.

Correlation of normal lung density changes with dose after stereotactic body radiotherapy (SBRT) for early stage lung cancer.

BACKGROUND AND PURPOSE: To investigate the correlation between normal lung CT density changes with dose accuracy and outcome after stereotactic body radiation therapy (SBRT) for patients with early stage non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Thirty-one patients (with a total of 33 lesions) with non-small cell lung cancer were selected out of 270 patients treated with SBRT at a single institution between 2003 and 2009. Out of these 31 patients, 10 patients had developed radiation pneumonitis (RP). Dose distributions originally planned using a 1-D pencil beam-based dose algorithm were retrospectively recomputed using different algorithms. Prescription dose was 48 Gy in 4 fractions in most patients. Planning CT images were rigidly registered to follow-up CT datasets at 3-9 months after treatment. Corresponding dose distributions were mapped from planning to follow-up CT images. Hounsfield Unit (HU) changes in lung density in individual, 5 Gy, dose bins from 5 to 45 Gy were assessed in the peri-tumoral region. Correlations between HU changes in various normal lung regions, dose indices (V20, MLD, generalized equivalent uniform dose (gEUD)), and RP grade were investigated. RESULTS: Strong positive correlation was found between HU changes in the peri-tumoral region and RP grade (Spearman's r = 0.760; p < 0.001). Positive correlation was also observed between RP and HU changes in the region covered by V20 for all algorithms (Spearman's r ≥ 0.738; p < 0.001). Additionally, V20, MLD, and gEUD were significantly correlated with RP grade (p < 0.01). MLD in the peri-tumoral region computed with model-based algorithms was 5-7% lower than the PB-based methods. CONCLUSION: Changes of lung density in the peri-tumoral lung and in the region covered by V20 were strongly associated with RP grade. Relative to model-based methods, PB algorithms over-estimated mean peri-tumoral dose and showed displacement of the high-dose region, which correlated with HU changes on follow-up CT scans.

Four-dimensional computed tomography-based biomechanical measurements of pulmonary function and their correlation with clinical outcome for lung stereotactic body radiation therapy patients.

BACKGROUND: Functional image guided radiotherapy allows for the delivery of an equivalent dose to tumor targets while sparing high ventilation lung tissues. In this study, we investigate whether radiation dose to functional lung is associated with clinical outcome for stereotactic body radiation therapy (SBRT) patients. METHODS: Four-dimensional computed tomography (4DCT) images were used to assess lung function. Deformable image registration (DIR) was performed from the end-inhale phase to the end-exhale phase with resultant displacement vectors used to calculate ventilation maps. In addition to the Jacobian-based ventilation we introduce a volumetric variation method (Rv) based on a biomechanical finite element method (FEM), to assess lung ventilation. Thirty NSCLC patients, treated with SBRT, were evaluated in this study. 4DCT images were used to calculate both Jacobian and Rv-based ventilation images. Areas under the receiver operating characteristic curve (AUC) were used to assess the predictive power of functional metrics. Metrics were calculated over the whole lung as well as high and low ventilated regions. RESULTS: Ventilation in dose regions between 1 and 5 Gy had higher AUC values compared to other dose regions. Rv based ventilation imaging method also showed to be less spatially variant and less heterogeneous, and the resultant Rv metrics had higher AUC values for predicting grade 2+ dyspnea. CONCLUSIONS: Low dose delivered to high ventilation areas may also increase the risk of compromised pulmonary function. Rv based ventilation images could be useful for the prediction of clinical toxicity for lung SBRT patients.

Single institution experience treating adrenal metastases with stereotactic body radiation therapy.

OBJECTIVE: The objective of the study is to present our experience of treating adrenal metastases using stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS: We retrospectively reviewed patients with adrenal metastases treated using SBRT from 2001 to 2014. Response Evaluation Criteria in Solid Tumors v1.1 was used. Maximum tumor response was defined as the greatest percentage tumor reduction noted on two or more post-SBRT CT scans. RESULTS: We identified 44 patients (median age 61.3 years, range: 25.8-85), with 54 adrenal metastases; primary diagnoses include non-small cell lung cancer (28 patients and 38 lesions), small cell lung cancer (1 patient), hepatocellular carcinoma (6 patients), and other (9 patients). Treatment was delivered in single (16 lesions, median dose 18 Gy [14-18]) or multiple fractions (38 lesions, median dose 30 Gy [16-40]). Median planning target volume was 49.65cc (3.21-984.54). Median response at first post-SBRT follow-up (median 1.65 months (m) (0.33-5.37), n = 46 lesions) was 10.8% with 91.3% local control. Median maximum tumor response was 31.8% (n = 32 lesions) at median follow-up of 5.4 m (0.9-44.8) with 96.6% local control. The response was comparable regardless of tumor histology or treatment fractionation. No patients experienced Grade 3/4 acute toxicities. One patient with a history of naproxen use required suturing with omental patch placement for perforated pyloric ulcer 14 m post-SBRT (18 Gy in single fraction) to the right adrenal metastasis; this region received <5 Gy. Ten patients treated for pain with available follow-up obtained relief. CONCLUSIONS: SBRT is a safe and efficacious treatment for adrenal metastases, demonstrating local tumor control. Further study of the impact on survival and quality of life is warranted.

Long-term Follow-up on NRG Oncology RTOG 0915 (NCCTG N0927): A Randomized Phase 2 Study Comparing 2 Stereotactic Body Radiation Therapy Schedules for Medically Inoperable Patients With Stage I Peripheral Non-Small Cell Lung Cancer.

PURPOSE: To present long-term results of RTOG 0915/NCCTG N0927, a randomized lung stereotactic body radiation therapy trial of 34 Gy in 1 fraction versus 48 Gy in 4 fractions. METHODS AND MATERIALS: This was a phase 2 multicenter study of patients with medically inoperable non-small cell lung cancer with biopsy-proven peripheral T1 or T2 N0M0 tumors, with 1-year toxicity rates as the primary endpoint and selected failure and survival outcomes as secondary endpoints. The study opened in September 2009 and closed in March 2011. Final data were analyzed through May 17, 2018. RESULTS: Eighty-four of 94 patients accrued were eligible for analysis: 39 in arm 1 and 45 in arm 2. Median follow-up time was 4.0 years for all patients and 6.0 years for those alive at analysis. Rates of grade 3 and higher toxicity were 2.6% in arm 1 and 11.1% in arm 2. Median survival times (in years) for 34 Gy and 48 Gy were 4.1 versus 4.6, respectively. Five-year outcomes (95% confidence interval) for 34 Gy and 48 Gy were a primary tumor failure rate of 10.6% (3.3%-23.1%) versus 6.8% (1.7%-16.9%); overall survival of 29.6% (16.2%-44.4%) versus 41.1% (26.6%-55.1%); and progression-free survival of 19.1% (8.5%-33.0%) versus 33.3% (20.2%-47.0%). Distant failure as the sole failure or a component of first failure occurred in 6 patients (37.5%) in the 34 Gy arm and in 7 (41.2%) in the 48 Gy arm. CONCLUSIONS: No excess in late-appearing toxicity was seen in either arm. Primary tumor control rates at 5 years were similar by arm. A median survival time of 4 years for each arm suggests similar efficacy, pending any larger studies appropriately powered to detect survival differences.

Utilization of a hybrid finite-element based registration method to quantify heterogeneous tumor response for adaptive treatment for lung cancer patients.

Tumor response to radiation treatment (RT) can be evaluated from changes in metabolic activity between two positron emission tomography (PET) images. Activity changes at individual voxels in pre-treatment PET images (PET1), however, cannot be derived until their associated PET-CT (CT1) images are appropriately registered to during-treatment PET-CT (CT2) images. This study aimed to investigate the feasibility of using deformable image registration (DIR) techniques to quantify radiation-induced metabolic changes on PET images. Five patients with non-small-cell lung cancer (NSCLC) treated with adaptive radiotherapy were considered. PET-CTs were acquired two weeks before RT and 18 fractions after the start of RT. DIR was performed from CT1 to CT2 using B-Spline and diffeomorphic Demons algorithms. The resultant displacements in the tumor region were then corrected using a hybrid finite element method (FEM). Bitmap masks generated from gross tumor volumes (GTVs) in PET1 were deformed using the four different displacement vector fields (DVFs). The conservation of total lesion glycolysis (TLG) in GTVs was used as a criterion to evaluate the quality of these registrations. The deformed masks were united to form a large mask which was then partitioned into multiple layers from center to border. The averages of SUV changes over all the layers were 1.0 ± 1.3, 1.0 ± 1.2, 0.8 ± 1.3, 1.1 ± 1.5 for the B-Spline, B-Spline + FEM, Demons and Demons + FEM algorithms, respectively. TLG changes before and after mapping using B-Spline, Demons, hybrid-B-Spline, and hybrid-Demons registrations were 20.2%, 28.3%, 8.7%, and 2.2% on average, respectively. Compared to image intensity-based DIR algorithms, the hybrid FEM modeling technique is better in preserving TLG and could be useful for evaluation of tumor response for patients with regressing tumors.

Stereotactic Body Radiotherapy for Elderly Patients With Medically Inoperable Pancreatic Cancer.

OBJECTIVES: People over the age of 75 years account for approximately 40% of patients diagnosed with pancreatic cancer, many with comorbidities that may limit their treatment options. This study reports on the use of stereotactic body radiation therapy (SBRT) in this population. MATERIALS AND METHODS: Twenty consecutively treated patients over the age of 75 with pathologically proven localized pancreatic cancer were included in this retrospective review. All had been evaluated by a multidisciplinary team as unable to tolerate surgery or combined chemoradiation therapy. Patient outcomes were analyzed to determine the safety and efficacy of SBRT in this elderly cohort. RESULTS: The median age was 83.2 years (minimum 77 y, maximum 90 y). Eighteen patients were treated at time of initial diagnosis, and 2 for recurrence after surgery. Eleven (55%) of the patients had an Adult Comorbidity Evaluation-27 comorbidity index score of 3 (severe) and 6 (30%) had a score of 2 (moderate). Fourteen patients were treated with 35 Gy in 5 fractions, 5 with 30 Gy in 5 fractions, and 1 patient with 36 Gy in 3 fractions. Seven (35%) patients had common terminology criteria for adverse events (CTCAE) V4.0 toxicity grade of 1-2, and 3 patients had a CTCAE V4.0 toxicity grade of 3-4, 2 with dehydration, and 1 had episodes of gastrointestinal bleeding. Three patients recurred locally, 10 had distant metastases, 4 of whom were found on the first posttreatment scan. Median overall survival was 6.4 months (95% confidence interval, 3.5-10.8 mo). Median recurrence-free survival was 6.8 months (95% confidence interval, 1.3-23.5 mo). Two patients survived >23 months. CONCLUSION: SBRT for pancreatic cancer appears to be a safe and effective method for treatment of elderly patients, even in the setting of severe comorbidities.

Development and evaluation of a clinical model for lung cancer patients using stereotactic body radiotherapy (SBRT) within a knowledge-based algorithm for treatment planning.

The purpose of this study was to describe the development of a clinical model for lung cancer patients treated with stereotactic body radiotherapy (SBRT) within a knowledge-based algorithm for treatment planning, and to evaluate the model performance and applicability to different planning techniques, tumor locations, and beam arrangements. 105 SBRT plans for lung cancer patients previously treated at our institution were included in the development of the knowledge-based model (KBM). The KBM was trained with a combination of IMRT, VMAT, and 3D CRT techniques. Model performance was validated with 25 cases, for both IMRT and VMAT. The full KBM encompassed lesions located centrally vs. peripherally (43:62), upper vs. lower (62:43), and anterior vs. posterior (60:45). Four separate sub-KBMs were created based on tumor location. Results were compared with the full KBM to evaluate its robustness. Beam templates were used in conjunction with the optimizer to evaluate the model's ability to handle suboptimal beam placements. Dose differences to organs-at-risk (OAR) were evaluated between the plans gener-ated by each KBM. Knowledge-based plans (KBPs) were comparable to clinical plans with respect to target conformity and OAR doses. The KBPs resulted in a lower maximum spinal cord dose by 1.0 ± 1.6 Gy compared to clinical plans, p = 0.007. Sub-KBMs split according to tumor location did not produce significantly better DVH estimates compared to the full KBM. For central lesions, compared to the full KBM, the peripheral sub-KBM resulted in lower dose to 0.035 cc and 5 cc of the esophagus, both by 0.4Gy ± 0.8Gy, p = 0.025. For all lesions, compared to the full KBM, the posterior sub-KBM resulted in higher dose to 0.035 cc, 0.35 cc, and 1.2 cc of the spinal cord by 0.2 ± 0.4Gy, p = 0.01. Plans using template beam arrangements met target and OAR criteria, with an increase noted in maximum heart dose (1.2 ± 2.2Gy, p = 0.01) and GI (0.2 ± 0.4, p = 0.01) for the nine-field plans relative to KBPs planned with custom beam angles. A knowledge-based model for lung SBRT consisting of multiple treatment modalities and lesion loca-tions produced comparable plan quality to clinical plans. With proper training and validation, a robust KBM can be created that encompasses both IMRT and VMAT techniques, as well as different lesion locations.

To gate or not to gate - dosimetric evaluation comparing Gated vs. ITV-based methodologies in stereotactic ablative body radiotherapy (SABR) treatment of lung cancer.

BACKGROUND: To compare retrospectively generated gated plans to conventional internal target volume (ITV)-based plans and to evaluate whether gated radiotherapy provides clinically relevant dosimetric improvements to organs-at-risk (OARs). METHODS: Evaluation was performed of 150 stereotactic ablative radiotherapy treatment plans delivered to 128 early-stage (T1-T3 (<5 cm)) NSCLC patients. To generate gated plans, original ITV-based plans were re-optimized and re-calculated on the end-exhale phase and using gated planning target volumes (PTV). Gated and ITV-based plans were produced for 3 × 18 Gy and 4 × 12 Gy fractionation regimens. Dose differences between gated and ITV-based plans were analyzed as a function of both three-dimensional motion and tumor volume. OARs were analyzed using RTOG and AAPM dose constraints. RESULTS: Differences between gated and ITV-based plans for all OAR indices were largest for the 3 × 18 Gy regimen. For this regimen, MLD differences calculated by subtracting the gated values from the ITV-based values (ITV vs. Gated) were 0.10 ± 0.56 Gy for peripheral island (N = 57), 0.16 ± 0.64 Gy for peripheral lung-wall seated (N = 57), and 0.10 ± 0.64 Gy for central tumors (N = 36). Variations in V20 were similarly low, with the greatest differences occurring in peripheral tumors (0.20 ± 1.17 %). Additionally, average differences (in 2Gy-equivalence) between ITV and gated lung indices fell well below clinical tolerance values for all fractionation regimens, with no clinically meaningful differences observed from the 4 × 12 Gy regimen and rarely for the 3 × 18 Gy regimen (<2 % of cases). Dosimetric differences between gated and ITV-based methods did generally increase with increasing tumor motion and decreasing tumor volume. Dose to ribs and bronchial tree were slightly higher in gated plans compared to ITV-based plans and slightly lower for esophagus, heart, spinal cord, and trachea. CONCLUSIONS: Analysis of 150 SABR-based lung cancer treatment plans did not show a substantial benefit for the gating regimen when compared to ITV-based treatment plans. Small benefits were observed only for the largest tumor motion (exceeding 2 cm) and the high dose treatment regimen (3 × 18 Gy), though these benefits did not appear to be clinically relevant.

Evaluation of gantry speed on image quality and imaging dose for 4D cone-beam CT acquisition.

BACKGROUND: This study investigates the effect of gantry speed on 4DCBCT image quality and dose for the Varian On-Board Imager®. METHODS: A thoracic 4DCBCT protocol was designed using a 125 kVp spectrum. Image quality parameters were evaluated for 4DCBCT acquisition using Catphan® phantom with real-time position management™ system for gantry speeds varying between 1.0 to 6.0°/s. Superior-inferior motion of the phantom was executed using a sinusoidal waveform with five second period. Scans were retrospectively sorted into 4 phases (CBCT-4 ph) and 10 phases (CBCT-10 ph); average 4DCBCT (CBCT-ave), using all image data from the 4DCBCT acquisitions was also evaluated. The 4DCBCT images were evaluated using the following image quality metrics: spatial resolution, contrast-to-noise ratio (CNR), and uniformity index (UI). Additionally, Hounsfield unit (HU) sensitivity compared to a baseline CBCT and percent differences and RMS errors (RMSE) of excursion were also determined. Imaging dose was evaluated using an IBA CC13 ion chamber placed within CIRS Thorax phantom using the same sinusoidal motion and image acquisition settings as mentioned above. RESULTS: Spatial resolution decreased linearly from 5.93 to 3.82 lp/cm as gantry speed increased from 1.0 to 6.0°/s. CNR decreased linearly from 4.80 to 1.82 with gantry speed increasing from 1.0 to 6.0°/s, respectively. No noteworthy variations in UI, HU sensitivity, or excursion metrics were observed with changes in gantry speed. Ion chamber dose rates measured ranged from 2.30 (lung) to 5.18 (bone) E-3 cGy/mAs. CONCLUSIONS: A quantitative analysis of the Varian OBI's 4DCBCT capabilities was explored. Changing gantry speed changes the number of projections used for reconstruction, affecting both image quality and imaging dose if x-ray tube current is held constant. From the results of this study, a gantry speed between 2 and 3°/s was optimal when considering image quality, dose, and reconstruction time. The future of 4DCBCT clinical utility relies on further investigation of image acquisition and reconstruction optimization.

Characteristics of a novel treatment system for linear accelerator-based stereotactic radiosurgery.

The purpose of this study is to characterize the dosimetric properties and accuracy of a novel treatment platform (Edge radiosurgery system) for localizing and treating patients with frameless, image-guided stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT). Initial measurements of various components of the system, such as a comprehensive assessment of the dosimetric properties of the flattening filter-free (FFF) beams for both high definition (HD120) MLC and conical cone-based treatment, positioning accuracy and beam attenuation of a six degree of freedom (6DoF) couch, treatment head leakage test, and integrated end-to-end accuracy tests, have been performed. The end-to-end test of the system was performed by CT imaging a phantom and registering hidden targets on the treatment couch to determine the localization accuracy of the optical surface monitoring system (OSMS), cone-beam CT (CBCT), and MV imaging systems, as well as the radiation isocenter targeting accuracy. The deviations between the percent depth-dose curves acquired on the new linac-based system (Edge), and the previously published machine with FFF beams (TrueBeam) beyond D(max) were within 1.0% for both energies. The maximum deviation of output factors between the Edge and TrueBeam was 1.6%. The optimized dosimetric leaf gap values, which were fitted using Eclipse dose calculations and measurements based on representative spine radiosurgery plans, were 0.700 mm and 1.000 mm, respectively. For the conical cones, 6X FFF has sharper penumbra ranging from 1.2-1.8 mm (80%-20%) and 1.9-3.8 mm (90%-10%) relative to 10X FFF, which has 1.2-2.2mm and 2.3-5.1mm, respectively. The relative attenuation measurements of the couch for PA, PA (rails-in), oblique, oblique (rails-out), oblique (rails-in) were: -2.0%, -2.5%, -15.6%, -2.5%, -5.0% for 6X FFF and -1.4%, -1.5%, -12.2%, -2.5%, -5.0% for 10X FFF, respectively, with a slight decrease in attenuation versus field size. The systematic deviation between the OSMS and CBCT was -0.4 ± 0.2 mm, 0.1± 0.3mm, and 0.0 ± 0.1 mm in the vertical, longitudinal, and lateral directions. The mean values and standard deviations of the average deviation and maximum deviation of the daily Winston-Lutz tests over three months are 0.20 ± 0.03 mm and 0.66 ± 0.18 mm, respectively. Initial testing of this novel system demonstrates the technology to be highly accurate and suitable for frameless, linac-based SRS and SBRT treatment.

Correlation of dose computed using different algorithms with local control following stereotactic ablative radiotherapy (SABR)-based treatment of non-small-cell lung cancer.

PURPOSE: To retrospectively compute dose distributions for lung cancer patients treated with SABR, and to correlate dose distributions with outcome using a tumor control probability (TCP) model. METHODS: Treatment plans for 133 NSCLC patients treated using 12 Gy/fxn × 4 (BED=106 Gy), and planned using a pencil-beam (1D-equivalent-path-length, EPL-1D) algorithm were retrospectively re-calculated using model-based algorithms (including convolution/superposition, Monte Carlo). 4D imaging was performed to manage motion. TCP was computed using the Marsden model and associations between dose and outcome were inferred. RESULTS: Mean D95 reductions of 20% (max.=33%) were noted with model-based algorithms (relative to EPL-1D) for the smallest tumors (PTV<20 cm(3)), corresponding to actual delivered D95 BEDs of ≈ 60-85 Gy. For larger tumors (PTV>100 cm(3)), D95 reductions were ≈ 10% (BED>100 Gy). Mean lung doses (MLDs) were 15% lower for model-based algorithms for PTVs<20 cm(3). No correlation between tumor size and 2-year local control rate was observed clinically, consistent with TCP calculations, both of which were ≈ 90% across all PTV bins. CONCLUSION: Results suggest that similar control rates might be achieved for smaller tumors using lower BEDs relative to larger tumors. However, more studies with larger patient cohorts are necessary to confirm this possible finding.

Evaluation of two synchronized external surrogates for 4D CT sorting.

The purpose of this study was to quantify the performance and agreement between two different external surrogate acquisition systems: Varian's Real-Time Position Management (RPM) and Philips Medical Systems' pneumatic bellows, in the context of waveform and 4D CT image analysis. Eight patient displacement curves derived from RPM data were inputted into a motion platform with varying amplitudes (0.5 to 3 cm) and patterns. Simultaneous 4D CT acquisition, with synchronized X-ray on detection, was performed with the bellows and RPM block placed on the platform. Bellows data were used for online retrospective phase-based sorting, while RPM data were used for off-line reconstruction of raw 4D CT data. RPM and bellows breathing curves were resampled, normalized, and analyzed to determine associations between different external surrogates, relative amplitude differences, and system latency. Maximum intensity projection (MIP) images were generated, phantom targets were delineated, and volume differences, overlap index, and Dice similarity coefficient differences were evaluated. A prospective patient study of ten patients was performed and waveforms were evaluated for latency (i.e., absolute time differences) and overall agreement. 4D CT sorting quality and subtraction images were assessed. Near perfect associations between the RPM and bellows-acquired breathing traces were found (Pearson's r = 0.987-0.999). Target volumes were 200.4 ± 12 cc and 199.8 ± 12.6 cc for RPM and bellows targets, respectively, which was not significantly different (U = 33, p > 0.05). Negligible centroid variations were observed between bellows and RPM-contoured MIP targets (largest discrepancy = -0.24 ± 0.31 mm in superior-inferior direction). The maximum volume difference was observed for an RPM target 2.5 cc (1%) less than bellows, yielding the largest difference in centroid displacement (0.9 mm). Strong correlations in bellows and RPM waveforms were observed for all patients (0.947 ± 0.037). Latency between external surrogates was < 100 ms for phantom and patient data. Negligible differences were observed between MIP, end-exhale, and end-inhale phase images for all cases, with delineated RPM and bellows lung volumes demonstrating a mean difference of -0.3 ± 0.51%. Dice similarity coefficients and overlap indices were near unity for phantom target volumes and patient lung volumes. Slight differences were observed in waveform and latency analysis between Philips bellows and Varian's RPM, although these did not translate to differences in image quality or impact delineations. Therefore, the two systems were found to be equivalent external surrogates in the context of 4D CT for treatment planning purposes.

Practical methods for improving dose distributions in Monte Carlo-based IMRT planning of lung wall-seated tumors treated with SBRT.

Current commercially available planning systems with Monte Carlo (MC)-based final dose calculation in IMRT planning employ pencil-beam (PB) algorithms in the optimization process. Consequently, dose coverage for SBRT lung plans can feature cold-spots at the interface between lung and tumor tissue. For lung wall (LW)-seated tumors, there can also be hot spots within nearby normal organs (example: ribs). This study evaluated two different practical approaches to limiting cold spots within the target and reducing high doses to surrounding normal organs in MC-based IMRT planning of LW-seated tumors. First, "iterative reoptimization", where the MC calculation (with PB-based optimization) is initially performed. The resultant cold spot is then contoured and used as a simultaneous boost volume. The MC-based dose is then recomputed. The second technique uses noncoplanar beam angles with limited path through lung tissue. Both techniques were evaluated against a conventional coplanar beam approach with a single MC calculation. In all techniques the prescription dose was normalized to cover 95% of the PTV. Fifteen SBRT lung cases with LW-seated tumors were planned. The results from iterative reoptimization showed that conformity index (CI) and/or PTV dose uniformity (UPTV) improved in 12/15 plans. Average improvement was 13%, and 24%, respectively. Nonimproved plans had PTVs near the skin, trachea, and/or very small lung involvement. The maximum dose to 1cc volume (D1cc) of surrounding OARs decreased in 14/15 plans (average 10%). Using noncoplanar beams showed an average improvement of 7% in 10/15 cases and 11% in 5/15 cases for CI and UPTV, respectively. The D1cc was reduced by an average of 6% in 10/15 cases to surrounding OARs. Choice of treatment planning technique did not statistically significantly change lung V5. The results showed that the proposed practical approaches enhance dose conformity in MC-based IMRT planning of lung tumors treated with SBRT, improving target dose coverage and potentially reducing toxicities to surrounding normal organs.

Clinical commissioning and use of the Novalis Tx linear accelerator for SRS and SBRT.

The purpose of this study was to perform comprehensive measurements and testing of a Novalis Tx linear accelerator, and to develop technical guidelines for com-missioning from the time of acceptance testing to the first clinical treatment. The Novalis Tx (NTX) linear accelerator is equipped with, among other features, a high-definition MLC (HD120 MLC) with 2.5 mm central leaves, a 6D robotic couch, an optical guidance positioning system, as well as X-ray-based image guidance tools to provide high accuracy radiation delivery for stereotactic radiosurgery and stereotactic body radiation therapy procedures. We have performed extensive tests for each of the components, and analyzed the clinical data collected in our clinic. We present technical guidelines in this report focusing on methods for: (1) efficient and accurate beam data collection for commissioning treatment planning systems, including small field output measurements conducted using a wide range of detectors; (2) commissioning tests for the HD120 MLC; (3) data collection for the baseline characteristics of the on-board imager (OBI) and ExacTrac X-ray (ETX) image guidance systems in conjunction with the 6D robotic couch; and (4) end-to-end testing of the entire clinical process. Established from our clinical experience thus far, recommendations are provided for accurate and efficient use of the OBI and ETX localization systems for intra- and extracranial treatment sites. Four results are presented. (1) Basic beam data measurements: Our measurements confirmed the necessity of using small detectors for small fields. Total scatter factors varied significantly (30% to approximately 62%) for small field measurements among detectors. Unshielded stereotactic field diode (SFD) overestimated dose by ~ 2% for large field sizes. Ion chambers with active diameters of 6 mm suffered from significant volume averaging. The sharpest profile penumbra was observed for the SFD because of its small active diameter (0.6 mm). (2) MLC commissioning: Winston Lutz test, light/radiation field congruence, and Picket Fence tests were performed and were within criteria established by the relevant task group reports. The measured mean MLC transmission and dynamic leaf gap of 6 MV SRS beam were 1.17% and 0.36 mm, respectively. (3) Baseline characteristics of OBI and ETX: The isocenter localization errors in the left/right, posterior/anterior, and superior/inferior directions were, respectively, -0.2 ± 0.2 mm, -0.8 ± 0.2 mm, and -0.8 ± 0.4 mm for ETX, and 0.5 ± 0.7 mm, 0.6 ± 0.5 mm, and 0.0 ± 0.5 mm for OBI cone-beam computed tomography. The registration angular discrepancy was 0.1 ± 0.2°, and the maximum robotic couch error was 0.2°. (4) End-to-end tests: The measured isocenter dose differences from the planned values were 0.8% and 0.4%, measured respectively by an ion chamber and film. The gamma pass rate, measured by EBT2 film, was 95% (3% DD and 1 mm DTA). Through a systematic series of quantitative commissioning experiments and end-to-end tests and our initial clinical experience, described in this report, we demonstrate that the NTX is a robust system, with the image guidance and MLC requirements to treat a wide variety of sites - in particular for highly accurate delivery of SRS and SBRT-based treatments.

Measurement of regional compliance using 4DCT images for assessment of radiation treatment.

PURPOSE: Radiation-induced damage, such as inflammation and fibrosis, can compromise ventilation capability of local functional units (alveoli) of the lung. Ventilation function as measured with ventilation images, however, is often complicated by the underlying mechanical variations. The purpose of this study is to present a 4DCT-based method to measure the regional ventilation capability, namely, regional compliance, for the evaluation of radiation-induced lung damage. METHODS: Six 4DCT images were investigated in this study: One previously used in the generation of a POPI model and the other five acquired at Henry Ford Health System. A tetrahedral geometrical model was created and scaled to encompass each of the 4DCT image domains. Image registrations were performed on each of the 4DCT images using a multiresolution Demons algorithm. The images at the end of exhalation were selected as a reference. Images at other exhalation phases were registered to the reference phase. For the POPI-modeled patient, each of these registration instances was validated using 40 landmarks. The displacement vector fields (DVFs) were used first to calculate the volumetric variation of each tetrahedron, which represents the change in the air volume. The calculated results were interpolated to generate 3D ventilation images. With the computed DVF, a finite element method (FEM) framework was developed to compute the stress images of the lung tissue. The regional compliance was then defined as the ratio of the ventilation and stress values and was calculated for each phase. Based on iterative FEM simulations, the potential range of the mechanical parameters for the lung was determined by comparing the model-computed average stress to the clinical reference value of airway pressure. The effect of the parameter variations on the computed stress distributions was estimated using Pearson correlation coefficients. RESULTS: For the POPI-modeled patient, five exhalation phases from the start to the end of exhalation were denoted by P(i), i = 1, ..., 5, respectively. The average lung volume variation relative to the reference phase (P5) was reduced from 18% at P1 to 4.8% at P4. The average stress at phase P(i) was 1.42, 1.34, 0.74, and 0.28 kPa, and the average regional compliance was 0.19, 0.20, 0.20, and 0.24 for i = 1, ..., 4, respectively. For the other five patients, their average R(v) value at the end-inhalation phase was 21.1%, 19.6%, 22.4%, 22.5%, and 18.8%, respectively, and the regional compliance averaged over all six patients is 0.2. For elasticity parameters chosen from the potential parameter range, the resultant stress distributions were found to be similar to each other with Pearson correlation coefficients greater than 0.81. CONCLUSIONS: A 4DCT-based mechanical model has been developed to calculate the ventilation and stress images of the lung. The resultant regional compliance represents the lung's elasticity property and is potentially useful in correlating regions of lung damage with radiation dose following a course of radiation therapy.

Impact of fraction size on lung radiation toxicity: hypofractionation may be beneficial in dose escalation of radiotherapy for lung cancers.

PURPOSE: To assess how fraction size impacts lung radiation toxicity and therapeutic ratio in treatment of lung cancers. METHODS AND MATERIALS: The relative damaged volume (RDV) of lung was used as the endpoint in the comparison of various fractionation schemes with the same normalized total dose (NTD) to the tumor. The RDV was computed from the biologically corrected lung dose-volume histogram (DVH), with an alpha/beta ratio of 3 and 10 for lung and tumor, respectively. Two different (linear and S-shaped) local dose-effect models that incorporated the concept of a threshold dose effect with a single parameter D(L50) (dose at 50% local dose effect) were used to convert the DVH into the RDV. The comparison was conducted using four representative DVHs at different NTD and D(L50) values. RESULTS: The RDV decreased with increasing dose/fraction when the NTD was larger than a critical dose (D(CR)) and increased when the NTD was less than D(CR). The D(CR) was 32-50 Gy and 58-87 Gy for a small tumor (11 cm(3)) for the linear and S-shaped local dose-effect models, respectively, when D(L50) was 20-30 Gy. The D(CR) was 66-97 Gy and 66-99 Gy, respectively, for a large tumor (266 cm(3)). Hypofractionation was preferred for small tumors and higher NTDs, and conventional fractionation was better for large tumors and lower NTDs. Hypofractionation might be beneficial for intermediate-sized tumors when NTD = 80-90 Gy, especially if the D(L50) is small (20 Gy). CONCLUSION: This computational study demonstrated that hypofractionated stereotactic body radiotherapy is a better regimen than conventional fractionation in lung cancer patients with small tumors and high doses, because it generates lower RDV when the tumor NTD is kept unchanged.