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Purpose: To report long-term outcome of fractionated stereotactic body radiation therapy (SBRT) for painful spinal metastases., Methods and Materials: This prospective, single-arm, multicenter phase 2 clinical trial enrolled 57 patients with 63 painful, unirradiated spinal metastases between March 2012 and July 2015. Patients were treated with 48.5 Gy in 10 SBRT fractions (long life expectancy [Mizumoto score ≤4]) or 35 Gy in 5 SBRT fractions (intermediate life expectancy [Mizumoto score 5-9]). Pain response was defined as pain improvement of a minimum of 2 points on a visual analog scale, and net pain relief was defined as the sum of time with pain response (complete and partial) divided by the overall follow-up time., Results: All 57 patients received treatment per protocol; 32 and 25 patients were treated with 10- and 5-fraction SBRT, respectively. The median follow-up of living patients was 60 months (range, 33-74 months). Of evaluable patients, 82% had complete or partial pain response (responders) at 3 months' follow-up (primary endpoint), and pain response remained stable over 5 years. Net pain relief was 74% (95% CI, 65%-80%). Overall survival rates of 1, 3, and 5 years were 59.6% (95% CI, 47%-72%), 33.3% (95% CI, 21%-46%), and 21% (95% CI, 10%-32%), respectively. Freedom from local spinal-metastasis progression was 82% at the last imaging follow-up. Late grade-3 toxicity was limited to pain in 2 patients (nonresponders). There were no cases of myelopathy. SBRT resulted in long-term improvements of all dimensions of the 5-level EuroQol 5-Dimension Questionnaire except anxiety/depression., Conclusions: Fractionated SBRT achieved durable pain response and improved quality of life at minimum late toxicity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Large variation regarding prescription and dose inhomogeneity exists in stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer. The aim of this modeling study was to identify which dose metric correlates best with local tumor control probability to make recommendations regarding SBRT prescription., Methods and Materials: We combined 2 retrospective databases of patients with non-small cell lung cancer, yielding 1500 SBRT treatments for analysis. Three dose parameters were converted to biologically effective doses (BEDs): (1) the (near-minimum) dose prescribed to the planning target volume (PTV) periphery (yielding BED min ); (2) the (near-maximum) dose absorbed by 1% of the PTV (yielding BED max ); and (3) the average between near-minimum and near-maximum doses (yielding BED ave ). These BED parameters were then correlated to the risk of local recurrence through Cox regression. Furthermore, BED-based prediction of local recurrence was attempted by logistic regression and fast and frugal trees. Models were compared using the Akaike information criterion., Results: There were 1500 treatments in 1434 patients; 117 tumors recurred locally. Actuarial local control rates at 12 and 36 months were 96.8% (95% confidence interval, 95.8%-97.8%) and 89.0% (87.0%-91.1%), respectively. In univariable Cox regression, BED ave was the best predictor of risk of local recurrence, and a model based on BED min had substantially less evidential support. In univariable logistic regression, the model based on BED ave also performed best. Multivariable classification using fast and frugal trees revealed BED max to be the most important predictor, followed by BED ave ., Conclusions: BED ave was generally better correlated with tumor control probability than either BED max or BED min . Because the average between near-minimum and near-maximum doses was highly correlated to the mean gross tumor volume dose, the latter may be used as a prescription target. More emphasis could be placed on achieving sufficiently high mean doses within the gross tumor volume rather than the PTV covering dose, a concept needing further validation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Stereotactic body radiation therapy has been associated with increased toxicity when delivered to patients with early-stage non-small cell lung cancer with a tumor within 2 cm of the proximal bronchial tree (PBT). We investigated noncancer deaths for these patients as related to gross tumor volume (GTV) proximity to the PBT, compared with peripheral tumors., Methods and Materials: We included 765 patients with early-stage non-small cell lung cancer who were treated with stereotactic body radiation therapy to a median of 3 × 18 Gy. Central tumors were treated with a risk-adapted (less-intense) schedule (mostly 8 fractions) in 55% of the patients in the first-centimeter group and 27% of the patients in the second-centimeter group. An average anatomy with contouring of PBT and organs at risk (OARs) was deformed onto each patient to obtain the distance of the GTV to the PBT and doses to OARs. Log-rank, 1-way analysis of variance, and Cox regressions were performed to assess differences in the first-centimeter, second centimeter, and peripheral groups and associations with noncancer deaths., Results: The median overall survival was 42.7 months, the median noncancer death occurred in 57.3 months, and the median follow-up was 34.8 months. Noncancer death in the first-centimeter group (31 patients) was significantly different from noncancer death in the other groups, with a hazard ratio of 3.175 (P < .001). Noncancer death in the second-centimeter group (71 patients) was not different from noncancer death in the peripheral group (P = .53). Doses to OARs were higher in the first- and second-centimeter groups than in the peripheral group for all OARs. High dose to the PBT was associated with noncancer death (D1%; hazard ratio, 1.006 Gy -1 ; P = .003)., Conclusions: Patients with a GTV in the first centimeter surrounding the PBT died more often from causes other than cancer compared with other patients. Noncancer death in patients with a GTV in the second centimeter, who partly received a risk-adapted schedule, was comparable to that in patients with a peripheral tumor., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Dose-escalation for patients with non-small cell lung cancer (NSCLC) in the positron emission tomography (PET)-boost trial (NCT01024829) exposes portions of normal lung tissue to high radiation doses. The relationship between lung parenchyma dose and density changes on computed tomography (CT) was analyzed., Materials and Methods: The CT scans of 59 patients with stage IB to III NSCLC, randomized between a boost to the whole primary tumor and an integrated boost to its 50% SUVmax (maximum standardized uptake value) volume. Patients were treated with concurrent or sequential chemoradiation or radiation only. Deformable registration mapped the 3-month follow-up CT to the planning CT. Hounsfield unit differences (ΔHU) were extracted to assess lung parenchyma density changes. Equivalent dose in 2 Gy fractions (EQD2)-ΔHU response was described sigmoidally, and regional response variation was studied by polar analysis. Prognostic factors of ΔHU were obtained through generalized linear modeling., Results: Saturation of ΔHU was observed above 60 Gy. No interaction was found between boost dose distribution (D 1cc and V 70Gy ) and ΔHU at lower doses. ΔHU was lowest peripherally from the tumor and peaked posteriorly at 3 cm from the tumor border (3.1 HU/Gy). Right lung location was an independent risk factor for ΔHU (P = .02)., Conclusions: No apparent increase of lung density changes at 3-month follow-up was observed above 60 Gy EQD2 for patients with NSCLC treated with (concurrent or sequential chemo) radiation. The mild response observed peripherally in the lung parenchyma might be exploited in plan optimization routines minimizing lung damage., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To determine the safety and efficacy of lung stereotactic body radiation therapy (SBRT) in octo- and nonagenarians and to compare their outcomes with those of younger patients., Methods and Materials: Patients with primary lung cancer treated with SBRT were identified from a multi-institutional (5 institutions) database of 1083 cases. Details of patient factors, treatment specifics, toxicity, and clinical outcomes were extracted from the database. All events were calculated from the end of radiation therapy. Estimates of local recurrence, regional recurrence, and distant metastases were calculated using the competing risk method. Cause-specific survival (CSS) and overall survival (OS) were calculated using the Kaplan-Meier method. Outcomes were compared for those aged <70, 70 to 79, and ≥80 years. Univariable and multivariable analyses were performed to determine associations with CSS and OS in patients aged ≥80 years., Results: The median (range) follow-up was 1.7 (1-10) years, and median age was 75 (41-94) years. There were 305 patients aged <70 years (28%), 448 aged 70 to 79 years (41%), and 330 aged ≥80 years (30%). There was no difference in 2-year local recurrence (4.2% vs 5.4% vs 3.7%, respectively, P=.7), regional recurrence (10.4% vs 7.8% vs 5.3%, P=.1), distant metastases (12.2% vs 7.7% vs 9.5%, P=.2), or CSS (90.6% vs 90.3% vs 90.4%, P=.6). Those aged ≥80 years had significantly lower 2-year OS (73.6% vs 67.2% vs 63.3%, P<.01). The grade 3+ pneumonitis rate was 1.3% versus 1.6% versus 1.5% (P=1.0) in patients aged <70, 70 to 79, and ≥80 years, respectively. The 90-day mortality rates for patients aged <70, 70 to 79, and ≥80 years were 1.3%, 2.5%, and 2.4% (P=.01), respectively. In patients aged ≥80 years OS was associated with T category (hazard ratio 1.7; P<.01)., Conclusion: Stereotactic body radiation therapy is a safe treatment modality in elderly patients (aged ≥80 years). Despite larger tumor volumes, the tumor control outcomes were comparable to those in younger patients treated with SBRT. All patients with early-stage lung cancer, regardless of age, should be considered for treatment with SBRT., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Fibrotic changes after stereotactic body radiation therapy (SBRT) for stage I non-small cell lung cancer (NSCLC) are difficult to distinguish from local recurrences (LR), hampering proper patient selection for salvage therapy. This study validates previously reported high-risk computed tomography (CT) features (HRFs) for detection of LR in an independent patient cohort., Methods and Materials: From a multicenter database, 13 patients with biopsy-proven LR were matched 1:2 to 26 non-LR control patients based on dose, planning target volume (PTV), follow-up time, and lung lobe. Tested HRFs were enlarging opacity, sequential enlarging opacity, enlarging opacity after 12 months, bulging margin, linear margin disappearance, loss of air bronchogram, and craniocaudal growth. Additionally, 2 new features were analyzed: the occurrence of new unilateral pleural effusion, and growth based on relative volume, assessed by manual delineation., Results: All HRFs were significantly associated with LR except for loss of air bronchogram. The best performing HRFs were bulging margin, linear margin disappearance, and craniocaudal growth. Receiver operating characteristic analysis of the number of HRFs to detect LR had an area under the curve (AUC) of 0.97 (95% confidence interval [CI] 0.9-1.0), which was identical to the performance described in the original report. The best compromise (closest to 100% sensitivity and specificity) was found at ≥4 HRFs, with a sensitivity of 92% and a specificity of 85%. A model consisting of only 2 HRFs, bulging margin and craniocaudal growth, resulted in a sensitivity of 85% and a specificity of 100%, with an AUC of 0.96 (95% CI 0.9-1.0) (HRFs ≥2). Pleural effusion and relative growth did not significantly improve the model., Conclusion: We successfully validated CT-based HRFs for detection of LR after SBRT for early-stage NSCLC. As an alternative to number of HRFs, we propose a simplified model with the combination of the 2 best HRFs: bulging margin and craniocaudal growth, although validation is warranted., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose/objective: In patients with locally advanced lung cancer, planning target volume margins for mediastinal lymph nodes and tumor after a correction protocol based on bony anatomy registration typically range from 1 to 1.5 cm. Detailed information about lymph node motion variability and differential motion with the primary tumor, however, is lacking from large series. In this study, lymph node and tumor position variability were analyzed in detail and correlated to the main carina to evaluate possible margin reduction., Methods and Materials: Small gold fiducial markers (0.35 × 5 mm) were placed in the mediastinal lymph nodes of 51 patients with non-small cell lung cancer during routine diagnostic esophageal or bronchial endoscopic ultrasonography. Four-dimensional (4D) planning computed tomographic (CT) and daily 4D cone beam (CB) CT scans were acquired before and during radical radiation therapy (66 Gy in 24 fractions). Each CBCT was registered in 3-dimensions (bony anatomy) and 4D (tumor, marker, and carina) to the planning CT scan. Subsequently, systematic and random residual misalignments of the time-averaged lymph node and tumor position relative to the bony anatomy and carina were determined. Additionally, tumor and lymph node respiratory amplitude variability was quantified. Finally, required margins were quantified by use of a recipe for dual targets., Results: Relative to the bony anatomy, systematic and random errors ranged from 0.16 to 0.32 cm for the markers and from 0.15 to 0.33 cm for the tumor, but despite similar ranges there was limited correlation (0.17-0.71) owing to differential motion. A large variability in lymph node amplitude between patients was observed, with an average motion of 0.56 cm in the cranial-caudal direction. Margins could be reduced by 10% (left-right), 27% (cranial-caudal), and 10% (anteroposterior) for the lymph nodes and -2%, 15%, and 7% for the tumor if an online carina registration protocol replaced a protocol based on bony anatomy registration., Conclusions: Detailed analysis revealed considerable lymph node position variability, differential motion, and respiratory motion. Planning target volume margins can be reduced up to 27% in lung cancer patients when the carina registration replaces bony anatomy registration., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To estimate the α/β ratio for which the dose-dependent lung perfusion reductions for stereotactic body radiation therapy (SBRT) and conventionally fractionated radiation therapy (CFRT) are biologically equivalent., Methods and Materials: The relations between local dose and perfusion reduction 4 months after treatment in lung cancer patients treated with SBRT and CFRT were scaled according to the linear-quadratic model using α/β ratios from 0 Gy to ∞ Gy. To test for which α/β ratio both treatments have equal biological effect, a 5-parameter logistic model was optimized for both dose-effect relationships simultaneously. Beside the α/β ratio, the other 4 parameters were d50, the steepness parameter k, and 2 parameters (MSBRT and MCFRT) representing the maximal perfusion reduction at high doses for SBRT and CFRT, respectively., Results: The optimal fitted model resulted in an α/β ratio of 1.3 Gy (0.5-2.1 Gy), MSBRT=42.6% (40.4%-44.9%), MCFRT=66.9% (61.6%-72.1%), d50=35.4 Gy (31.5-9.2 Gy), and k=2.0 (1.7-2.3)., Conclusions: An equal reduction of lung perfusion in lung cancer was observed in SBRT and CFRT if local doses were converted by the linear-quadratic model with an α/β ratio equal to 1.3 Gy (0.5-2.1 Gy)., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Four-dimensional positron emission tomography (4D PET) imaging of the thorax produces sharper images with reduced motion artifacts. Current radiation therapy planning systems, however, do not facilitate 4D plan optimization. When images are acquired in a 2-minute time slot, the signal-to-noise ratio of each 4D frame is low, compromising image quality. The purpose of this study was to implement and evaluate the construction of mid-position 3D PET scans, with motion compensated using a 4D computed tomography (CT)-derived motion model., Methods and Materials: All voxels of 4D PET were registered to the time-averaged position by using a motion model derived from the 4D CT frames. After the registration the scans were summed, resulting in a motion-compensated 3D mid-position PET scan. The method was tested with a phantom dataset as well as data from 27 lung cancer patients., Results: PET motion compensation using a CT-based motion model improved image quality of both phantoms and patients in terms of increased maximum SUV (SUV(max)) values and decreased apparent volumes. In homogenous phantom data, a strong relationship was found between the amplitude-to-diameter ratio and the effects of the method. In heterogeneous patient data, the effect correlated better with the motion amplitude. In case of large amplitudes, motion compensation may increase SUV(max) up to 25% and reduce the diameter of the 50% SUV(max) volume by 10%., Conclusions: 4D CT-based motion-compensated mid-position PET scans provide improved quantitative data in terms of uptake values and volumes at the time-averaged position, thereby facilitating more accurate radiation therapy treatment planning of pulmonary lesions., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To demonstrate the use of generalized equivalent uniform dose (gEUD) atlas for data pooling in radiation pneumonitis (RP) modeling, to determine the dependence of RP on gEUD, to study the consistency between data sets, and to verify the increased statistical power of the combination., Methods and Materials: Patients enrolled in prospective phase I/II dose escalation studies of radiation therapy of non-small cell lung cancer at Memorial Sloan-Kettering Cancer Center (MSKCC) (78 pts) and the Netherlands Cancer Institute (NKI) (86 pts) were included; 10 (13%) and 14 (17%) experienced RP requiring steroids (RPS) within 6 months after treatment. gEUD was calculated from dose-volume histograms. Atlases for each data set were created using 1-Gy steps from exact gEUDs and RPS data. The Lyman-Kutcher-Burman model was fit to the atlas and exact gEUD data. Heterogeneity and inconsistency statistics for the fitted parameters were computed. gEUD maps of the probability of RPS rate≥20% were plotted., Results: The 2 data sets were homogeneous and consistent. The best fit values of the volume effect parameter a were small, with upper 95% confidence limit around 1.0 in the joint data. The likelihood profiles around the best fit a values were flat in all cases, making determination of the best fit a weak. All confidence intervals (CIs) were narrower in the joint than in the individual data sets. The minimum P value for correlations of gEUD with RPS in the joint data was .002, compared with P=.01 and .05 for MSKCC and NKI data sets, respectively. gEUD maps showed that at small a, RPS risk increases with gEUD., Conclusions: The atlas can be used to combine gEUD and RPS information from different institutions and model gEUD dependence of RPS. RPS has a large volume effect with the mean dose model barely included in the 95% CI. Data pooling increased statistical power., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: Hypofractionated stereotactic body radiation therapy (SBRT) has emerged as an effective treatment option for early-stage non-small cell lung cancer (NSCLC). Using data collected by the Elekta Lung Research Group, we generated a tumor control probability (TCP) model that predicts 2-year local control after SBRT as a function of biologically effective dose (BED) and tumor size., Methods and Materials: We formulated our TCP model as follows: TCP = e([BED10 - c ∗ L - TCD50]/k) ÷ (1 + e([BED10 - c ∗ L - TCD50]/k)), where BED10 is the biologically effective SBRT dose, c is a constant, L is the maximal tumor diameter, and TCD50 and k are parameters that define the shape of the TCP curve. Least-squares optimization with a bootstrap resampling approach was used to identify the values of c, TCD50, and k that provided the best fit with observed actuarial 2-year local control rates., Results: Data from 504 NSCLC tumors treated with a variety of SBRT schedules were available. The mean follow-up time was 18.4 months, and 26 local recurrences were observed. The optimal values for c, TCD50, and k were 10 Gy/cm, 0 Gy, and 31 Gy, respectively. Thus, size-adjusted BED (sBED) may be defined as BED minus 10 times the tumor diameter (in centimeters). Our TCP model indicates that sBED values of 44 Gy, 69 Gy, and 93 Gy provide 80%, 90%, and 95% chances of tumor control at 2 years, respectively. When patients were grouped by sBED, the model accurately characterized the relationship between sBED and actuarial 2-year local control (r=0.847, P=.008)., Conclusion: We have developed a TCP model that predicts 2-year local control rate after hypofractionated SBRT for early-stage NSCLC as a function of biologically effective dose and tumor diameter. Further testing of this model with additional datasets is warranted., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to investigate the dose-effect relation between acute esophageal toxicity (AET) and the dose-volume parameters of the esophagus after intensity modulated radiation therapy (IMRT) and concurrent chemotherapy for patients with non-small cell lung cancer (NSCLC)., Patients and Methods: One hundred thirty-nine patients with inoperable NSCLC treated with IMRT and concurrent chemotherapy were prospectively analyzed. The fractionation scheme was 66 Gy in 24 fractions. All patients received concurrently a daily dose of cisplatin (6 mg/m(2)). Maximum AET was scored according to Common Toxicity Criteria 3.0. Dose-volume parameters V5 to V70, D(mean) and D(max) of the esophagus were calculated. A logistic regression analysis was performed to analyze the dose-effect relation between these parameters and grade ≥ 2 and grade ≥ 3 AET. The outcome was compared with the clinically used esophagus V35 prediction model for grade ≥ 2 after radical 3-dimensional conformal radiation therapy (3DCRT) treatment., Results: In our patient group, 9% did not experience AET, and 31% experienced grade 1 AET, 38% grade 2 AET, and 22% grade 3 AET. The incidence of grade 2 and grade 3 AET was not different from that in patients treated with CCRT using 3DCRT. The V50 turned out to be the most significant dosimetric predictor for grade ≥ 3 AET (P=.012). The derived V50 model was shown to predict grade ≥ 2 AET significantly better than the clinical V35 model (P<.001)., Conclusions: For NSCLC patients treated with IMRT and concurrent chemotherapy, the V50 was identified as most accurate predictor of grade ≥ 3 AET. There was no difference in the incidence of grade ≥ 2 AET between 3DCRT and IMRT in patients treated with concurrent chemoradiation therapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To demonstrate the potential of volumetric-modulated arc therapy (VMAT) compared with intensity-modulated radiotherapy (IMRT) techniques with a limited number of segments for stereotactic body radiotherapy (SBRT) for early-stage lung cancer., Methods and Materials: For a random selection of 27 patients eligible for SBRT, coplanar and noncoplanar IMRT and coplanar VMAT (using SmartArc) treatment plans were generated in Pinnacle(3) and compared. In addition, film measurements were performed using an anthropomorphic phantom to evaluate the skin dose for the different treatment techniques., Results: Using VMAT, the delivery times could be reduced to an average of 6.6 min compared with 23.7 min with noncoplanar IMRT. The mean dose to the healthy lung was 4.1 Gy for VMAT and noncoplanar IMRT and 4.2 Gy for coplanar IMRT. The volume of healthy lung receiving>5 Gy and >20 Gy was 18.0% and 5.4% for VMAT, 18.5% and 5.0% for noncoplanar IMRT, and 19.4% and 5.7% for coplanar IMRT, respectively. The dose conformity at 100% and 50% of the prescribed dose of 54 Gy was 1.13 and 5.17 for VMAT, 1.11 and 4.80 for noncoplanar IMRT and 1.12 and 5.31 for coplanar IMRT, respectively. The measured skin doses were comparable for VMAT and noncoplanar IMRT and slightly greater for coplanar IMRT., Conclusions: Coplanar VMAT for SBRT for early-stage lung cancer achieved plan quality and skin dose levels comparable to those using noncoplanar IMRT and slightly better than those with coplanar IMRT. In addition, the delivery time could be reduced by ≤70% with VMAT., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Lymphatic spread is an important pathway of progression in non-small-cell lung cancer (NSCLC), along with local spread and distant metastasis. The probability of lymph node (LN) involvement is dependent on the site of the primary tumor, stage, and histology. Elective nodal irradiation (ENI) is the irradiation of clinical and radiological uninvolved LN to account for microscopic tumor invasion in these LNs because we have not been able to determine the extent of LN spread accurately. The clinical value of ENI is uncertain. The impact of ENI is dependent on many (staging-, treatment-, and patient-related) factors. The purpose of this report is to analyze the current status of ENI and to provide comprehensive in-depth analysis and guidance on how to generally approach this issue in NSCLC.

Thoracic radiotherapy (RT) is an integral part of the management of small-cell lung cancer (SCLC) because its administration provides a survival benefit in patients with limited-stage disease. However, there are many areas of controversy with respect to the delivery of curative RT, and these include definition of the target to be irradiated. A current area of concern is defining what the RT portal must encompass with respect to the mediastinal lymph nodes; that is, whether one should electively treat all mediastinal nodes, or selectively include those with some clinical risk for harboring disease, or perhaps omit elective nodal irradiation altogether. The purpose of the present report is therefore to address the concepts underlying elective or selective nodal irradiation as it applies to SCLC, looking at clinical, imaging, and RT reports to help define the parameters appropriate to treating individual patients.

Purpose: To discuss planning target volumes (PTVs) based on internal target volume (PTVITV), exhale-gated radiotherapy (PTVGating), and a new proposed midposition (PTVMidP; time-weighted mean tumor position) and compare them with the conventional free-breathing CT scan PTV (PTVConv)., Methods and Materials: Respiratory motion induces systematic and random geometric uncertainties. Their contribution to the clinical target volume (CTV)-to-PTV margins differs for each PTV approach. The uncertainty margins were calculated using a dose-probability-based margin recipe (based on patient statistics). Tumor motion in four-dimensional CT scans was determined using a local rigid registration of the tumor. Geometric uncertainties for interfractional setup errors and tumor baseline variation were included. For PTVGating, the residual motion within a 30% gating (time) window was determined. The concepts were evaluated in terms of required CTV-to-PTV margin and PTV volume for 45 patients., Results: Over the patient group, the PTVITV was on average larger (+6%) and the PTVGating and PTVMidP smaller (-10%) than the PTVConv using an off-line (bony anatomy) setup correction protocol. With an on-line (soft tissue) protocol the differences in PTV compared with PTVConv were +33%, -4%, and 0, respectively., Conclusions: The internal target volume method resulted in a significantly larger PTV than conventional CT scanning. The exhale-gated and mid-position approaches were comparable in terms of PTV. However, mid-position (or mid-ventilation) is easier to use in the clinic because it only affects the planning part of treatment and not the delivery.

Purpose: Four-dimensional (4D) respiration-correlated imaging techniques can be used to obtain (respiration) artifact-free computed tomography (CT) images of the thorax. Current radiotherapy planning systems, however, do not accommodate 4D-CT data. The purpose of this study was to develop a simple, new concept to incorporate patient-specific motion information, using 4D-CT scans, in the radiotherapy planning process of lung cancer patients to enable smaller error margins., Methods and Materials: A single CT scan was selected from the 4D-CT data set. This scan represented the tumor in its time-averaged position over the respiratory cycle (the mid-ventilation CT scan). To select the appropriate CT scan, two methods were used. First, the three-dimensional tumor motion was analyzed semiautomatically to calculate the mean tumor position and the corresponding respiration phase. An alternative automated method was developed to select the correct CT scan using the diaphragm motion., Results: Owing to hysteresis, mid-ventilation selection using the three-dimensional tumor motion had a tumor position accuracy (with respect to the mean tumor position) better than 1.1 +/- 1.1 mm for all three directions (inhalation and exhalation). The accuracy in the diaphragm motion method was better than 1.1 +/- 1.1 mm. Conventional free-breathing CT scanning had an accuracy better than 0 +/- 3.9 mm. The mid-ventilation concept can result in an average irradiated volume reduction of 20% for tumors with a diameter of 40 mm., Conclusion: Tumor motion and the diaphragm motion method can be used to select the (artifact-free) mid-ventilation CT scan, enabling a significant reduction of the irradiated volume.

Purpose: Target delineation using only CT information introduces large geometric uncertainties in radiotherapy for lung cancer. Therefore, a reduction of the delineation variability is needed. The impact of including a matched CT scan with 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and adaptation of the delineation protocol and software on target delineation in lung cancer was evaluated in an extensive multi-institutional setting and compared with the delineations using CT only., Methods and Materials: The study was separated into two phases. For the first phase, 11 radiation oncologists (observers) delineated the gross tumor volume (GTV), including the pathologic lymph nodes of 22 lung cancer patients (Stages I-IIIB) on CT only. For the second phase (1 year later), the same radiation oncologists delineated the GTV of the same 22 patients on a matched CT-FDG-PET scan using an adapted delineation protocol and software (according to the results of the first phase). All delineated volumes were analyzed in detail. The observer variation was computed in three dimensions by measuring the distance between the median GTV surface and each individual GTV. The variation in distance of all radiation oncologists was expressed as a standard deviation. The observer variation was evaluated for anatomic regions (lung, mediastinum, chest wall, atelectasis, and lymph nodes) and interpretation regions (agreement and disagreement; i.e., >80% vs. <80% of the radiation oncologists delineated the same structure, respectively). All radiation oncologist-computer interactions were recorded and analyzed with a tool called "Big Brother.", Results: The overall three-dimensional observer variation was reduced from 1.0 cm (SD) for the first phase (CT only) to 0.4 cm (SD) for the second phase (matched CT-FDG-PET). The largest reduction in the observer variation was seen in the atelectasis region (SD 1.9 cm reduced to 0.5 cm). The mean ratio between the common and encompassing volume was 0.17 and 0.29 for the first and second phases, respectively. For the first phase, the common volume was 0 in 4 patients (i.e., no common point for all GTVs). In the second phase, the common volume was always >0. For all anatomic regions, the interpretation differences among the radiation oncologists were reduced. The amount of disagreement was 45% and 18% for the first and second phase, respectively. Furthermore, the mean delineation time (12 vs. 16 min, p<0.001) and mean number of corrections (25 vs. 39, p<0.001) were reduced in the second phase compared with the first phase., Conclusion: For high-precision radiotherapy, the delineation of lung target volumes using only CT introduces too great a variability among radiation oncologists. Implementing matched CT-FDG-PET and adapted delineation protocol and software reduced observer variation in lung cancer delineation significantly with respect to CT only. However, the remaining observer variation was still large compared with other geometric uncertainties (setup variation and organ motion).

Purpose: To evaluate the changes in pulmonary function after high-dose radiotherapy (RT) for non-small-cell lung cancer in patients with a long-term disease-free survival., Methods and Materials: Pulmonary function was measured in 34 patients with inoperable non-small-cell lung cancer before RT and at 3 and 18 months of follow-up. Thirteen of these patients had a pulmonary function test (PFT) 36 months after RT. The pulmonary function parameters (forced expiratory volume in 1 s [FEV(1)], diffusion capacity [T(lcoc)], forced vital capacity, and alveolar volume) were expressed as a percentage of normal values. Changes were expressed as relative to the pre-RT value. We evaluated the impact of chronic obstructive pulmonary disease, radiation pneumonitis, mean lung dose, and PFT results before RT on the changes in pulmonary function., Results: At 3, 18, and 36 months, a significant decrease was observed for the T(lcoc) (9.5%, 14.6%, and 22.0%, respectively) and the alveolar volume (5.8%, 6.6%, and 15.8%, respectively). The decrease in FEV(1) was significant at 18 and 36 months (8.8% and 13.4%, respectively). No recovery of any of the parameters was observed. Chronic obstructive pulmonary disease was an important risk factor for larger PFT decreases. FEV(1) and T(lcoc) decreases were dependent on the mean lung dose., Conclusion: A significant decrease in pulmonary function was observed 3 months after RT. No recovery in pulmonary function was seen at 18 and 36 months after RT. The decrease in pulmonary function was dependent on the mean lung dose, and patients with chronic obstructive pulmonary disease had larger reductions in the PFTs.

Purpose: To study regional differences in lung radiosensitivity by evaluating the incidence of radiation pneumonitis (RP) in relation to regional dose distributions., Methods and Materials: Registered chest CT and single photon emission CT lung perfusion scans were obtained in 106 patients before curative or radical radiotherapy for non-small-cell lung cancer. The mean lung dose (MLD) was calculated. The single photon-emission CT perfusion data were used to weigh the MLD with perfusion, resulting in the mean perfusion-weighted lung dose. In addition, the lungs were geometrically divided into different subvolumes. The mean regional dose (MRD) for each region was calculated and weighted with the perfusion of each region to obtain the mean perfusion-weighted regional dose. RP was defined as respiratory symptoms requiring steroids. The incidence of RP for patients with tumors in a specific subvolume was calculated. The normal tissue complication probability (NTCP) parameter values for the TD(50), and an offset NTCP parameter for tumor location were fitted for both lungs and for each lung subvolume to the observed data using maximum likelihood analysis., Results: The incidence of RP correlated significantly with the MLD and MRD of the posterior, caudal, ipsilateral, central, and peripheral lung subvolumes (p between 0.05 and 0.002); no correlation was seen for the anterior, cranial, and contralateral regions Similarly, a statistically significant correlation was observed between the incidence of RP and the perfusion-weighted MLD and perfusion-weighted MRD for all regions, except the anterior lung region. For this region, the dose-effect relation improved remarkably after weighting the local dose with the local perfusion. A statistically significant difference (p = 0.01) in the incidence of RP was found between patients with cranial and caudal tumors (11% and 40%, respectively). Therefore, a dose-independent offset NTCP parameter for caudal tumors was included in the NTCP model, improving most correlations significantly, confirming that patients with caudal tumors have a greater probability of developing RP., Conclusion: The incidence of RP correlated significantly with the MLD and MRD of most lung regions, except for the anterior, cranial, and contralateral regions. Weighting the local dose with the local perfusion improved the dose-effect relation for the anterior lung region. Irradiation of caudally located lung tumors resulted in a greater risk of RP than irradiation of tumors located in other parts of the lungs.

Purpose: In dose-escalation studies of radiotherapy (RT) for non-small-cell lung cancer (NSCLC), radiation pneumonitis (RP) is the most important dose-limiting complication. Transforming growth factor-beta1 (TGF-beta1) has been reported to be associated with the incidence of RP. It has been proposed that serial measurements of plasma TGF-beta1 can be valuable to estimate the risk of RP and to decide whether additional dose-escalation can be safely applied. The aim of this study was to evaluate prospectively the time course of TGF-beta1 levels in patients irradiated for NSCLC in relation to the development of RP and dose-volume parameters., Methods and Materials: Plasma samples were obtained in 68 patients irradiated for medically inoperable or locally advanced NSCLC (dose range, 60.8-94.5 Gy) before and 4, 6, and 18 weeks after the start of RT. Plasma TGF-beta1 levels were determined using a bioassay on the basis of TGF-beta1-induced plasminogen activator inhibitor-1 expression in mink lung cells. All patients underwent chest computed tomography scans before RT that were repeated at 18 weeks after RT. The computed tomography data were used to calculate the mean lung dose (MLD) and to score the radiation-induced radiologic changes. RP was defined on the basis of the presence of either radiographic changes or clinical symptoms. Symptomatic RP was scored according to the Common Toxicity Criteria (Grade 1 or worse) and the Southwestern Oncology Group criteria (Grade 2 or worse). Multivariate analyses were performed to investigate which factors (pre- or posttreatment TGF-beta1 level, MLD) were associated with the incidence of RP. To improve our understanding of the time course of TGF-beta1 levels, we performed a multivariate analysis to investigate which factors (pre-RT TGF-beta1 level, MLD, RP) were independently associated with the posttreatment TGF-beta1 levels., Results: The pre-RT TGF-beta1 levels were increased in patients with NSCLC (median 21 ng/mL, range, 5-103 ng/mL) compared with healthy individuals (range, 4-12 ng/mL). On average, the TGF-beta1 levels normalized toward the end of treatment and remained stable until 18 weeks after RT. In 29 patients, however, TGF-beta1 was increased at the end of RT with respect to the pre-RT value. The multivariate analyses revealed that the MLD was the only variable that correlated significantly with the risk of both radiographic RP (p = 0.05) and symptomatic RP, independent of the scoring system used (p = 0.05 and 0.03 for Southwestern Oncology Group and Common Toxicity Criteria systems, respectively). The TGF-beta1 level at the end of RT was significantly associated with the MLD (p <0.001) and pre-RT TGF-beta1 level (p = 0.001)., Conclusion: The MLD correlated significantly with the incidence of both radiographic and symptomatic RP. The results of our study did not confirm the reports that increased levels of TGF-beta1 at the end of RT are an independent additional risk factor for developing symptomatic RP. However, the TGF-beta1 level at the end of a RT was significantly associated with the MLD and the pre-RT level.

Purpose: To study changes of pulmonary function tests (PFTs) after radiotherapy (RT) of non-small-cell lung cancer (NSCLC) in relation to radiation dose, tumor regression, and changes in lung perfusion., Methods and Materials: Eighty-two patients with inoperable NSCLC were evaluated with PFTs (forced expiratory volume in 1 s [FEV(1)] and diffusion capacity [T(L,COc)]), a computed tomography (CT) scan of the chest, and a single photon emission CT (SPECT) lung perfusion scan, before and 3-4 months after RT. The reductions of PFTs and tumor volume were calculated. The lung perfusion was measured from pre- and post-RT SPECT scans, and the difference was defined as the measured perfusion reduction (MPR). In addition, the perfusion post-RT was estimated from the dose distribution using a dose-effect relation for regional lung perfusion, and compared with the pre-RT lung perfusion to obtain the predicted perfusion reduction (PPR). The difference between the actually measured and the PPR was defined as reperfusion. The mean lung dose (MLD) was computed and weighted with the pre-RT perfusion, resulting in the mean perfusion-weighted lung dose (MpLD). Changes of PFTs were evaluated in relation to tumor dose, MLD, MpLD, tumor regression, and parameters related to perfusion changes., Results: In a multivariate analysis, the total tumor dose and MLD were not associated with reductions of PFTs. Tumor regression resulted in a significant improvement of FEV(1) (p = 0.02), but was associated with a reduction of T(L,COc) (p = 0.05). The MpLD and the PPR showed a significant (p = 0.01 to 0.04) but low correlation (r = 0.24 to 0.31) with the reduction of both PFTs. The other parameters for perfusion changes, the MPR and reperfusion were not correlated with changes in PFTs., Conclusion: The perfusion-related dose variables, the MpLD or the PPR, are the best parameters to estimate PFTs after RT. Tumor regression is associated with an improvement of FEV(1) and a decline of T(L,COc). Reperfusion was not associated with an improvement of global pulmonary function.

Purpose: To compare different normal tissue complication probability (NTCP) models to predict the incidence of radiation pneumonitis on the basis of the dose distribution in the lung., Methods and Materials: The data from 382 breast cancer, malignant lymphoma, and inoperable non-small-cell lung cancer patients from two centers were studied. Radiation pneumonitis was scored using the Southwestern Oncology Group criteria. Dose-volume histograms of the lungs were calculated from the dose distributions that were corrected for dose per fraction effects. The dose-volume histogram of each patient was reduced to a single parameter using different local dose-effect relationships. Examples of single parameters were the mean lung dose (MLD) and the volume of lung receiving more than a threshold dose (V(Dth)). The parameters for the different NTCP models were fit to patient data using a maximum likelihood analysis., Results: The best fit resulted in a linear local dose-effect relationship, with the MLD as the resulting single parameter. The relationship between the MLD and NTCP could be described with a median toxic dose (TD(50)) of 30.8 Gy and a steepness parameter m of 0.37. The best fit for the relationship between the V(Dth) and the NTCP was obtained with a D(th) of 13 Gy. The MLD model was found to be significantly better than the V(Dth) model (p <0.03). However, for 85% of the studied patients, the difference in NTCP calculated with both models was <10%, because of the high correlation between the two parameters. For dose distributions outside the range of the studied dose-volume histograms, the difference in NTCP, using the two models could be >35%. For arbitrary dose distributions, an estimate of the uncertainty in the NTCP could be determined using the probability distribution of the parameter values of the Lyman-Kutcher-Burman model., Conclusion: The maximum likelihood method revealed that the underlying local dose-effect relation for radiation pneumonitis was linear (the MLD model), rather than a step function (the V(Dth) model). Thus, for the studied patient population, the MLD was the most accurate predictor for the incidence of radiation pneumonitis.