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Stereotactic body radiation therapy (SBRT) and hypofractionation using pencil-beam scanning (PBS) proton therapy (PBSPT) is an attractive option for thoracic malignancies. Combining the advantages of target coverage conformity and critical organ sparing from both PBSPT and SBRT, this new delivery technique has great potential to improve the therapeutic ratio, particularly for tumors near critical organs. Safe and effective implementation of PBSPT SBRT/hypofractionation to treat thoracic malignancies is more challenging than the conventionally fractionated PBSPT because of concerns of amplified uncertainties at the larger dose per fraction. The NRG Oncology and Particle Therapy Cooperative Group Thoracic Subcommittee surveyed proton centers in the United States to identify practice patterns of thoracic PBSPT SBRT/hypofractionation. From these patterns, we present recommendations for future technical development of proton SBRT/hypofractionation for thoracic treatment. Among other points, the recommendations highlight the need for volumetric image guidance and multiple computed tomography-based robust optimization and robustness tools to minimize further the effect of uncertainties associated with respiratory motion. Advances in direct motion analysis techniques are urgently needed to supplement current motion management techniques., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Immunotherapeutic agents have revolutionized cancer treatment over the past decade. However, most patients fail to respond to immunotherapy alone. A growing body of preclinical studies highlights the potential for synergy between radiation therapy and immunotherapy, but the outcomes of clinical studies have been mixed. This review summarizes the current state of immunotherapy and radiation combination therapy across cancers, highlighting existing challenges and promising areas for future investigation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

It is crucial to economically justify the use of promising therapies such as stereotactic ablative radiotherapy (SABR) for oligometastatic disease (OMD). The goal of this systematic review was to provide a summative evaluation of publications that analyzed the cost-effectiveness (CE) of SABR for OMD. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided methodology, PubMed and Embase were searched for modeling-based CE studies for various forms of limited metastatic disease. Only full publications that specifically compared SABR with a systemic therapy-based approach were included. In total, 9 studies met inclusion criteria; 4 pertained to OMD with mixed histologies, 2 to oligometastatic non-small cell lung cancer, 1 to pulmonary OMD, 1 to liver OMD, and 1 to low-volume oligorecurrent castration-sensitive prostate cancer. All but 1 investigation illustrated that SABR was cost-effective for the studied population (or a subpopulation); of these studies, the incremental CE ratios for SABR (when reported) ranged from $28,000/quality-adjusted life-year (QALY) to $55,000/QALY. Of studies that reported the probability of SABR being cost-effective at common willingness-to-pay values, the median (range) probability of achieving CE was roughly 61% (30%-88%) at a $50,000/QALY threshold and 78% (31%-100%) at a $100,000/QALY threshold. Taken together, the available evidence suggests that SABR appears to be a cost-effective approach for OMD, which has implications for value-based oncologic practice and construction of future health policies. However, reassessment is required in the context of modern systemic therapies (eg, immunotherapy) as well as long-term follow-up of existing and newly reported randomized trials. Prudent patient selection remains the single most important factor influencing the CE of SABR for OMD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: The successes of local therapy for oligometastatic cancers cannot be extrapolated to oligoprogressive disease (OPD) because they are distinct clinical entities. Given the limited prospective data on OPD to date, summative analyses are urgently needed., Methods and Materials: Inclusion criteria for this Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review were as follows. First, only prospective data were included. Second, progression had to have occurred on active/ongoing systemic therapy. Third, the number of progressing areas of disease had to be explicitly listed and ≤5 in number. Fourth, all progressing sites had to undergo local therapy (radiation therapy [RT] /surgery/nonradiation ablative procedures)., Results: Eight trials met criteria (summing 290 patients), the vast majority of which used stereotactic RT as the local modality (most commonly, 19-20 Gy in 1 fraction, 27-33 Gy in 3 fractions, or 35-50 Gy in 5 fractions). A study on non-small cell lung cancer (NSCLC) demonstrated that stereotactic RT improved progression-free survival (PFS) and overall survival compared with historical values with systemic therapy alone. Two additional studies on epidermal growth factor receptor mutated (EGFRm) NSCLC also showed acceptable PFS with local therapy, particularly in patients who oligoprogressed on osimertinib. The only randomized trial analyzed herein showed that local therapy improved PFS for NSCLC but not breast cancer. Two trials in castration-resistant prostate cancer illustrated that a substantial proportion of patients did not require any changes in hormonal therapy or delayed the need to change systemic therapies. Lastly, 2 trials of renal cell carcinoma showed high (90%-100%) local control and median PFS of 9 months, and potentially a prolonged time to change systemic therapy. Lastly, from all patients in all trials, local therapy was tolerated well, with only 7 instances of grade 3+ toxicities., Conclusions: Based on the limited data, local therapy for oligoprogression is safe and yields encouraging short-term preliminary outcomes, but trials with larger sample sizes and longer follow-up are required for more robust conclusions., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: The role of local consolidative therapy (LCT) for metastatic cancers most likely varies by the particular cancer type. We therefore performed a systematic review with a comparative meta-analysis of LCT versus systemic therapy alone, specifically for metastatic non-small cell lung cancer (mNSCLC)., Methods and Materials: Article eligibility for this Preferred Reporting Items for Systematic Reviews and Meta-Analyses/Population, Intervention, Comparison, Outcomes and Design-guided systematic review was histologic confirmation of mNSCLC, comparison of LCT (irradiation/surgery) versus lack thereof in a randomized or propensity-matched retrospective manner, and sufficient quantitative data examining progression-free survival (PFS), overall survival (OS), and/or adverse events (AEs). Both polymetastatic and oligometastatic disease (OMD) were allowed, but not oligoprogressive/oligorecurrent disease. Statistics used the Mantel-Haenszel fixed-effect or random-effect model depending on the heterogeneity (I 2 )., Results: From 7 articles, 346 patients received LCT and 347 received systemic therapy alone. With LCT, the hazard ratio (HR) for PFS in all patients was 0.37 (95% confidence interval, 0.25-0.55; P = .01), and for OMD it was 0.30 (0.24-0.38; P < .001). For OS, the HRs were 0.53 (0.45-0.62; P < .001) in all patients, and 0.41 (0.33-0.52; P < .001) in patients with OMD. The findings remained significant when stratifying by epidermal growth factor receptor status (HRs for PFS/OS: 0.29/0.44 for mutants and 0.31/0.39 for wild-type, respectively, P < .001 for all) and study type (HRs for PFS/OS: 0.40/0.52 for randomized and 0.33/0.41 for retrospective, respectively, P < .05 for all). LCT was not associated with a higher rate of grade ≥3 AEs (odds ratio, 1.28; 95% confidence interval, 0.81-2.05; P = .29)., Conclusions: Meta-analyzing the available data shows that LCT may improve the PFS and OS of mNSCLC without increasing the risk of high-grade AEs. However, further data on polymetastatic mNSCLC are required, and these conclusions cannot be extrapolated to other (non-mNSCLC) histologies. Although many existing/ongoing trials of LCT for OMD commonly comprise mixed-histology populations, focusing on the interaction between specific tumor biology and systemic agents is required to enhance the clarity and applicability of these trials., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Recent randomized studies have suggested improvements in progression-free and overall survival with the addition of stereotactic body radiation therapy (SBRT, also known as SABR) in patients with oligometastatic non-small cell lung cancer. Given the novelty and complexity of incorporating SBRT in the oligometastatic setting, the multidisciplinary American Radium Society Lung Cancer Panel was assigned to create appropriate use criteria on SBRT as part of consolidative local therapy for patients with oligometastatic and oligoprogressive non-small cell lung cancer., Methods and Materials: A review of the current literature was conducted from January 1, 2008, to December 25, 2020, using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to systematically search the PubMed database to retrieve a comprehensive set of relevant articles., Results: Based on representation in existing randomized trials, the panel defined the term "oligometastasis" as ≤3 metastatic deposits (not including the primary tumor) in the previously untreated setting or after first-line systemic therapy after the initial diagnosis. "Oligoprogression" also referred to ≤3 discrete areas of progression in the setting of prior or ongoing receipt of systemic therapy. In all appropriate patients, the panel strongly recommends enrollment in a clinical trial whenever available. For oligometastatic disease, administering first-line systemic therapy followed by consolidative radiation therapy (to all sites plus the primary/nodal disease) is preferred over up-front radiation therapy. Owing to a dearth of data, the panel recommended that consolidative radiation therapy be considered on a case-by-case basis for 4 to 5 sites of oligometastatic disease, driver mutation-positive oligometastatic disease without progression on up-front targeted therapy, and oligoprogressive cases., Conclusions: Although SBRT/SABR appears to be both safe and effective in treating patients with limited metastatic sites of disease, many clinical circumstances require individualized management and strong multidisciplinary discussion on account of the limited existing data., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Metastatic cancer is a heterogeneous entity, some of which could benefit from local consolidative radiation therapy (RT). Although randomized evidence is growing in support of using RT for oligometastatic disease, a highly active area of investigation relates to whether RT could benefit patients with polymetastatic disease. This article highlights the preclinical and clinical rationale for using RT for polymetastatic disease, proposes an exploratory framework for selecting patients best suited for these types of treatments, and briefly reviews potential challenges. The goal of this hypothesis-generating review is to address personalized multimodality systemic treatment for patients with metastatic cancer. The rationale for using high-dose RT is primarily for local control and immune activation in either oligometastatic or polymetastatic disease. However, the primary application of low-dose RT is to activate distinct antitumor immune pathways and modulate the tumor stroma in efforts to better facilitate T cell infiltration. We explore clinical cases involving high- and low-dose RT to demonstrate the potential efficacy of such treatment. We then group patients by extent of disease burden to implement high- and/or low-dose RT. Patients with low-volume disease may receive high-dose RT to all sites as part of an oligometastatic paradigm. Subjects with high-volume disease (for whom standard of care remains palliative RT only) could be treated with a combination of high-dose RT to a few sites for immune activation, while receiving low-dose RT to several remaining lesions to enhance systemic responses from high-dose RT and immunotherapy. We further discuss how emerging but speculative concepts such as immune function may be integrated into this approach and examine therapies currently under investigation that may help address immune deficiencies. The review concludes by addressing challenges in using RT for polymetastatic disease, such as concerns about treatment planning workflows, treatment times, dose constraints for multiple-isocenter treatments, and economic considerations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Clinical trials are considered the gold standard in evidence-based medicine, yet few patients with cancer ultimately enroll. Here we examine patients screened for thoracic radiation oncology clinical trials to better understand enrollment trends., Methods and Materials: A prospective database tracking screening and enrollment for patients referred for thoracic radiation oncology consultation at our institution from 2016 to 2019 was evaluated. Proportional enrollment rates, patient and disease characteristics, self-reported socioeconomic factors, and reasons for ineligibility or nonenrollment across 17 radiation therapy trials were compared., Results: Enrollment data on 2372 patients were available for analysis. Of these patients, 40.0% (949) were deemed "not eligible" (NE) for any trial or were unwilling to be further screened. Reasons for ineligibility included stage (44%), histology (13%), radiation therapy not indicated (12%), patient decision (7%), and enrollment in a competing medical or surgical oncology trial (5%). The remaining 60.0% (1423) were "potentially eligible" (PE) for one or more trials. Most had non-small cell lung cancer (71%) or esophageal cancer (16%), and there were significantly fewer stage IV PE (29%) versus NE (49%) patients (P < .0001). Of 2372 patients, 281 (11.9%) enrolled. Notable reasons for nonenrollment were inclusion and exclusion criteria (58%), patients declining enrollment (14%), and physician decision (5%). The proportion of white patients was higher in the PE versus NE group (82.5% vs 75.8%; P < .001). Additionally, white race (87.9% vs 81.2%; P = .008), English language preference (96.4% vs 92.9%; P = .032), and non-Hispanic/Latino ethnicity (94.0% vs 90.1%; P = .042) were significantly different in enrolled versus nonenrolled PE patients., Conclusions: Only 12% of patients screened for radiation therapy trials ultimately enrolled, and more than two-thirds had no trial available or were found ineligible. In addition, 19% of potential eligible patients did not enroll because the patient or physician declined. Future trials may benefit from pragmatic designs with more inclusive enrollment criteria and multidisciplinary engagement of referring providers., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: Management of synchronous early-stage non-small cell lung cancer (NSCLC) remains controversial because resection is not always feasible. This study evaluates efficacy and patterns of failure after SABR for synchronous early-stage NSCLC., Methods and Materials: From 2005 to 2015, patients presenting with ≥2 synchronous NSCLC tumors (T1a-T2b) and receiving SABR to ≥1 lesion were reviewed. The most common prescriptions were 50 Gy in 4 or 70 Gy in 10 fractions. Patients underwent multidisciplinary management with workup including chest computed tomography and positron emission tomography/computed tomography, plus brain imaging and endoscopic bronchial ultrasound for most patients to rule out mediastinal and distant disease. Synchronous lesions were defined as multiple ipsilateral or contralateral intrapulmonary lesions diagnosed within 6 months., Results: Of 912 patients treated with SABR for early-stage NSCLC at our institution, 82 (9%) presented with synchronous disease, with a total of 169 lesions. SABR was delivered to 142 lesions (84%), with 57 patients (69.5%) receiving SABR for all sites. Median overall survival (OS) and progression-free survival (PFS) were 5.1 and 2.7 years, respectively. At a median follow-up of 58 months, OS was 67% and 52% at 3 and 5 years, and corresponding PFS was 47% and 29%. Thirty-nine patients (48%) had progression, with 21 (26%) experiencing distant failure, and intralobar recurrence was among the first failure for 15 patients (18%). Of the 142 SABR-treated sites, these included 6 in-field (4%) and 4 marginal (3%) recurrences. There were no grade ≥3 adverse events. Among patients receiving SABR for all sites, there were no differences in OS (P = .946), PFS (P = .980), local control (P = .683), regional and distant control (P = .656), or toxicity (P = .791). On multivariable analysis, ipsilateral synchronous disease was associated with greater regional and distant failure (hazard ratio, 2.691; P = .025)., Conclusions: Synchronous NSCLC can be managed with definitive local therapy. With high control rates and favorable outcomes, SABR is an effective and feasible treatment for synchronous early-stage NSCLC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: In patients with non-small cell lung cancer (NSCLC), concurrent chemoradiation therapy (CRT) exacerbates a cluster of difficult-to-manage symptoms, especially cancer-related fatigue. Minocycline is a readily available, low-cost antibiotic with antiinflammatory properties. We conducted a phase 2 randomized, double-blinded, placebo-controlled trial to investigate the effect of minocycline in reducing CRT-symptom burden in NSCLC., Methods and Materials: Patients with NSCLC scheduled to receive CRT provided consent and were randomized to receive either minocycline (100 mg twice daily) or a matching placebo during 6 to 7 weeks of CRT. Patient-reported fatigue and other symptoms were assessed on MD Anderson Symptom Inventory weekly from the start of CRT for 12 weeks. The primary outcome was 12-week (±2 days) area under the curve for symptom burden, which was compared between treatment groups., Results: Forty of 49 enrolled patients (80%) were evaluable (19 on minocycline and 21 on placebo). There were no grade 3 + adverse events related to the study medication. Fatigue was significantly reduced in the minocycline group compared with placebo group during the 12-week trial period (area under the curve = 31.2 ± 14.2 vs 45.0 ± 20.9, P = .011), with a large effect size (Cohen's d = 0.77). Pain (Cohen's d = 0.54) and shortness of breath (Cohen's d = 0.55) were also significantly reduced in the minocycline group (all P < .05)., Conclusions: Minocycline during CRT for NSCLC was feasible, had a low toxicity profile, and yielded a clinically and statistically significant positive signal in reducing symptom burden related to NSCLC and CRT. This study is a proof of concept so a larger trial in CRT patients is warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Our purpose was to develop predictive nomograms for overall survival (OS), progression-free survival (PFS), and time-to-progression (TTP) at 5 years in patients with early-stage non-small cell lung cancer (ES-NSCLC) treated with stereotactic ablative radiation therapy (SABR)., Methods and Materials: The study cohort included 714 ES-NSCLC patients treated with SABR from 2004-2015 with median follow-up of 59 months, divided into training and testing sets (8:2), with the former used for nomogram development. The least absolute shrinkage and selection operator were initially employed to screen for predictors of OS, PFS, and TTP, and identified predictors were subsequently applied toward Cox proportional hazards regression modeling. Significant predictors (P < .05) on multivariable regression were then used to develop nomograms, which were validated via evaluation of concordance indexes (C-index) and calibration plots. Finally, Kaplan-Meier method and Gray's test were employed to compare and confirm differences in outcomes among various groups and explore prognostic factors associated with local versus distant disease progression., Results: Significant predictors of both OS and PFS at 5 years included age, sex, Charlson comorbidity index, diffusing capacity of carbon monoxide, systemic immune-inflammation index, and tumor size (P ≤ .01 for all). Eastern Cooperative Oncology Group performance status predicted for OS as well (P = .01), and both tumor size (P < .01) and minimum biological equivalent dose to 95% of planning target volume (PTV D95 BED 10 ; P < .01) were predictive of TTP. The C-indexes for the OS, PFS, and TTP nomograms were 0.73, 0.68, and 0.60 in the training data set and 0.72, 0.66, and 0.59 in the testing data set, respectively. Tumor size > 2.45 cm and PTV D95 BED 10 < 113 Gy were significantly associated with both local and distant progression., Conclusions: These prognostic nomograms can accurately predict for OS, PFS, and TTP at 5 years after SABR for ES-NSCLC and may thus help identify high-risk patients who could benefit from additional systemic therapy., (Published by Elsevier Inc.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To develop and validate a radiomics signature that can predict the clinical outcomes for patients with stage I non-small cell lung cancer (NSCLC)., Methods and Materials: We retrospectively analyzed contrast-enhanced computed tomography images of patients from a training cohort (n = 147) treated with surgery and an independent validation cohort (n = 295) treated with stereotactic ablative radiation therapy. Twelve radiomics features with established strategies for filtering and preprocessing were extracted. The random survival forests (RSF) method was used to build models from subsets of the 12 candidate features based on their survival relevance and generate a mortality risk index for each observation in the training set. An optimal model was selected, and its ability to predict clinical outcomes was evaluated in the validation set using predicted mortality risk indexes., Results: The optimal RSF model, consisting of 2 predictive features, kurtosis and the gray level co-occurrence matrix feature homogeneity2, allowed for significant risk stratification (log-rank P < .0001) and remained an independent predictor of overall survival after adjusting for age, tumor volume and histologic type, and Karnofsky performance status (hazard ratio [HR] 1.27; P < 2e-16) in the training set. The resultant mortality risk indexes were significantly associated with overall survival in the validation set (log-rank P = .0173; HR 1.02, P = .0438). They were also significant for distant metastasis (log-rank P < .05; HR 1.04, P = .0407) and were borderline significant for regional recurrence on univariate analysis (log-rank P < .05; HR 1.04, P = .0617)., Conclusions: Our radiomics model accurately predicted several clinical outcomes and allowed pretreatment risk stratification in stage I NSCLC, allowing the choice of treatment to be tailored to each patient's individual risk profile., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To report the feasibility of conducting a randomized study to compare the toxicity and efficacy of stereotactic body radiation therapy (SBRT) versus stereotactic body proton therapy (SBPT) for high-risk, medically inoperable, early-stage non-small cell lung cancer (NSCLC)., Patients and Methods: Patients with medically inoperable NSCLC with high-risk features (centrally located or <5 cm T3 tumor or isolated lung parenchymal recurrences) were randomly assigned to SBRT or SBPT. Radiation dose was 50 Gy(relative biological effectiveness [RBE]) in 4 12.5-Gy(RBE) fractions prescribed to the planning target volume. Stereotactic body radiation therapy was given using 3-dimensional conformal radiation therapy or intensity modulated radiation therapy, and SBPT was given using passive scattering. Consistency in patient setup was ensured with on-board cone beam computed tomography for the SBRT group and with orthogonal X rays for the SBPT group., Results: The study closed early owing to poor accrual, largely because of insurance coverage and lack of volumetric imaging in the SBPT group. Ultimately, 21 patients were enrolled, and 19 patients who received 50 Gy in 4 fractions were included for analysis (9 SBRT, 10 SBPT). At a median follow-up time of 32 months, median overall survival time was 28 months in the SBRT group and not reached in the SBPT group. Three-year overall survival was 27.8% and 90%, 3-year local control was 87.5% (8 of 9) and 90.0% (9 of 10), and 3-year regional control was 47.6% (5 of 9) and 90% (9 of 10) in the SBRT and SBPT groups, respectively. One patient in the SBPT group developed grade 3 skin fibrosis. No patients experienced grade 4/5 toxicity., Conclusion: Poor accrual, due to lack of volumetric imaging and insurance coverage for proton therapy, led to early closure of the trial and precluded accurate assessment of efficacy and toxicity. Comparable maturity of 2 radiation therapy modalities, particularly on-board imaging, and better insurance coverage for SBPT should be considered for future studies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To investigate how spot size and spacing affect plan quality, robustness, and interplay effects of robustly optimized intensity modulated proton therapy (IMPT) for lung cancer., Methods and Materials: Two robustly optimized IMPT plans were created for 10 lung cancer patients: first by a large-spot machine with in-air energy-dependent large spot size at isocenter (σ: 6-15 mm) and spacing (1.3 σ), and second by a small-spot machine with in-air energy-dependent small spot size (σ: 2-6 mm) and spacing (5 mm). Both plans were generated by optimizing radiation dose to internal target volume on averaged 4-dimensional computed tomography scans using an in-house-developed IMPT planning system. The dose-volume histograms band method was used to evaluate plan robustness. Dose evaluation software was developed to model time-dependent spot delivery to incorporate interplay effects with randomized starting phases for each field per fraction. Patient anatomy voxels were mapped phase-to-phase via deformable image registration, and doses were scored using in-house-developed software. Dose-volume histogram indices, including internal target volume dose coverage, homogeneity, and organs at risk (OARs) sparing, were compared using the Wilcoxon signed-rank test., Results: Compared with the large-spot machine, the small-spot machine resulted in significantly lower heart and esophagus mean doses, with comparable target dose coverage, homogeneity, and protection of other OARs. Plan robustness was comparable for targets and most OARs. With interplay effects considered, significantly lower heart and esophagus mean doses with comparable target dose coverage and homogeneity were observed using smaller spots., Conclusions: Robust optimization with a small spot-machine significantly improves heart and esophagus sparing, with comparable plan robustness and interplay effects compared with robust optimization with a large-spot machine. A small-spot machine uses a larger number of spots to cover the same tumors compared with a large-spot machine, which gives the planning system more freedom to compensate for the higher sensitivity to uncertainties and interplay effects for lung cancer treatments., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To compare clinical outcomes between proton beam therapy (PBT) and intensity modulated radiation therapy (IMRT) in patients with esophageal cancer (EC) treated with definitive chemoradiotherapy (CRT)., Methods and Materials: From 2007 through 2014, 343 EC patients who received definitive CRT with either PBT (n=132) or IMRT (n=211) were retrospectively analyzed. Survival, recurrence, and treatment toxicity were compared between groups. A Cox proportional hazards regression model was performed to test the association between patient/treatment variables and survival., Results: Patient/treatment variables were overall well balanced, except for age and race. Compared with IMRT, PBT had significantly better overall survival (OS; P=.011), progression-free survival (PFS; P=.001), distant metastasis-free survival (DMFS; P=.031), as well as marginally better locoregional failure-free survival (LRFFS; P=.075). No significant differences in rates of treatment-related toxicities were observed between groups. On multivariate analysis, IMRT had worse OS (hazard ratio [HR] 1.454; P=.01), PFS (HR 1.562; P=.001), and LRFFS (HR 1.461; P=.041) than PBT. Subgroup analysis by clinical stage revealed considerably higher 5-year OS (34.6% vs 25.0%, P=.038) and PFS rates (33.5% vs 13.2%, P=.005) in the PBT group for patients with stage III disease. However, no significant intergroup differences in survival were identified for stage I/II patients., Conclusions: Compared with IMRT, PBT might be associated with improved OS, PFS, and LRFFS, especially in EC patients with locally advanced disease. These results need confirmation by prospective studies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Pencil-beam scanning (PBS) proton therapy (PT), particularly intensity modulated PT, represents the latest advanced PT technology for treating cancers, including thoracic malignancies. On the basis of virtual clinical studies, PBS-PT appears to have great potential in its ability to tightly tailor the dose to the target while sparing critical structures, thereby reducing treatment-related toxicities, particularly for tumors in areas with complicated anatomy. However, implementing PBS-PT for moving targets has several additional technical challenges compared with intensity modulated photon radiation therapy or passive scattering PT. Four-dimensional computed tomography-based motion management and robust optimization and evaluation are crucial for minimizing uncertainties associated with beam range and organ motion. Rigorous quality assurance is required to validate dose delivery both before and during the course of treatment. Active motion management (eg, breath hold), beam gating, rescanning, tracking, or adaptive planning may be needed for cases involving significant motion or changes in motion or anatomy over the course of treatment., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To discern the effectiveness and toxicity of stereotactic ablative radiation therapy (SABR) in the elderly population (aged ≥75 years) and to consider how SABR outcomes compare with surgical outcomes historically reported in the elderly., Methods and Materials: A total of 772 patients with clinical early-stage I-II non-small cell lung cancer (NSCLC; stage T1-T3N0M0) underwent SABR (50 Gy in 4 fractions or 70 Gy in 10 fractions) from 2004 to 2014 at our center (n=442, aged <75 years; n=330, aged ≥75 years). The primary endpoints included overall survival (OS), time-to-progression, and grade ≥3 toxicity. The median follow-up time was approximately 55 months., Results: Compared with patients aged <75 years, those aged ≥75 years had no difference in the time-to-progression (P=.419), lung cancer-specific survival (P=.275), or toxicity (P=.536). OS was the same between both age groups at 2 years of follow-up but diverged thereafter, with patients aged <75 years when treatment began having greater OS rates at 5 years. The median OS rates for patients aged ≥75 years were 86% at 1 year, 57.5% at 3 years, and 39.5% at 5 years. The median OS rates for patients aged <75 years were 87.3% at 1 year, 67.6% at 3 years, and 51.5% at 5 years. No patient aged ≥75 years experienced any grade 4 or 5 toxicity., Conclusions: The effectiveness of SABR was the same for the elderly as for the average-age population according to lung cancer-specific survival and time-to-progression. It also poses no increased toxicity. Compared with the historical outcomes with surgery in the elderly, SABR outcomes can be considered comparable for stage I-II disease but with less morbidity., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To identify the optimal dose parameters predictive for local/lobar control after stereotactic ablative radiation therapy (SABR) in early-stage non-small cell lung cancer (NSCLC)., Methods and Materials: This study encompassed a total of 1092 patients (1200 lesions) with NSCLC of clinical stage T1-T2 N0M0 who were treated with SABR of 50 Gy in 4 fractions or 70 Gy in 10 fractions, depending on tumor location/size, using computed tomography-based heterogeneity corrections and a convolution superposition calculation algorithm. Patients were monitored by chest CT or positron emission tomography/CT and/or biopsy after SABR. Factors predicting local/lobar recurrence (LR) were determined by competing risk multivariate analysis. Continuous variables were divided into 2 subgroups at cutoff values identified by receiver operating characteristic curves., Results: At a median follow-up time of 31.7 months (interquartile range, 14.8-51.3 months), the 5-year time to local recurrence within the same lobe and overall survival rates were 93.8% and 44.8%, respectively. Total cumulative number of patients experiencing LR was 40 (3.7%), occurring at a median time of 14.4 months (range, 4.8-46 months). Using multivariate competing risk analysis, independent predictive factors for LR after SABR were minimum biologically effective dose (BED10) to 95% of planning target volume (PTVD95 BED10) ≤86 Gy (corresponding to PTV D95 physics dose of 42 Gy in 4 fractions or 55 Gy in 10 fractions) and gross tumor volume ≥8.3 cm(3). The PTVmean BED10 was highly correlated with PTVD95 BED10. In univariate analysis, a cutoff of 130 Gy for PTVmean BED10 (corresponding to PTVmean physics dose of 55 Gy in 4 fractions or 75 Gy in 10 fractions) was also significantly associated with LR., Conclusions: In addition to gross tumor volume, higher radiation dose delivered to the PTV predicts for better local/lobar control. We recommend that both PTVD95 BED10 >86 Gy and PTVmean BED10 >130 Gy should be considered for SABR plan optimization., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Radiation dose escalation has been shown to improve local control and survival in patients with non-small cell lung cancer in some studies, but randomized data have not supported this premise, possibly owing to adverse effects. Because of the physical characteristics of the Bragg peak, proton therapy (PT) delivers minimal exit dose distal to the target volume, resulting in better sparing of normal tissues in comparison to photon-based radiation therapy. This is particularly important for lung cancer given the proximity of the lung, heart, esophagus, major airways, large blood vessels, and spinal cord. However, PT is associated with more uncertainty because of the finite range of the proton beam and motion for thoracic cancers. PT is more costly than traditional photon therapy but may reduce side effects and toxicity-related hospitalization, which has its own associated cost. The cost of PT is decreasing over time because of reduced prices for the building, machine, maintenance, and overhead, as well as newer, shorter treatment programs. PT is improving rapidly as more research is performed particularly with the implementation of 4-dimensional computed tomography-based motion management and intensity modulated PT. Given these controversies, there is much debate in the oncology community about which patients with lung cancer benefit significantly from PT. The Particle Therapy Co-operative Group (PTCOG) Thoracic Subcommittee task group intends to address the issues of PT indications, advantages and limitations, cost-effectiveness, technology improvement, clinical trials, and future research directions. This consensus report can be used to guide clinical practice and indications for PT, insurance approval, and clinical or translational research directions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to compare the impact of uncertainties and interplay on 3-dimensional (3D) and 4D robustly optimized intensity modulated proton therapy (IMPT) plans for lung cancer in an exploratory methodology study., Methods and Materials: IMPT plans were created for 11 nonrandomly selected non-small cell lung cancer (NSCLC) cases: 3D robustly optimized plans on average CTs with internal gross tumor volume density overridden to irradiate internal target volume, and 4D robustly optimized plans on 4D computed tomography (CT) to irradiate clinical target volume (CTV). Regular fractionation (66 Gy [relative biological effectiveness; RBE] in 33 fractions) was considered. In 4D optimization, the CTV of individual phases received nonuniform doses to achieve a uniform cumulative dose. The root-mean-square dose-volume histograms (RVH) measured the sensitivity of the dose to uncertainties, and the areas under the RVH curve (AUCs) were used to evaluate plan robustness. Dose evaluation software modeled time-dependent spot delivery to incorporate interplay effect with randomized starting phases of each field per fraction. Dose-volume histogram (DVH) indices comparing CTV coverage, homogeneity, and normal tissue sparing were evaluated using Wilcoxon signed rank test., Results: 4D robust optimization plans led to smaller AUC for CTV (14.26 vs 18.61, respectively; P=.001), better CTV coverage (Gy [RBE]) (D95% CTV: 60.6 vs 55.2, respectively; P=.001), and better CTV homogeneity (D5%-D95% CTV: 10.3 vs 17.7, respectively; P=.002) in the face of uncertainties. With interplay effect considered, 4D robust optimization produced plans with better target coverage (D95% CTV: 64.5 vs 63.8, respectively; P=.0068), comparable target homogeneity, and comparable normal tissue protection. The benefits from 4D robust optimization were most obvious for the 2 typical stage III lung cancer patients., Conclusions: Our exploratory methodology study showed that, compared to 3D robust optimization, 4D robust optimization produced significantly more robust and interplay-effect-resistant plans for targets with comparable dose distributions for normal tissues. A further study with a larger and more realistic patient population is warranted to generalize the conclusions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To compare 2 stereotactic body radiation therapy (SBRT) schedules for medically inoperable early-stage lung cancer to determine which produces the lowest rate of grade ≥3 protocol-specified adverse events (psAEs) at 1 year., Methods and Materials: Patients with biopsy-proven peripheral (≥2 cm from the central bronchial tree) T1 or T2, N0 (clinically node negative by positron emission tomography), M0 tumors were eligible. Patients were randomized to receive either 34 Gy in 1 fraction (arm 1) or 48 Gy in 4 consecutive daily fractions (arm 2). Rigorous central accreditation and quality assurance confirmed treatment per protocol guidelines. This study was designed to detect a psAEs rate >17% at a 10% significance level (1-sided) and 90% power. Secondary endpoints included rates of primary tumor control (PC), overall survival (OS), and disease-free survival (DFS) at 1 year. Designating the better of the 2 regimens was based on prespecified rules of psAEs and PC for each arm., Results: Ninety-four patients were accrued between September 2009 and March 2011. The median follow-up time was 30.2 months. Of 84 analyzable patients, 39 were in arm 1 and 45 in arm 2. Patient and tumor characteristics were balanced between arms. Four (10.3%) patients on arm 1 (95% confidence interval [CI] 2.9%-24.2%) and 6 (13.3%) patients on arm 2 (95% CI 5.1%-26.8%) experienced psAEs. The 2-year OS rate was 61.3% (95% CI 44.2%-74.6%) for arm 1 patients and 77.7% (95% CI 62.5%-87.3%) for arm 2. The 2-year DFS was 56.4% (95% CI 39.6%-70.2%) for arm 1 and 71.1% (95% CI 55.5%-82.1%) for arm 2. The 1-year PC rate was 97.0% (95% CI 84.2%-99.9%) for arm 1 and 92.7% (95% CI 80.1%-98.5%) for arm 2., Conclusions: 34 Gy in 1 fraction met the prespecified criteria and, of the 2 schedules, warrants further clinical research., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To investigate safety, efficacy, and recurrence after hemithoracic intensity modulated radiation therapy after pleurectomy/decortication (PD-IMRT) and after extrapleural pneumonectomy (EPP-IMRT)., Methods and Materials: In 2009-2013, 24 patients with mesothelioma underwent PD-IMRT to the involved hemithorax to a dose of 45 Gy, with an optional integrated boost; 22 also received chemotherapy. Toxicity was scored with the Common Terminology Criteria for Adverse Events v4.0. Pulmonary function was compared at baseline, after surgery, and after IMRT. Kaplan-Meier analysis was used to calculate overall survival (OS), progression-free survival (PFS), time to locoregional failure, and time to distant metastasis. Failures were in-field, marginal, or out of field. Outcomes were compared with those of 24 patients, matched for age, nodal status, performance status, and chemotherapy, who had received EPP-IMRT., Results: Median follow-up time was 12.2 months. Grade 3 toxicity rates were 8% skin and 8% pulmonary. Pulmonary function declined from baseline to after surgery (by 21% for forced vital capacity, 16% for forced expiratory volume in 1 second, and 19% for lung diffusion of carbon monoxide [P for all = .01]) and declined still further after IMRT (by 31% for forced vital capacity [P=.02], 25% for forced expiratory volume in 1 second [P=.01], and 30% for lung diffusion of carbon monoxide [P=.01]). The OS and PFS rates were 76% and 67%, respectively, at 1 year and 56% and 34% at 2 years. Median OS (28.4 vs 14.2 months, P=.04) and median PFS (16.4 vs 8.2 months, P=.01) favored PD-IMRT versus EPP-IMRT. No differences were found in grade 4-5 toxicity (0 of 24 vs 3 of 24, P=.23), median time to locoregional failure (18.7 months vs not reached, P not calculable), or median time to distant metastasis (18.8 vs 11.8 months, P=.12)., Conclusions: Hemithoracic intensity modulated radiation therapy after pleurectomy/decortication produced little high-grade toxicity but led to progressive declines in pulmonary function; OS and PFS were better in PD-IMRT compared with EPP-IMRT., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Intrathoracic recurrence of non-small cell lung cancer (NSCLC) after initial treatment remains a dominant cause of death. We report our experience using proton beam therapy and intensity modulated radiation therapy for reirradiation in such cases, focusing on patterns of failure, criteria for patient selection, and predictors of toxicity., Methods and Materials: A total of 102 patients underwent reirradiation for intrathoracic recurrent NSCLC at a single institution. All doses were recalculated to an equivalent dose in 2-Gy fractions (EQD2). All patients had received radiation therapy for NSCLC (median initial dose of 70 EQD2 Gy), with median interval to reirradiation of 17 months and median reirradiation dose of 60.48 EQD2 Gy. Median follow-up time was 6.5 months (range, 0-72 months)., Results: Ninety-nine patients (97%) completed reirradiation. Median local failure-free survival, distant metastasis-free survival (DMFS), and overall survival times were 11.43 months (range, 8.6-22.66 months), 11.43 months (range, 6.83-23.84 months), and 14.71 (range, 10.34-20.56 months), respectively. Toxicity was acceptable, with rates of grade ≥3 esophageal toxicity of 7% and grade ≥3 pulmonary toxicity of 10%. Of the patients who developed local failure after reirradiation, 88% had failure in either the original or the reirradiation field. Poor local control was associated with T4 disease, squamous histology, and Eastern Cooperative Oncology Group performance status score >1. Concurrent chemotherapy improved DMFS, but T4 disease was associated with poor DMFS. Higher T status, Eastern Cooperative Oncology Group performance status ≥1, squamous histology, and larger reirradiation target volumes led to worse overall survival; receipt of concurrent chemotherapy and higher EQD2 were associated with improved OS., Conclusions: Intensity modulated radiation therapy and proton beam therapy are options for treating recurrent non-small cell lung cancer. However, rates of locoregional recurrence and distant metastasis are high, and patients should be selected carefully to maximize the benefit of additional aggressive local therapy while minimizing the risk of adverse side effects., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Intensity modulated proton therapy (IMPT) can improve dose conformality and better spare normal tissue over passive scattering techniques, but range uncertainties complicate its use, particularly for moving targets. We report our early experience with IMPT for thoracic malignancies in terms of motion analysis and management, plan optimization and robustness, and quality assurance., Methods and Materials: Thirty-four consecutive patients with lung/mediastinal cancers received IMPT to a median 66 Gy(relative biological equivalence [RBE]). All patients were able to undergo definitive radiation therapy. IMPT was used when the treating physician judged that IMPT conferred a dosimetric advantage; all patients had minimal tumor motion (<5 mm) and underwent individualized tumor-motion dose-uncertainty analysis and 4-dimensional (4D) computed tomographic (CT)-based treatment simulation and motion analysis. Plan robustness was optimized by using a worst-case scenario method. All patients had 4D CT repeated simulation during treatment., Results: IMPT produced lower mean lung dose (MLD), lung V5 and V20, heart V40, and esophageal V60 than did IMRT (P<.05) and lower MLD, lung V20, and esophageal V60 than did passive scattering proton therapy (PSPT) (P<.05). D5 to the gross tumor volume and clinical target volume was higher with IMPT than with intensity modulated radiation therapy or PSPT (P<.05). All cases were analyzed for beam-angle-specific motion, water-equivalent thickness, and robustness. Beam angles were chosen to minimize the effect of respiratory motion and avoid previously treated regions, and the maximum deviation from the nominal dose-volume histogram values was kept at <5% for the target dose and met the normal tissue constraints under a worst-case scenario. Patient-specific quality assurance measurements showed that a median 99% (range, 95% to 100%) of the pixels met the 3% dose/3 mm distance criteria for the γ index. Adaptive replanning was used for 9 patients (26.5%)., Conclusions: IMPT using 4D CT-based planning, motion management, and optimization was implemented successfully and met our quality assurance parameters for treating challenging thoracic cancers., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: We extended our previous experience with stereotactic ablative radiation therapy (SABR; 50 Gy in 4 fractions) for centrally located non-small cell lung cancer (NSCLC); explored the use of 70 Gy in 10 fractions for cases in which dose-volume constraints could not be met with the previous regimen; and suggested modified dose-volume constraints., Methods and Materials: Four-dimensional computed tomography (4DCT)-based volumetric image-guided SABR was used for 100 patients with biopsy-proven, central T1-T2N0M0 (n=81) or isolated parenchymal recurrence of NSCLC (n=19). All disease was staged with positron emission tomography/CT; all tumors were within 2 cm of the bronchial tree, trachea, major vessels, esophagus, heart, pericardium, brachial plexus, or vertebral body. Endpoints were toxicity, overall survival (OS), local and regional control, and distant metastasis., Results: At a median follow-up time of 30.6 months, median OS time was 55.6 months, and the 3-year OS rate was 70.5%. Three-year cumulative actuarial local, regional, and distant control rates were 96.5%, 87.9%, and 77.2%, respectively. The most common toxicities were chest-wall pain (18% grade 1, 13% grade 2) and radiation pneumonitis (11% grade 2 and 1% grade 3). No patient experienced grade 4 or 5 toxicity. Among the 82 patients receiving 50 Gy in 4 fractions, multivariate analyses showed mean total lung dose >6 Gy, V20 >12%, or ipsilateral lung V30 >15% to independently predict radiation pneumonitis; and 3 of 9 patients with brachial plexus Dmax >35 Gy experienced brachial neuropathy versus none of 73 patients with brachial Dmax <35 Gy (P=.001). Other toxicities were analyzed and new dose-volume constraints are proposed., Conclusions: SABR for centrally located lesions produces clinical outcomes similar to those for peripheral lesions when normal tissue constraints are respected., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Photon therapy has been reported to induce resets of implanted cardiac devices, but the clinical sequelae of treating patients with such devices with proton beam therapy (PBT) are not well known. We reviewed the incidence of device malfunctions among patients undergoing PBT., Methods and Materials: From March 2009 through July 2012, 42 patients with implanted cardiac implantable electronic devices (CIED; 28 pacemakers and 14 cardioverter-defibrillators) underwent 42 courses of PBT for thoracic (23, 55%), prostate (15, 36%), liver (3, 7%), or base of skull (1, 2%) tumors at a single institution. The median prescribed dose was 74 Gy (relative biological effectiveness; range 46.8-87.5 Gy), and the median distance from the treatment field to the CIED was 10 cm (range 0.8-40 cm). Maximum proton and neutron doses were estimated for each treatment course. All CIEDs were checked before radiation delivery and monitored throughout treatment., Results: Median estimated peak proton and neutron doses to the CIED in all patients were 0.8 Gy (range 0.13-21 Gy) and 346 Sv (range 11-1100 mSv). Six CIED malfunctions occurred in 5 patients (2 pacemakers and 3 defibrillators). Five of these malfunctions were CIED resets, and 1 patient with a defibrillator (in a patient with a liver tumor) had an elective replacement indicator after therapy that was not influenced by radiation. The mean distance from the proton beam to the CIED among devices that reset was 7.0 cm (range 0.9-8 cm), and the mean maximum neutron dose was 655 mSv (range 330-1100 mSv). All resets occurred in patients receiving thoracic PBT and were corrected without clinical incident. The generator for the defibrillator with the elective replacement indicator message was replaced uneventfully after treatment., Conclusions: The incidence of CIED resets was about 20% among patients receiving PBT to the thorax. We recommend that PBT be avoided in pacing-dependent patients and that patients with any type of CIED receiving thoracic PBT be followed closely., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: Two choices are widely used for radiation delivery, 3-dimensional conformal radiation therapy (3DCRT) and intensity modulated radiation therapy (IMRT). No randomized comparisons have been conducted in the setting of lung cancer, but theoretical concerns suggest that IMRT may negatively impact disease control. We analyzed a large cohort of limited-stage small-cell lung cancer (LS-SCLC) patients treated before and after institutional conversion from 3DCRT to IMRT to compare outcomes., Methods and Materials: Patients with LS-SCLC treated with definitive radiation at our institution between 2000 and 2009 were retrospectively reviewed. Both multivariable Cox regression and propensity score matching were used to compare oncologic outcomes of 3DCRT and IMRT in the context of other clinically relevant covariables. Acute and chronic toxicities associated with the 2 techniques were compared using Fisher exact and log-rank tests, respectively., Results: A total of 223 patients were treated during the study period, with 119 receiving 3DCRT and 104 receiving IMRT. Their median age was 64 years (range, 39-90 years). Median follow-up times for 3DCRT and IMRT were 27 months (range, 2-147 months) and 22 months (range, 4-83 months), respectively. Radiation modality was not associated with differences in overall survival or disease-free survival in either multivariable or propensity score-matched analyses. IMRT patients required significantly fewer percutaneous feeding tube placements (5% vs 17%, respectively, P=.005)., Conclusions: IMRT was not associated with worse oncologic outcomes than those of 3DCRT. IMRT was associated with a lower rate of esophagitis-related percutaneous feeding tube placements., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Many patients with locally advanced non-small cell lung cancer (NSCLC) cannot undergo concurrent chemotherapy because of comorbidities or poor performance status. Hypofractionated radiation regimens, if tolerable, may provide an option to these patients for effective local control., Methods and Materials: Twenty-five patients were enrolled in a phase 1 dose-escalation trial of proton beam therapy (PBT) from September 2010 through July 2012. Eligible patients had histologically documented lung cancer, thymic tumors, carcinoid tumors, or metastatic thyroid tumors. Concurrent chemotherapy was not allowed, but concurrent treatment with biologic agents was. The dose-escalation schema comprised 15 fractions of 3 Gy(relative biological effectiveness [RBE])/fraction, 3.5 Gy(RBE)/fraction, or 4 Gy(RBE)/fraction. Dose constraints were derived from biologically equivalent doses of standard fractionated treatment., Results: The median follow-up time for patients alive at the time of analysis was 13 months (range, 8-28 months). Fifteen patients received treatment to hilar or mediastinal lymph nodes. Two patients experienced dose-limiting toxicity possibly related to treatment; 1 received 3.5-Gy(RBE) fractions and experienced an in-field tracheoesophageal fistula 9 months after PBT and 1 month after bevacizumab. The other patient received 4-Gy(RBE) fractions and was hospitalized for bacterial pneumonia/radiation pneumonitis 4 months after PBT., Conclusion: Hypofractionated PBT to the thorax delivered over 3 weeks was well tolerated even with significant doses to the lungs and mediastinal structures. Phase 2/3 trials are needed to compare the efficacy of this technique with standard treatment for locally advanced NSCLC., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To analyze dosimetric variables and outcomes after adaptive replanning of radiation therapy during concurrent high-dose protons and chemotherapy for locally advanced non-small cell lung cancer (NSCLC)., Methods and Materials: Nine of 44 patients with stage III NSCLC in a prospective phase II trial of concurrent paclitaxel/carboplatin with proton radiation [74 Gy(RBE) in 37 fractions] had modifications to their original treatment plans after re-evaluation revealed changes that would compromise coverage of the target volume or violate dose constraints; plans for the other 35 patients were not changed. We compared patients with adaptive plans with those with nonadaptive plans in terms of dosimetry and outcomes., Results: At a median follow-up of 21.2 months (median overall survival, 29.6 months), no differences were found in local, regional, or distant failure or overall survival between groups. Adaptive planning was used more often for large tumors that shrank to a greater extent (median, 107.1 cm(3) adaptive and 86.4 cm(3) nonadaptive; median changes in volume, 25.3% adaptive and 1.2% nonadaptive; P<.01). The median number of fractions delivered using adaptive planning was 13 (range, 4-22). Adaptive planning generally improved sparing of the esophagus (median absolute decrease in V(70), 1.8%; range, 0%-22.9%) and spinal cord (median absolute change in maximum dose, 3.7 Gy; range, 0-13.8 Gy). Without adaptive replanning, target coverage would have been compromised in 2 cases (57% and 82% coverage without adaptation vs 100% for both with adaptation); neither patient experienced local failure. Radiation-related grade 3 toxicity rates were similar between groups., Conclusions: Adaptive planning can reduce normal tissue doses and prevent target misses, particularly for patients with large tumors that shrink substantially during therapy. Adaptive plans seem to have acceptable toxicity and achieve similar local, regional, and distant control and overall survival, even in patients with larger tumors, vs nonadaptive plans., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: The incidence of early-stage non-small cell lung cancer (NSCLC) among older adults is expected to increase because of demographic trends and computed tomography-based screening; yet, optimal treatment in the elderly remains controversial. Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare cohort spanning 2001-2007, we compared survival outcomes associated with 5 strategies used in contemporary practice: lobectomy, sublobar resection, conventional radiation therapy, stereotactic ablative radiation therapy (SABR), and observation., Methods and Materials: Treatment strategy and covariates were determined in 10,923 patients aged ≥ 66 years with stage IA-IB NSCLC. Cox regression, adjusted for patient and tumor factors, compared overall and disease-specific survival for the 5 strategies. In a second exploratory analysis, propensity-score matching was used for comparison of SABR with other options., Results: The median age was 75 years, and 29% had moderate to severe comorbidities. Treatment distribution was lobectomy (59%), sublobar resection (11.7%), conventional radiation (14.8%), observation (12.6%), and SABR (1.1%). In Cox regression analysis with a median follow-up time of 3.2 years, SABR was associated with the lowest risk of death within 6 months of diagnosis (hazard ratio [HR] 0.48; 95% confidence interval [CI] 0.38-0.63; referent is lobectomy). After 6 months, lobectomy was associated with the best overall and disease-specific survival. In the propensity-score matched analysis, survival after SABR was similar to that after lobectomy (HR 0.71; 95% CI 0.45-1.12; referent is SABR). Conventional radiation and observation were associated with poor outcomes in all analyses., Conclusions: In this population-based experience, lobectomy was associated with the best long-term outcomes in fit elderly patients with early-stage NSCLC. Exploratory analysis of SABR early adopters suggests efficacy comparable with that of surgery in select populations. Evaluation of these therapies in randomized trials is urgently needed., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To determine the incidence of and risk factors for radiation pneumonitis (RP) after stereotactic ablative radiation therapy (SABR) to the lung in patients who had previously undergone conventional thoracic radiation therapy., Methods and Materials: Seventy-two patients who had previously received conventionally fractionated radiation therapy to the thorax were treated with SABR (50 Gy in 4 fractions) for recurrent disease or secondary parenchymal lung cancer (T<4 cm, N0, M0, or Mx). Severe (grade≥3) RP and potential predictive factors were analyzed by univariate and multivariate logistic regression analyses. A scoring system was established to predict the risk of RP., Results: At a median follow-up time of 16 months after SABR (range, 4-56 months), 15 patients had severe RP (14 [18.9%] grade 3 and 1 [1.4%] grade 5) and 1 patient (1.4%) had a local recurrence. In univariate analyses, Eastern Cooperative Oncology Group performance status (ECOG PS) before SABR, forced expiratory volume in 1 second (FEV1), and previous planning target volume (PTV) location were associated with the incidence of severe RP. The V10 and mean lung dose (MLD) of the previous plan and the V10-V40 and MLD of the composite plan were also related to RP. Multivariate analysis revealed that ECOG PS scores of 2-3 before SABR (P=.009), FEV1≤65% before SABR (P=.012), V20≥30% of the composite plan (P=.021), and an initial PTV in the bilateral mediastinum (P=.025) were all associated with RP., Conclusions: We found that severe RP was relatively common, occurring in 20.8% of patients, and could be predicted by an ECOG PS score of 2-3, an FEV1≤65%, a previous PTV spanning the bilateral mediastinum, and V20≥30% on composite (previous RT+SABR) plans. Prospective studies are needed to validate these predictors and the scoring system on which they are based., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To compare the quality of volumetric modulated arc therapy (VMAT) or intensity-modulated radiation therapy (IMRT) plans generated by an automated inverse planning system with that of dosimetrist-generated IMRT treatment plans for patients with stage III lung cancer., Methods and Materials: Two groups of 8 patients with stage III lung cancer were randomly selected. For group 1, the dosimetrists spent their best effort in designing IMRT plans to compete with the automated inverse planning system (mdaccAutoPlan); for group 2, the dosimetrists were not in competition and spent their regular effort. Five experienced radiation oncologists independently blind-reviewed and ranked the three plans for each patient: a rank of 1 was the best and 3 was the worst. Dosimetric measures were also performed to quantitatively evaluate the three types of plans., Results: Blind rankings from different oncologists were generally consistent. For group 1, the auto-VMAT, auto-IMRT, and manual IMRT plans received average ranks of 1.6, 2.13, and 2.18, respectively. The auto-VMAT plans in group 1 had 10% higher planning tumor volume (PTV) conformality and 24% lower esophagus V70 (the volume receiving 70 Gy or more) than the manual IMRT plans; they also resulted in more than 20% higher complication-free tumor control probability (P+) than either type of IMRT plans. The auto- and manual IMRT plans in this group yielded generally comparable dosimetric measures. For group 2, the auto-VMAT, auto-IMRT, and manual IMRT plans received average ranks of 1.55, 1.75, and 2.75, respectively. Compared to the manual IMRT plans in this group, the auto-VMAT plans and auto-IMRT plans showed, respectively, 17% and 14% higher PTV dose conformality, 8% and 17% lower mean lung dose, 17% and 26% lower mean heart dose, and 36% and 23% higher P+., Conclusions: mdaccAutoPlan is capable of generating high-quality VMAT and IMRT treatment plans for stage III lung cancer. Manual IMRT plans could achieve quality similar to auto-IMRT plans if best effort was spent., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: We analyzed whether positron emission tomography (PET)/computed tomography standardized uptake values (SUVs) after stereotactic body radiotherapy (SBRT) could predict local recurrence (LR) in non-small-cell lung cancer (NSCLC)., Methods and Materials: This study comprised 128 patients with Stage I (n = 68) or isolated recurrent/secondary parenchymal (n = 60) NSCLC treated with image-guided SBRT to 50 Gy over 4 consecutive days; prior radiotherapy was allowed. PET/computed tomography scans were obtained before therapy and at 1 to 6 months after therapy, as well as subsequently as clinically indicated. Continuous variables were analyzed with Kruskal-Wallis tests and categorical variables with Pearson chi-square or Fisher exact tests. Actuarial local failure rates were calculated with the Kaplan-Meier method., Results: At a median follow-up of 31 months (range, 6-71 months), the actuarial 1-, 2-, and 3-year local control rates were 100%, 98.5%, and 98.5%, respectively, in the Stage I group and 95.8%, 87.6%, and 85.8%, respectively, in the recurrent group. The cumulative rates of regional nodal recurrence and distant metastasis were 8.8% (6 of 68) and 14.7% (10 of 68), respectively, for the Stage I group and 11.7% (7 of 60) and 16.7% (10 of 60), respectively, for the recurrent group. Univariate analysis showed that SUVs obtained 12.1 to 24 months after treatment for the Stage I group (p = 0.007) and 6.1 to 12 months and 12.1 to 24 months after treatment for the recurrent group were associated with LR (p < 0.001 for both). Of the 128 patients, 17 (13.3%) had ipsilateral consolidation after SBRT but no elevated metabolic activity on PET; none had LR. The cutoff maximum SUV of 5 was found to have 100% sensitivity, 91% specificity, a 50% positive predictive value, and a 100% negative predictive value for predicting LR., Conclusions: PET was helpful for distinguishing SBRT-induced consolidation from LR. SUVs obtained more than 6 months after SBRT for NSCLC were associated with local failure. A maximum SUV greater than 5, especially at more than 6 months after SBRT, should prompt biopsy to rule out LR., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Omitting elective nodal irradiation from planning target volumes does not compromise outcomes in patients with non-small-cell lung cancer, but whether the same is true for those with limited-stage small-cell lung cancer (LS-SCLC) is unknown. Therefore, in the present study, we sought to determine the clinical outcomes and the frequency of elective nodal failure in patients with LS-SCLC staged using positron emission tomography/computed tomography and treated with involved-field intensity-modulated radiotherapy., Methods and Materials: Between 2005 and 2008, 60 patients with LS-SCLC at our institution underwent disease staging using positron emission tomography/computed tomography before treatment using an intensity-modulated radiotherapy plan in which elective nodal irradiation was intentionally omitted from the planning target volume (mode and median dose, 45 Gy in 30 fractions; range, 40.5 Gy in 27 fractions to 63.8 Gy in 35 fractions). In most cases, concurrent platinum-based chemotherapy was administered. We retrospectively reviewed the clinical outcomes to determine the overall survival, relapse-free survival, and failure patterns. Elective nodal failure was defined as recurrence in initially uninvolved hilar, mediastinal, or supraclavicular nodes. Survival was assessed using the Kaplan-Meier method., Results: The median age of the study patients at diagnosis was 63 years (range, 39-86). The median follow-up duration was 21 months (range, 4-58) in all patients and 26 months (range, 4-58) in the survivors. The 2-year actuarial overall survival and relapse-free survival rate were 58% and 43%, respectively. Of the 30 patients with recurrence, 23 had metastatic disease and 7 had locoregional failure. We observed only one isolated elective nodal failure., Conclusions: To our knowledge, this is the first study to examine the outcomes in patients with LS-SCLC staged with positron emission tomography/computed tomography and treated with definitive intensity-modulated radiotherapy. In these patients, elective nodal irradiation can be safely omitted from the planning target volume for the purposes of dose escalation and toxicity reduction., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To determine an optimal standardized uptake value (SUV) threshold for detecting lymph node (LN) metastases in esophageal cancer using (18)F-Fluorodeoxyglucose positron emission tomography/computer tomography (18FDG PET/CT) and to define the resulting nodal target volume, using histopathology as a "gold standard.", Methods: Sixteen patients with esophageal squamous cell carcinoma who underwent radical esophagectomy and three-field LN dissection after 18FDG PET/CT and CT scans were enrolled into this study. Locations of LN groups were recorded according to a uniform LN map. Diagnostic performance of different SUV thresholds was assessed by receiver operating characteristic analysis. The optimal cutoff SUV was determined by plotting the false-negative rate (FNR) and false-positive rate (FPR), the sum of both error rates (FNR+FPR), and accuracy against a hypothetical SUV threshold. For each patient, nodal gross tumor volumes (GTVNs) were generated with CT alone (GTVNCT), PET/CT (GTVNPET), and pathologic data (GTVNpath). GTVNCT or GTVNPET was compared with GTVNpath by means of a conformity index (CI), which is the intersection of the two GTVNs divided by the sum of them minus the intersection, e.g., CICT&path=GTVNCT&path/(GTVNCT+GTVNpath-GTVNCT&path)., Results: LN metastases occurred in 21 LN groups among the 144 specimens taken from the 16 patients. The area under the receiver operating characteristic curve was 0.9017±0.0410. The plot of error rates showed a minimum of FNR+FPR for an SUV of 2.36, at which the sensitivity, specificity, and accuracy were 76.19%, 95.93%, and 93.06%, respectively, whereas those of CT were 33.33%, 94.31%, and 85.42% (p values: 0.0117, 0.7539, and 0.0266). Mean GTVNCT, GTVNPET, and GTVNpath were 1.52±2.38, 2.82±4.51, and 2.68±4.16 cm3, respectively. Mean CICT&path and CIPET&path were 0.31 and 0.65 (p value=0.0352)., Conclusions: Diagnostic superiority of PET/CT at an SUV threshold of 2.36 over CT has potential value in nodal target volume definition, but whether this can contribute to better treatment outcomes needs prospective analyses of recurrences in a larger cohort of patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Stereotactic body radiation therapy (SBRT) is increasingly being used to treat thoracic tumors. We attempted here to identify dose-volume parameters that predict chest wall toxicity (pain and skin reactions) in patients receiving thoracic SBRT., Patients and Methods: We screened a database of patients treated with SBRT between August 2004 and August 2008 to find patients with pulmonary tumors within 2.5 cm of the chest wall. All patients received a total dose of 50 Gy in four daily 12.5-Gy fractions. Toxicity was scored according to the NCI-CTCAE V3.0., Results: Of 360 patients in the database, 265 (268 tumors) had tumors within <2.5 cm of the chest wall; 104 (39%) developed skin toxicity (any grade); 14 (5%) developed acute pain (any grade), and 45 (17%) developed chronic pain (Grade 1 in 22 cases [49%] and Grade 2 or 3 in 23 cases [51%]). Both skin toxicity and chest wall pain were associated with the V30, or volume of the chest wall receiving 30 Gy. Body mass index (BMI) was also strongly associated with the development of chest pain: patients with BMI≥29 had almost twice the risk of chronic pain (p=0.03). Among patients with BMI>29, diabetes mellitus was a significant contributing factor to the development of chest pain., Conclusion: Safe use of SBRT with 50 Gy in four fractions for lesions close to the chest wall requires consideration of the chest wall volume receiving 30 Gy and the patient's BMI and diabetic state., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To analyze the toxicity and patterns of failure of proton therapy given in ablative doses for medically inoperable early-stage non-small cell lung cancer (NSCLC)., Methods and Materials: Eighteen patients with medically inoperable T1N0M0 (central location) or T2-3N0M0 (any location) NSCLC were treated with proton therapy at 87.5 Gy (relative biological effectiveness) at 2.5 Gy /fraction in this Phase I/II study. All patients underwent treatment simulation with four-dimensional CT; internal gross tumor volumes were delineated on maximal intensity projection images and modified by visual verification of the target volume in 10 breathing phases. The internal gross tumor volumes with maximal intensity projection density was used to design compensators and apertures to account for tumor motion. Therapy consisted of passively scattered protons. All patients underwent repeat four-dimensional CT simulations during treatment to assess the need for adaptive replanning., Results: At a median follow-up time of 16.3 months (range, 4.8-36.3 months), no patient had experienced Grade 4 or 5 toxicity. The most common adverse effect was dermatitis (Grade 2, 67%; Grade 3, 17%), followed by Grade 2 fatigue (44%), Grade 2 pneumonitis (11%), Grade 2 esophagitis (6%), and Grade 2 chest wall pain (6%). Rates of local control were 88.9%, regional lymph node failure 11.1%, and distant metastasis 27.8%. Twelve patients (67%) were still alive at the last follow-up; five had died of metastatic disease and one of preexisting cardiac disease., Conclusions: Proton therapy to ablative doses is well tolerated and produces promising local control rates for medically inoperable early-stage NSCLC., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To minimize toxicity while maintaining tumor coverage with stereotactic body radiation therapy (SBRT) for centrally or superiorly located stage I non-small-cell lung cancer (NSCLC), we investigated passive-scattering proton therapy (PSPT) and intensity-modulated proton therapy (IMPT)., Methods and Materials: Fifteen patients with centrally or superiorly located (within 2 cm of critical structures) stage I NSCLC were treated clinically with three-dimensional photon SBRT (50 Gy in 4 fractions). The photon SBRT plan was compared with the PSPT and IMPT plans. The maximum tolerated dose (MTD) was defined as the dose that exceeded the dose--volume constraints in the critical structures., Results: Only 6 photon plans satisfied the >95% planning target volume (PTV) coverage and MTD constraints, compared to 12 PSPT plans (p = 0.009) and 14 IMPT plans (p = 0.001). Compared with the photon SBRT plans, the PSPT and IMPT plans significantly reduced the mean total lung dose from 5.4 Gy to 3.5 Gy (p < 0.001) and 2.8 Gy (p < 0.001) and reduced the total lung volume receiving 5 Gy, 10 Gy, and 20 Gy (p < 0.001). When the PTV was within 2 cm of the critical structures, the PSPT and IMPT plans significantly reduced the mean maximal dose to the aorta, brachial plexus, heart, pulmonary vessels, and spinal cord., Conclusions: For centrally or superiorly located stage I NSCLC, proton therapy, particularly IMPT, delivered ablative doses to the target volume and significantly reduced doses to the surrounding normal tissues compared with photon SBRT., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To analyze tumor position reproducibility of feedback-guided voluntary deep inspiration breath-hold (FGBH) gating for cone beam computed tomography (CBCT)-based stereotactic body radiotherapy (SBRT)., Methods and Materials: Thirteen early-stage lung cancer patients eligible for SBRT with tumor motion of >1cm were evaluated for FGBH-gated treatment. Multiple FGBH CTs were acquired at simulation, and single FGBH CBCTs were also acquired prior to each treatment. Simulation CTs and treatment CBCTs were analyzed to quantify reproducibility of tumor positions during FGBH. Benefits of FGBH gating compared to treatment during free breathing, as well treatment with gating at exhalation, were examined for lung sparing, motion margins, and reproducibility of gross tumor volume (GTV) position relative to nonmoving anatomy., Results: FGBH increased total lung volumes by 1.5 times compared to free breathing, resulting in a proportional drop in total lung volume receiving 10 Gy or more. Intra- and inter-FGBH reproducibility of GTV centroid positions at simulation were 1.0 ± 0.5 mm, 1.3 ± 1.0 mm, and 0.6 ± 0.4 mm in the anterior-posterior (AP), superior-inferior (SI), and left-right lateral (LR) directions, respectively, compared to more than 1 cm of tumor motion at free breathing. During treatment, inter-FGBH reproducibility of the GTV centroid with respect to bony anatomy was 1.2 ± 0.7 mm, 1.5 ± 0.8 mm, and 1.0 ± 0.4 mm in the AP, SI, and LR directions. In addition, the quality of CBCTs was improved due to elimination of motion artifacts, making this technique attractive for poorly visualized tumors, even with small motion., Conclusions: The extent of tumor motion at normal respiration does not influence the reproducibility of the tumor position under breath hold conditions. FGBH-gated SBRT with CBCT can improve the reproducibility of GTV centroids, reduce required margins, and minimize dose to normal tissues in the treatment of mobile tumors., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To determine the extent of interfractional setup errors and day-to-day organ motion errors by assessing daily bone alignment results and changes in soft tissue tumor position during hypofractionated, in-room computed tomography (CT)-guided stereotactic body radiation therapy (SBRT) of lung cancer., Methods and Materials: Daily alignment results during SBRT were analyzed for 117 tumors in 112 patients. Patients received 40-50 Gy of SBRT in four to five fractions using an integrated CT-LINAC system. The free-breathing CT scans acquired during treatment setup were retrospectively realigned to match with each of the bony references and the gross tumor volume (GTV) defined on the reference CT by rigid-body registration, and the daily deviations were calculated., Results: The mean magnitude (± SD) three-dimensional shift from the initial skin marks to the final bone-aligned positions was 9.4 ± 5.7 mm. The mean daily GTV deviation from the bone position was 0.1 ± 3.8 mm in the anterior-posterior direction, -0.01 ± 4.2 mm in the superior-inferior direction, and 0.2 ± 2.5 mm in the lateral direction. A clinically noteworthy trend (net change >5 mm in any direction) in GTV position relative to the bone was observed in 23 cases (20%)., Conclusions: Soft tissue target position can change significantly beyond the motion envelope defined in the original internal target volume in four-dimensional CT-based treatment planning for SBRT of lung cancer. Additional margin should be considered for adequate coverage of interfractional changes., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Stereotactic body radiation therapy (SBRT) provides excellent local control with acceptable toxicity for patients with early-stage non-small cell lung cancer. However, the efficacy and safety of SBRT for patients previously given thoracic radiation therapy is not known. In this study, we retrospectively reviewed outcomes after SBRT for recurrent disease among patients previously given radiation therapy to the chest., Materials and Methods: A search of medical records for patients treated with SBRT to the thorax after prior fractionated radiation therapy to the chest at The University of Texas M. D. Anderson Cancer Center revealed 36 such cases. The median follow-up time after SBRT was 15 months. The endpoints analyzed were overall survival, local control, and the incidence and severity of treatment-related toxicity., Results: SBRT provided in-field local control for 92% of patients; at 2 years, the actuarial overall survival rate was 59%, and the actuarial progression-free survival rate was 26%, with the primary site of failure being intrathoracic relapse. Fifty percent of patients experienced worsening of dyspnea after SBRT, with 19% requiring oxygen supplementation; 30% of patients experienced chest wall pain and 8% Grade 3 esophagitis. No Grade 4 or 5 toxic effects were noted., Conclusions: SBRT can provide excellent in-field tumor control in patients who have received prior radiation therapy. Toxicity was significant but manageable. The high rate of intrathoracic failure indicates the need for further study to identify patients who would derive the most benefit from SBRT for this purpose., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Purpose: To compare dose volume histograms of intensity-modulated proton therapy (IMPT) with those of intensity-modulated radiation therapy (IMRT) and passive scattering proton therapy (PSPT) for the treatment of stage IIIB non-small-cell lung cancer (NSCLC) and to explore the possibility of individualized radical radiotherapy., Methods and Materials: Dose volume histograms designed to deliver IMRT at 60 to 63 Gy, PSPT at 74 Gy, and IMPT at the same doses were compared and the use of individualized radical radiotherapy was assessed in patients with extensive stage IIIB NSCLC (n = 10 patients for each approach). These patients were selected based on their extensive disease and were considered to have no or borderline tolerance to IMRT at 60 to 63 Gy, based on the dose to normal tissue volume constraints (lung volume receiving 20 Gy [V20] of <35%, total mean lung dose <20 Gy; spinal cord dose, <45 Gy). The possibility of increasing the total tumor dose with IMPT for each patient without exceeding the dose volume constraints (maximum tolerated dose [MTD]) was also investigated., Results: Compared with IMRT, IMPT spared more lung, heart, spinal cord, and esophagus, even with dose escalation from 63 Gy to 83.5 Gy, with a mean MTD of 74 Gy. Compared with PSPT, IMPT allowed further dose escalation from 74 Gy to a mean MTD of 84.4 Gy (range, 79.4-88.4 Gy) while all parameters of normal tissue sparing were kept at lower or similar levels. In addition, IMPT prevented lower-dose target coverage in patients with complicated tumor anatomies., Conclusions: IMPT reduces the dose to normal tissue and allows individualized radical radiotherapy for extensive stage IIIB NSCLC., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the margins currently used to generate the planning target volume for lung tumors and to determine whether image-guided patient setup or respiratory gating is more effective in reducing uncertainties in tumor position., Methods and Materials: Lung tumors in 7 patients were contoured on serial four-dimensional computed tomography (4DCT) data sets (4-8 4DCTs/patient; 50 total) obtained throughout the course of treatment. Simulations were performed to determine the tumor position when the patient was aligned using skin marks, image-guided setup based on vertebral bodies, fiducials implanted near the tumor, and the actual tumor volume under various scenarios of respiratory gating., Results: Because of the presence of setup uncertainties, the reduction in overall margin needed to completely encompass the tumor was observed to be larger for imaged-guided patient setup than for a simple respiratory-gated treatment. Without respiratory gating and image-guided patient setup, margins ranged from 0.9 cm to 3.1 cm to completely encompass the tumor. These were reduced to 0.7-1.7 cm when image-guided patient setup was simulated and further reduced with respiratory gating., Conclusions: Our results indicate that if respiratory motion management is used, it should be used in conjunction with image-guided patient setup in order to reduce the overall treatment margin effectively.