Feasibility of using ring-mounted Halcyon Linac for single-isocenter/two-lesion lung stereotactic body radiation therapy.

PURPOSE: To demonstrate the plan quality and delivery efficiency of volumetric-modulated arc therapy (VMAT) with the Halcyon Linac ring delivery system (RDS) in the treatment of single-isocenter/two-lesion lung stereotactic body radiation therapy (SBRT). MATERIALS/METHODS: Sixteen previously treated non-coplanar VMAT single-isocenter/two-lesion lung SBRT plans delivered with SBRT-dedicated C-arm TrueBeam Linac were selected. Prescribed dose was 50 Gy to each lesion over five fractions with treatment delivery every other day and AcurosXB algorithm as the final dose calculation algorithm. TrueBeam single-isocenter plans were reoptimized for Halcyon Linac with coplanar geometry. Both TrueBeam and Halcyon plans were normalized for identical combined target coverage and evaluated. Conformity indices (CIs), heterogeneity index (HI), gradient index (GI), gradient distance (GD), and D2cm were compared. The normal lung V5Gy, V10Gy, V20Gy, mean lung dose (MLD), and dose to organs at risk (OAR) were evaluated. Treatment delivery parameters, including beam-on time, were recorded. RESULTS: Halcyon plans were statistically similar to clinically delivered TrueBeam plans. No statistical differences in target conformity, dose heterogeneity, or intermediate-dose spillage were observed (all, p > 0.05). Halcyon plans, on average, demonstrated statistically insignificant reduced maximum dose to most adjacent OAR and normal lung. However, Halcyon yielded statistically significant lower maximal dose to the ribs (p = 0.041) and heart (p = 0.026), dose to 1 cc of ribs (p = 0.035) and dose to 5 cc of esophagus (p = 0.043). Plan complexity slightly increased as seen in the average increase of total monitor units, modulation factor, and beam-on time by 480, 0.48, and 2.78 min, respectively. However, the estimated overall treatment time was reduced by 2.22 min, on average. Mean dose delivery accuracy of clinical TrueBeam plans and the corresponding Halcyon plans was 98.9 ± 0.85% (range: 98.1%-100%) and 98.45 ± 0.99% (range: 97.9%-100%), respectively, demonstrating similar treatment delivery accuracy. CONCLUSION: SBRT treatment of synchronous lung lesions via single-isocenter VMAT on Halcyon RDS is feasible and dosimetrically equivalent to clinically delivered TrueBeam plans. Halcyon provides excellent plan quality and shorter overall treatment time that may improve patient compliance, reduce intrafraction movement, improve clinic efficiency, and potentially offering lung SBRT treatments for underserved patients on a Halcyon only clinic.

An Automated knowledge-based planning routine for stereotactic body radiotherapy of peripheral lung tumors via DCA-based volumetric modulated arc therapy.

PURPOSE: To develop a knowledge-based planning (KBP) routine for stereotactic body radiotherapy (SBRT) of peripherally located early-stage non-small-cell lung cancer (NSCLC) tumors via dynamic conformal arc (DCA)-based volumetric modulated arc therapy (VMAT) using the commercially available RapidPlanTM software. This proposed technique potentially improves plan quality, reduces complexity, and minimizes interplay effect and small-field dosimetry errors associated with treatment delivery. METHODS: KBP model was developed and validated using 70 clinically treated high quality non-coplanar VMAT lung SBRT plans for training and 20 independent plans for validation. All patients were treated with 54 Gy in three treatments. Additionally, a novel k-DCA planning routine was deployed to create plans incorporating historical three-dimensional-conformal SBRT planning practices via DCA-based approach prior to VMAT optimization in an automated planning engine. Conventional KBPs and k-DCA plans were compared with clinically treated plans per RTOG-0618 requirements for target conformity, tumor dose heterogeneity, intermediate dose fall-off and organs-at-risk (OAR) sparing. Treatment planning time, treatment delivery efficiency, and accuracy were recorded. RESULTS: KBPs and k-DCA plans were similar or better than clinical plans. Average planning target volume for validation was 22.4 ± 14.1 cc (7.1-62.3 cc). KBPs and k-DCA plans provided similar conformity to clinical plans with average absolute differences of 0.01 and 0.01, respectively. Maximal doses to OAR were lowered in both KBPs and k-DCA plans. KBPs increased monitor units (MU) on average 1316 (P < 0.001) while k-DCA reduced total MU on average by 1114 (P < 0.001). This routine can create k-DCA plan in less than 30 min. Independent Monte Carlo calculation demonstrated that k-DCA plans showed better agreement with planned dose distribution. CONCLUSION: A k-DCA planning routine was developed in concurrence with a knowledge-based approach for the treatment of peripherally located lung tumors. This method minimizes plan complexity associated with model-based KBP techniques and improve plan quality and treatment planning efficiency.

Development and clinical validation of a robust knowledge-based planning model for stereotactic body radiotherapy treatment of centrally located lung tumors.

PURPOSE: To develop a robust and adaptable knowledge-based planning (KBP) model with commercially available RapidPlanTM for early stage, centrally located non-small-cell lung tumors (NSCLC) treated with stereotactic body radiotherapy (SBRT) and improve a patient's"simulation to treatment" time. METHODS: The KBP model was trained using 86 clinically treated high-quality non-coplanar volumetric modulated arc therapy (n-VMAT) lung SBRT plans with delivered prescriptions of 50 or 55 Gy in 5 fractions. Another 20 independent clinical n-VMAT plans were used for validation of the model. KBP and n-VMAT plans were compared via Radiation Therapy Oncology Group (RTOG)-0813 protocol compliance criteria for conformity (CI), gradient index (GI), maximal dose 2 cm away from the target in any direction (D2cm), dose to organs-at-risk (OAR), treatment delivery efficiency, and accuracy. KBP plans were re-optimized with larger calculation grid size (CGS) of 2.5 mm to assess feasibility of rapid adaptive re-planning. RESULTS: Knowledge-based plans were similar or better than n-VMAT plans based on a range of target coverage and OAR metrics. Planning target volume (PTV) for validation cases was 30.5 ± 19.1 cc (range 7.0-71.7 cc). KBPs provided an average CI of 1.04 ± 0.04 (0.97-1.11) vs. n-VMAT plan'saverage CI of 1.01 ± 0.04 (0.97-1.17) (P < 0.05) with slightly improved GI with KBPs (P < 0.05). D2cm was similar between the KBPs and n-VMAT plans. KBPs provided lower lung V10Gy (P = 0.003), V20Gy (P = 0.007), and mean lung dose (P < 0.001). KBPs had overall better sparing of OAR at the minimal increased of average total monitor units and beam-on time by 460 (P < 0.05) and 19.2 s, respectively. Quality assurance phantom measurement showed similar treatment delivery accuracy. Utilizing a CGS of 2.5 mm in the final optimization improved planning time (mean, 5 min) with minimal or no cost to the plan quality. CONCLUSION: The RTOG-compliant adaptable RapidPlan model for early stage SBRT treatment of centrally located lung tumors was developed. All plans met RTOG dosimetric requirements in less than 30 min of planning time, potentially offering shorter "simulation to treatment" times. OAR sparing via KBPs may permit tumorcidal dose escalation with minimal penalties. Same day adaptive re-planning is plausible with a 2.5-mm CGS optimizer setting.

Automation and integration of a novel restricted single-isocenter stereotactic body radiotherapy (a-RESIST) method for synchronous two lung lesions.

Synchronous treatment of two lung lesions using a single-isocenter volumetric modulated arc therapy (VMAT) stereotactic body radiation therapy (SBRT) plan can decrease treatment time and reduce the impact of intrafraction motion. However, alignment of both lesions on a single cone beam CT (CBCT) can prove difficult and may lead to setup errors and unacceptable target coverage loss. A Restricted Single-Isocenter Stereotactic Body Radiotherapy (RESIST) method was created to minimize setup uncertainties and provide treatment delivery flexibility. RESIST utilizes a single-isocenter placed at patient's midline and allows both lesions to be planned separately but treated in the same session. Herein is described a process of automation of this novel RESIST method. Automation of RESIST significantly reduced treatment planning time while maintaining the benefits of RESIST. To demonstrate feasibility, ten patients with two lung lesions previously treated with a single-isocenter clinical VMAT plan were replanned manually with RESIST (m-RESIST) and with automated RESIST (a-RESIST). a-RESIST method automatically sets isocenter, creates beam geometry, chooses appropriate dose calculation algorithms, and performs VMAT optimization using an in-house trained knowledge-based planning model for lung SBRT. Both m-RESIST and a-RESIST showed lower dose to normal tissues compared to manually planned clinical VMAT although a-RESIST provided slightly inferior, but still clinically acceptable, dose conformity and gradient indices. However, a-RESIST significantly reduced the treatment planning time to less than 20 min and provided a higher dose to the lung tumors. The a-RESIST method provides guidance for inexperienced planners by standardizing beam geometry and plan optimization using DVH estimates. It produces clinically acceptable two lesions VMAT lung SBRT plans efficiently. We have further validated a-RESIST on phantom measurement and independent pretreatment dose verification of another four selected 2-lesions lung SBRT patients and implemented clinically. Further development of a-RESIST for more than two lung lesions and refining this approach for extracranial oligometastastic abdominal/pelvic SBRT, including development of automated simulated collision detection algorithm, merits future investigation.

Risk of target coverage loss for stereotactic body radiotherapy treatment of synchronous lung lesions via single-isocenter volumetric modulated arc therapy.

Treating multiple lung lesions synchronously via single-isocenter volumetric modulated arc therapy (VMAT) stereotactic body radiation therapy (SBRT) improves treatment efficiency and patient compliance. However, aligning multiple lung tumors accurately on single pretreatment cone beam CTs (CBCTs) can be problematic. Tumors misaligned could lead to target coverage loss. To quantify this potential target coverage loss due to small, clinically realistic setup errors, a novel simulation method was developed. This method was used on 26 previously treated patients with two metastatic lung lesions. Patients were treated with 4D CT-based, highly conformal noncoplanar VMAT plans (clinical VMAT) with 6MV-flattening filter free (FFF) beam using AcurosXB dose calculation algorithm with heterogeneity corrections. A single isocenter was placed approximately between the lesions to improve patient convenience and clinic workflow. Average isocenter to tumor distance was 5.9 cm. Prescription dose was 54 Gy/50 Gy in 3/5 fractions. For comparison, a plan summation (simulated VMAT) was executed utilizing randomly simulated, clinically relevant setup errors, obtained from pretreatment setup, per treatment fraction, in Eclipse treatment planning system for each of the six degrees of freedom within ± 5.0 mm and ± 2°. Simulations yielded average deviations of 27.4% (up to 72% loss) (P < 0.001) from planned target coverage when treating multiple lung lesions using a single-isocenter plan. The largest deviations from planned coverage and desired biological effective dose (BED10, with α/ß = 10 Gy) were seen for the smallest targets (<10 cc), some of which received < 100 Gy BED10. Patient misalignment resulted in substantial decrease in conformity and increase in the gradient index, violating major characteristics of SBRT. Statistically insignificant differences were seen for normal tissue dose. Although, clinical follow-up of these patients is ongoing, the authors recommend an alternative treatment planning strategy to minimize the probability of a geometric miss when treating small lung lesions synchronously with single-isocenter VMAT SBRT plans.

Fast generation of lung SBRT plans with a knowledge-based planning model on ring-mounted Halcyon Linac.

PURPOSE: To demonstrate fast treatment planning feasibility of stereotactic body radiation therapy (SBRT) for centrally located lung tumors on Halcyon Linac via a previously validated knowledge-based planning (KBP) model to support offline adaptive radiotherapy. MATERIALS/METHODS: Twenty previously treated non-coplanar volumetric-modulated arc therapy (VMAT) lung SBRT plans (c-Truebeam) on SBRT-dedicated C-arm Truebeam Linac were selected. Patients received 50 Gy in five fractions. c-Truebeam plans were re-optimized for Halcyon manually (m-Halcyon) and with KBP model (k-Halcyon). Both m-Halcyon and k-Halcyon plans were normalized for identical or better target coverage than clinical c-Truebeam plans and compared for target conformity, dose heterogeneity, dose fall-off, and dose tolerances to the organs-at-risk (OAR). Treatment delivery parameters and planning times were evaluated. RESULTS: k-Halcyon plans were dosimetrically similar or better than m-Halcyon and c-Truebeam plans. k-Halcyon and m-Halcyon plan comparisons are presented with respect to c-Truebeam. Differences in conformity index were statistically insignificant in k-Halcyon and on average 0.02 higher (p = 0.04) in m-Halcyon plans. Gradient index was on average 0.43 (p = 0.006) lower and 0.27 (p = 0.02) higher for k-Halcyon and m-Halcyon, respectively. Maximal dose 2 cm away in any direction from target was statistically insignificant. k-Halcyon increased maximal target dose on average by 2.9 Gy (p < 0.001). Mean lung dose was on average reduced by 0.10 Gy (p = 0.004) in k-Halcyon and increased by 0.14 Gy (p < 0.001) in m-Halcyon plans. k-Halcyon plans lowered bronchial tree dose on average by 1.2 Gy. Beam-on-time (BOT) was increased by 2.85 and 1.67 min, on average for k-Halcyon and m-Halcyon, respectively. k-Halcyon plans were generated in under 30 min compared to estimated dedicated 180 ± 30 min for m-Halcyon or c-Truebeam plan. CONCLUSION: k-Halcyon plans were generated in under 30 min with excellent plan quality. This adaptable KBP model supports high-volume clinics in the expansion or transfer of lung SBRT patients to Halcyon.

Flattening filter free VMAT for a stereotactic, single-dose of 30 Gy to lung lesion in a 15-min treatment slot.

Cone-beam CT-guided single dose of lung stereotactic body radiotherapy (SBRT) treatment with a flattening filter free (FFF) beam and volumetric modulated arc therapy (VMAT) is a safe and highly effective treatment modality for selective small lung lesions. Four-dimensional (4D) CT-based treatment plans were generated using advanced AcurosXB algorithm for heterogeneity corrections. 6X-FFF beam produced highly conformal radiosurgical dose distribution to the target and reduced lung SBRT fraction duration to less than 10 min for a single dose of 30 Gy, significantly improving patient comfort and clinic workflow. Early follow-up CT imaging results (mean, 8 months) show high local control rates (100%) with no acute lung or rib toxicity. Longer clinical follow-up in a larger patient cohort managed in this fashion is underway to further validate this treatment approach.

Multi-institutional experience of stereotactic body radiotherapy for large (≥5 centimeters) non-small cell lung tumors.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is the standard of care for patients with nonoperative, early-stage non-small cell lung cancer (NSCLC) measuring < 5 cm, but its use among patients with tumors measuring ≥5 cm is considerably less defined, with the existing literature limited to small, single-institution reports. The current multi-institutional study reported outcomes evaluating the largest such population reported to date. METHODS: Clinical/treatment characteristics, outcomes, toxicities, and patterns of failure were assessed in patients with primary NSCLC measuring ≥5 cm without evidence of distant/lymph node metastasis who underwent SBRT using ≤5 fractions. Statistics included Kaplan-Meier survival analyses and univariate/multivariate Cox proportional hazards models. RESULTS: A total of 92 patients treated from 2004 through 2016 were analyzed from 12 institutions. The median follow-up was 12 months (15 months in survivors). The median age and tumor size among the patients were 73 years (range, 50-95 years) and 5.4 cm (range, 5.0-7.5 cm), respectively. The median dose/fractionation was 50 Gray/5 fractions. The actuarial local control rates at 1 year and 2 years were 95.7% and 73.2%, respectively. The disease-free survival rate was 72.1% and 53.5%, respectively, at 1 year and 2 years. The 1-year and 2-year disease-specific survival rates were 95.5% and 78.6%, respectively. The median, 1-year, and 2-year overall survival rates were 21.4 months, 76.2%, and 46.4%, respectively. On multivariate analysis, lung cancer history and pre-SBRT positron emission tomography maximum standardized uptake value were found to be associated with overall survival. Posttreatment failures were most commonly distant (33% of all disease recurrences), followed by local (26%) and those occurring elsewhere in the lung (23%). Three patients had isolated local failures. Grade 3 to 4 toxicities included 1 case (1%) and 4 cases (4%) of grade 3 dermatitis and radiation pneumonitis, respectively (toxicities were graded according to the Common Terminology Criteria for Adverse Events [version 4.0]). Grades 2 to 5 radiation pneumonitis occurred in 11% of patients. One patient with a tumor measuring 7.5 cm and a smoking history of 150 pack-years died of radiation pneumonitis. CONCLUSIONS: The results of the current study, which is the largest study of patients with NSCLC measuring ≥5 cm reported to date, indicate that SBRT is a safe and efficacious option. Cancer 2017;123:688-696. © 2016 American Cancer Society.

High-performing dry powder inhalers of paclitaxel DPPC/DPPG lung surfactant-mimic multifunctional particles in lung cancer: physicochemical characterization, in vitro aerosol dispersion, and cellular studies.

Inhalable lung surfactant-based carriers composed of synthetic phospholipids, dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG), along with paclitaxel (PTX), were designed and optimized as respirable dry powders using organic solution co-spray-drying particle engineering design. These materials can be used to deliver and treat a wide variety of pulmonary diseases with this current work focusing on lung cancer. In particular, this is the first time dry powder lung surfactant-based particles have been developed and characterized for this purpose. Comprehensive physicochemical characterization was carried out to analyze the particle morphology, surface structure, solid-state transitions, amorphous character, residual water content, and phospholipid bilayer structure. The particle chemical composition was confirmed using attenuated total reflectance-Fourier-transform infrared (ATR-FTIR) spectroscopy. PTX loading was high, as quantified using UV-VIS spectroscopy, and sustained PTX release was measured over weeks. In vitro cellular characterization on lung cancer cells demonstrated the enhanced chemotherapeutic cytotoxic activity of paclitaxel from co-spray-dried DPPC/DPPG (co-SD DPPC/DPPG) lung surfactant-based carrier particles and the cytotoxicity of the particles via pulmonary cell viability analysis, fluorescent microscopy imaging, and transepithelial electrical resistance (TEER) testing at air-interface conditions. In vitro aerosol performance using a Next Generation Impactor™ (NGI™) showed measurable powder deposition on all stages of the NGI and was relatively high on the lower stages (nanometer aerodynamic size). Aerosol dispersion analysis of these high-performing DPIs showed mass median diameters (MMADs) that ranged from 1.9 to 2.3 µm with excellent aerosol dispersion performance as exemplified by high values of emitted dose, fine particle fractions, and respirable fractions.

Nicotinic modulation of therapeutic response in vitro and in vivo.

Tobacco use significantly increases the risk of developing cancer. Moreover, there is growing evidence that tobacco use decreases survival in cancer patients. Nicotine, a systemically available component of tobacco, is associated with tumor promotion and decreased apoptosis in cell culture; however, the role of nicotine on response to radiotherapy (RT) or chemoradiotherapy (CRT) in vivo has not been evaluated. Our study evaluated the effects of nicotine administration on cancer cell survival in cell culture and mouse models. Nicotine increased survival in two cell lines following RT in vitro. Nicotine administration in mice during fractionated RT or CRT increased xenograft regrowth as compared to RT or CRT alone. Nicotine increased hypoxia-inducible factor 1-alpha (HIF-1α) expression in tumor xenografts without altering expression of carbonic-anhydrase, a clinical marker of tumor hypoxia. The effects of nicotine on HIF-1α expression were transient, returning to baseline levels within 2-3 days after nicotine removal. Further mechanistic studies indicated that inhibition of phosphoinositide-3-kinase (PI3K) prevented nicotine-mediated increases in HIF-1α expression as well as the prosurvival effects of nicotine on RT. These findings imply that during tobacco use, nicotine may function as a systemic agent through acute and reversible regulation of HIF-1α expression and a decreased therapeutic response.

A novel restricted single-isocenter stereotactic body radiotherapy (RESIST) method for synchronous multiple lung lesions to minimize setup uncertainties.

Treating multiple lung lesions synchronously using a single-isocenter volumetric modulated arc therapy (VMAT) stereotactic body radiation therapy (SBRT) plan can improve treatment efficiency and patient compliance. However, due to set up uncertainty, aligning multiple lung tumors on a single daily cone beam CT (CBCT) image has shown clinically unacceptable loss of target(s) coverage. Herein, we propose a Restricted Single-Isocenter Stereotactic Body Radiotherapy (RESIST), an alternative treatment that mitigates patient setup uncertainties. Twenty-one patients with two lung lesions were treated with single-isocenter VMAT-SBRT using a 6MV-FFF beam to 54 Gy in 3 fractions (n = 7) or 50 Gy in 5 fractions (n = 14) prescribed to 70-80% isodose line. To minimize setup uncertainties, each plan was re-planned using the RESIST method, utilizing a single-isocenter placed at the patient's mediastinum. It allows for an individual plan to be created for each tumor, using the first plan as the base-dose for the second plan, while still allowing both tumors to be treated in the same session. The technique uses novel features in Eclipse, including dynamic conformal arc (DCA)-based dose and aperture shape controller before each VMAT optimization. RESIST plans provided better target dose conformity (p < 0.001) and gradient indices (p < 0.001) and lower dose to adjacent critical organs. Using RESIST to treat synchronous lung lesions with VMAT-SBRT significantly reduces plan complexity as demonstrated by smaller beam modulation factors (p < 0.001), without unreasonably increasing treatment time. RESIST reduces the chance of a geometric miss due by allowing CBCT matching of one tumor at a time. Placement of isocenter at the mediastinum avoids potential patient/gantry collisions, provides greater flexibility of noncoplanar arcs and eliminates the need for multiple couch movements during CBCT imaging. Efficacy of RESIST has been demonstrated for two lesions and can potentially be used for more lesions. Clinical implementation of this technique is ongoing.

Addition of Metformin to Concurrent Chemoradiation in Patients With Locally Advanced Non-Small Cell Lung Cancer: The NRG-LU001 Phase 2 Randomized Clinical Trial.

IMPORTANCE: Non-small cell lung cancer (NSCLC) has relatively poor outcomes. Metformin has significant data supporting its use as an antineoplastic agent. OBJECTIVE: To compare chemoradiation alone vs chemoradiation and metformin in stage III NSCLC. DESIGN, SETTING, AND PARTICIPANTS: The NRG-LU001 randomized clinical trial was an open-label, phase 2 study conducted from August 24, 2014, to December 15, 2016. Patients without diabetes who were diagnosed with unresectable stage III NSCLC were stratified by performance status, histology, and stage. The setting was international and multi-institutional. This study examined prespecified endpoints, and data were analyzed on an intent-to-treat basis. Data were analyzed from February 25, 2019, to March 6, 2020. INTERVENTIONS: Chemoradiation and consolidation chemotherapy with or without metformin. MAIN OUTCOMES AND MEASURES: The primary outcome was 1-year progression-free survival (PFS), designed to detect 15% improvement in 1-year PFS from 50% to 65% (hazard ratio [HR], 0.622). Secondary end points included overall survival, time to local-regional recurrence, time to distant metastasis, and toxicity per Common Terminology Criteria for Adverse Events, version 4.03. RESULTS: A total of 170 patients were enrolled, with 167 eligible patients analyzed after exclusions (median age, 64 years [interquartile range, 58-72 years]; 97 men [58.1%]; 137 White patients [82.0%]), with 81 in the control group and 86 in the metformin group. Median follow-up was 27.7 months (range, 0.03-47.21 months) among living patients. One-year PFS rates were 60.4% (95% CI, 48.5%-70.4%) in the control group and 51.3% (95% CI, 39.8%-61.7%) in the metformin group (HR, 1.15; 95% CI, 0.77-1.73; P = .24). Clinical stage was the only factor significantly associated with PFS on multivariable analysis (HR, 1.79; 95% CI, 1.19-2.69; P = .005). One-year overall survival was 80.2% (95% CI, 69.3%-87.6%) in the control group and 80.8% (95% CI, 70.2%-87.9%) in the metformin group. There were no significant differences in local-regional recurrence or distant metastasis at 1 or 2 years. No significant difference in adverse events was observed between treatment groups. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02186847.

Clinical evaluation of photon optimizer (PO) MLC algorithm for stereotactic, single-dose of VMAT lung SBRT.

Recently implemented photon optimizer (PO) MLC optimization algorithm is mandatory for RapidPlan modeling in Eclipse. This report quantifies and compares the dosimetry and treatment delivery parameters of PO vs its predecessor progressive resolution optimizer (PRO) algorithm for a single-dose of volumetric modulated arc therapy (VMAT) lung stereotactic body radiation therapy (SBRT). Clinical SBRT treatment plans for 12 early-stage non-small-cell lung cancer patients receiving 30 Gy in 1 fraction using PRO-VMAT were re-optimized using the PO-VMAT MLC algorithm with identical planning parameters and objectives. Average planning target volume derived from the 4D CT scans was 13.6 ± 12.0 cc (range: 4.3 to 41.1 cc) Patients were treated with 6 MV flattening filter free beam using Acuros-based calculations and 2.5 mm calculation grid-size (CGS). Both treatment plans were normalized to receive same target coverage and identical CGS to isolate effects of MLC positioning optimizers. Original PRO and re-optimized PO plans were compared via RTOG-0915 protocol compliance criteria for target conformity, gradient indices, dose to organs at risks and delivery efficiency. Additionally, PO-VMAT plans with a 1.25 mm CGS were evaluated. Both plans met RTOG protocol requirements. Conformity indices showed no statistical difference between PO 2.5 mm CGS and PRO 2.5 mm CGS plans. Gradient index (p = 0.03), maximum dose to 2 cm away from planning target volume in any direction (D2cm) (p < 0.05), and gradient distance (p < 0.05) presented statistically significant differences for both plans with 2.5 mm CGS. Some organs at risks showed statistically significant differences for both plans calculated with 2.5 mm CGS; however, no clinically significant dose differences were observed between the plans. Beam modulation factor was statistically significant for both PO 1.25 mm CGS (p = 0.001) and PO 2.5 mm CGS (p < 0.001) compared to clinical PRO 2.5 mm CGS plans. PO-VMAT plans provided decreased beam-on time by an average of 0.2 ± 0.1 minutes (up to 1.0 minutes) with PO 2.5 mm and 1.2 ± 0.39 minutes (maximum up to 3.22 minutes) with PO 1.25 mm plans compared to PRO 2.5 mm plans. PO-VMAT single-dose of VMAT lung SBRT plans showed slightly increased intermediate-dose spillage but boasted overall similar plan quality with less beam modulation and hence shorter beam-on time. However, PO 1.25 mm CGS had less intermediate-dose spillage and analogous plan quality compared to clinical PRO-VMAT plans with no additional cost of plan optimization. Further investigation into peripheral targets with PO-MLC algorithm is warranted. This study indicates that PO 1.25 mm CGS plans can be used for RapidPlan modeling for a single dose of lung SBRT patients. PO-MLC 1.25 mm algorithm is recommended for future clinical single-dose lung SBRT plan optimization.

Management of local recurrences and regional failure in early stage non-small cell lung cancer after stereotactic body radiation therapy.

Stereotactic body radiation therapy (SBRT) is a very effective way to treat early stage non-small cell lung cancer (NSCLC) and small oligometastatic lung lesions with consistently high rates of local control, but both local and regional/distant recurrences still occur. The management of recurrences remains unsettled and may entail repeat SBRT, conventionally fractionated external beam RT (EF-EBRT), chemotherapy or surgery. Most patients with local recurrences [within the initial planning target volume (PTV)] can be salvaged successfully with good cancer specific survival. Nonetheless, proximity of the initial SBRT delivery to organs at risk (ribs, blood vessels, airways) may make retreatment more difficult. With attention to detail and careful patient selection, both surgery and reirradiation can be performed safely and effectively. Strategies for management of regional (nodal) recurrences may require conventional therapies tailored to the patterns of failure. The role of immunotherapy in salvage has not been elucidated as yet. We review here data on the available literature concerning salvage of SBRT lung patients.

Is the Importance of Heart Dose Overstated in the Treatment of Non-Small Cell Lung Cancer? A Systematic Review of the Literature.

PURPOSE: Some recent studies have suggested a relationship between cardiac dose and mortality in non-small cell lung cancer (NSCLC), but others have reported conflicting data. The goal of this study was to conduct a systematic review and meta-analysis to provide an evidence-based estimate of the relationship between cardiac dose and mortality in these patients. METHODS AND MATERIALS: A systematic review of MEDLINE (PubMed) and Embase databases (inception to January 2018) was performed according to PRISMA guidelines. Studies that evaluated cardiac dosimetric factors in patients with NSCLC and included outcomes of cardiac events, cardiac mortality, and/or overall survival were identified. RESULTS: From 5614 patients across 22 studies, a total of 214 cardiac dosimetric parameters (94 unique) were assessed as possible predictors of cardiac toxicity or death. Assessed predictors included general (eg, mean heart dose [MHD]), threshold-based (eg, heart V5), and anatomic-based (eg, atria, ventricles) dosimetric factors. The most commonly analyzed parameters were MHD, heart V5, and V30. Most studies did not make corrections for multiplicity of testing. For overall survival, V5 was found to be significant on multivariable analysis (MVA) in 1 of 11 studies and V30 in 2 of 12 studies; MHD was not significant in any of 8 studies. For cardiac events, V5 was found to be significant on multivariable analysis in 1 of 2 studies, V30 in 1 of 3 studies, and MHD in 2 of 4 studies. A meta-analysis of the data could not be performed because most negative studies did not report effect estimates. CONCLUSIONS: Consistent heart dose-volume parameters associated with overall survival of patients with NSCLC were not identified. Multiplicity of testing is a major issue and likely inflates the overall risk of type I errors in the literature. Future studies should specify predictors a priori, correct for multiplicity of testing, and report effect estimates for nonsignificant variables.

Safety and Efficacy of a Five-Fraction Stereotactic Body Radiotherapy Schedule for Centrally Located Non-Small-Cell Lung Cancer: NRG Oncology/RTOG 0813 Trial.

PURPOSE: Patients with centrally located early-stage non-small-cell lung cancer (NSCLC) are at a higher risk of toxicity from high-dose ablative radiotherapy. NRG Oncology/RTOG 0813 was a phase I/II study designed to determine the maximum tolerated dose (MTD), efficacy, and toxicity of stereotactic body radiotherapy (SBRT) for centrally located NSCLC. MATERIALS AND METHODS: Medically inoperable patients with biopsy-proven, positron emission tomography-staged T1 to 2 (≤ 5 cm) N0M0 centrally located NSCLC were accrued into a dose-escalating, five-fraction SBRT schedule that ranged from 10 to 12 Gy/fraction (fx) delivered over 1.5 to 2 weeks. Dose-limiting toxicity (DLT) was defined as any treatment-related grade 3 or worse predefined toxicity that occurred within the first year. MTD was defined as the SBRT dose at which the probability of DLT was closest to 20% without exceeding it. RESULTS: One hundred twenty patients were accrued between February 2009 and September 2013. Patients were elderly, there were slightly more females, and the majority had a performance status of 0 to 1. Most cancers were T1 (65%) and squamous cell (45%). Organs closest to planning target volume/most at risk were the main bronchus and large vessels. Median follow-up was 37.9 months. Five patients experienced DLTs; MTD was 12.0 Gy/fx, which had a probability of a DLT of 7.2% (95% CI, 2.8% to 14.5%). Two-year rates for the 71 evaluable patients in the 11.5 and 12.0 Gy/fx cohorts were local control, 89.4% (90% CI, 81.6% to 97.4%) and 87.9% (90% CI, 78.8% to 97.0%); overall survival, 67.9% (95% CI, 50.4% to 80.3%) and 72.7% (95% CI, 54.1% to 84.8%); and progression-free survival, 52.2% (95% CI, 35.3% to 66.6%) and 54.5% (95% CI, 36.3% to 69.6%), respectively. CONCLUSION: The MTD for this study was 12.0 Gy/fx; it was associated with 7.2% DLTs and high rates of tumor control. Outcomes in this medically inoperable group of mostly elderly patients with comorbidities were comparable with that of patients with peripheral early-stage tumors.

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.

Comparison of outcomes of stereotactic body radiation therapy delivered with three different technologies to the lung.

PURPOSE/OBJECTIVES: Since the inception of stereotactic body radiation therapy (SBRT), treatment delivery has been performed with volumetric modulated arc therapy (VMAT), helical tomotherapy (HT) and noncoplanar static fields (SF). The purpose of this study is to compare SBRT delivery among these treatment modalities to the lung. MATERIALS/METHODS: A retrospective review of SBRT treatments of 30 to 60 Gy in 1 to 5 fractions from 2007 to 2015 was performed. Dosimetric parameters included V5, V20, D2cm, gross tumor volume (GTV) and planning target volume (PTV) size and coverage, rib/esophageal minimum/maximum doses, R30Gy, R50%, and the conformality index (CI). Clinical outcomes evaluated included local control, pneumonitis and other toxicities. ANOVA, Student's t-test and Kruskal-Wallis test were used to compare the parameters among modalities. Kaplan-Meier estimates of time-to-local failure were produced. RESULTS: 176 Treatments included 106 SF, 36 VMAT and 34 HT. HT had better PTV coverage (p=0.0166) but higher lung V5 and esophageal doses (p<0.001 and p=0.0032). R30Gy, R50%, and CI were significantly better with VMAT SBRT (p<0.001). Clinically, Grade 2+ pneumonitis was associated with larger median GTV's of 21.39 cc versus 7.65 cc (p=0.0016), larger median PTV's of 65.62 cc versus 31.75 cc (p=0.0030), and higher V20 6.62% versus 4.08% (p=0.0408). For patients surviving >1 year, overall local failure rate was 9.4%. Actuarial control rates trended toward statistical significance with time to local failure with VMAT being the most favorable group on the Kaplan-Meier curve (p=0.0733). CONCLUSION: VMAT showed superior conformality compared to the other modalities. Among the modalities examined, HT had higher values for parameters associated with toxicity such as V5 and maximum esophageal dose, but all were within acceptable limits. There was a trend to better local control with VMAT.

Stereotactic Body Radiation Therapy for Operable Early-Stage Lung Cancer: Findings From the NRG Oncology RTOG 0618 Trial.

Importance: Stereotactic body radiation therapy (SBRT) has become a standard treatment for patients with medically inoperable early-stage lung cancer. However, its effectiveness in patients medically suitable for surgery is unclear. Objective: To evaluate whether noninvasive SBRT delivered on an outpatient basis can safely eradicate lung cancer and cure selected patients with operable lung cancer, obviating the need for surgical resection. Design, Setting, and Participants: Single-arm phase 2 NRG Oncology Radiation Therapy Oncology Group 0618 study enrolled patients from December 2007 to May 2010 with median follow-up of 48.1 months (range, 15.4-73.7 months). The setting was a multicenter North American academic and community practice cancer center consortium. Patients had operable biopsy-proven peripheral T1 to T2, N0, M0 non-small cell tumors no more than 5 cm in diameter, forced expiratory volume in 1 second (FEV1) and diffusing capacity greater than 35% predicted, arterial oxygen tension greater than 60 mm Hg, arterial carbon dioxide tension less than 50 mm Hg, and no severe medical problems. The data analysis was performed in October 2014. Interventions: The SBRT prescription dose was 54 Gy delivered in 3 18-Gy fractions over 1.5 to 2.0 weeks. Main Outcomes and Measures: Primary end point was primary tumor control, with survival, adverse events, and the incidence and outcome of surgical salvage as secondary end points. Results: Of 33 patients accrued, 26 were evaluable (23 T1 and 3 T2 tumors; 15 [58%] male; median age, 72.5 [range, 54-88] years). Median FEV1 and diffusing capacity of the lung for carbon monoxide at enrollment were 72.5% (range, 38%-136%) and 68% (range, 22%-96%) of predicted, respectively. Only 1 patient had a primary tumor recurrence. Involved lobe failure, the other component defining local failure, did not occur in any patient, so the estimated 4-year primary tumor control and local control rate were both 96% (95% CI, 83%-100%). As per protocol guidelines, the single patient with local recurrence underwent salvage lobectomy 1.2 years after SBRT, complicated by a grade 4 cardiac arrhythmia. The 4-year estimates of disease-free and overall survival were 57% (95% CI, 36%-74%) and 56% (95% CI, 35%-73%), respectively. Median overall survival was 55.2 months (95% CI, 37.7 months to not reached). Protocol-specified treatment-related grade 3, 4, and 5 adverse events were reported in 2 (8%; 95% CI, 0.1%-25%), 0, and 0 patients, respectively. Conclusions and Relevance: As given, SBRT appears to be associated with a high rate of primary tumor control, low treatment-related morbidity, and infrequent need for surgical salvage in patients with operable early-stage lung cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT00551369.

Randomized phase II trial of high-dose melatonin and radiation therapy for RPA class 2 patients with brain metastases (RTOG 0119).

PURPOSE: To determine if high-dose melatonin for Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) Class 2 patients with brain metastases improved survival over historical controls, and to determine if the time of day melatonin was given affected its toxicity or efficacy. RTOG 0119 was a phase II randomized trial for this group of patients. METHODS AND MATERIALS: RTOG RPA Class 2 patients with brain metastases were randomized to 20 mg of melatonin, given either in the morning (8-9 AM) or in the evening (8-9 PM). All patients received radiation therapy (30 Gy in 10 fractions) in the afternoon. Melatonin was continued until neurologic deterioration or death. The primary endpoint was overall survival time. Neurologic deterioration, as reflected by the Mini-Mental Status Examination, was also measured. RESULTS: Neither of the randomized groups had survival distributions that differed significantly from the historic controls of patients treated with whole-brain radiotherapy. The median survivals of the morning and evening melatonin treatments were 3.4 and 2.8 months, while the RTOG historical control survival was 4.1 months. CONCLUSIONS: High-dose melatonin did not show any beneficial effect in this group of patients.