Severe radiation-induced lymphopenia during concurrent chemoradiotherapy for stage III non-small cell lung cancer: external validation of two prediction models.

Background: Severe radiation-induced lymphopenia (RIL) in patients undergoing chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is associated with decreased immunotherapy efficacy and survival. At The Christie and MD Anderson Cancer Center (MDACC), prediction models for lymphopenia were developed in lung and esophageal cancer patients, respectively. The aim of this study was to externally validate both models in patients with stage III NSCLC. Methods: Patients who underwent concurrent CRT for stage III NSCLC in 2019-2021 were studied. Outcomes were grade ≥3 and grade 4 lymphopenia during CRT. The Christie model predictors for grade ≥3 lymphopenia included age, baseline lymphocyte count, radiotherapy duration, chemotherapy, mean heart and lung doses, and thoracic vertebrae V20Gy. MDACC predictors for grade 4 lymphopenia were age, baseline lymphocyte count, planning target volume (PTV), and BMI. The external performance of both models was assessed. Results: Among 100 patients, 78 patients (78%) developed grade ≥3 lymphopenia, with grade 4 lymphopenia in 17 (17%). For predicting grade ≥3 lymphopenia, the Christie and MDACC models yielded c-statistics of 0.77 and 0.79, respectively. For predicting grade 4 lymphopenia, c-statistics were 0.69 and 0.80, respectively. Calibration for the Christie and MDACC models demonstrated moderate and good agreement, respectively. Conclusion: The PTV-based MDACC prediction model for severe RIL demonstrated superior external performance in NSCLC patients compared to the dosimetry-based Christie model. As such, the MDACC model can aid in identifying patients at high risk for severe lymphopenia. However, to optimize radiotherapy planning, further improvement and external validation of dosimetry-based models is desired.

Bronchial Stenosis in Central Pulmonary Tumors Treated With Stereotactic Body Radiation Therapy.

PURPOSE: Stereotactic body radiation therapy (SBRT) in lung tumors has an excellent local control due to the high delivered dose. Proximity of the proximal bronchial tree (PBT) to the high dose area may result in pulmonary toxicity. Bronchial stenosis is an adverse event that can occur after high dose to the PBT. Literature on the risk of developing bronchial stenosis is limited. We therefore evaluated the risk of bronchial stenosis for tumors central to the PBT and correlated the dose to the bronchi. METHODS AND MATERIALS: Patients with a planning tumor volume (PTV) ≤2 cm from PBT receiving SBRT (8 × 7.5 Gy) between 2015 to 2019 were retrospectively reviewed. Main bronchi and lobar bronchi were manually delineated. Follow-up computed tomography scans were analyzed for bronchial stenosis and atelectasis. Bronchial stenosis was assessed using Common Terminology Criteria for Adverse Events Version 4.0 (CTCAEv4). Patient, tumor, dosimetric factors and survival were evaluated between patients with and without stenosis using uni- and multivariate and Kaplan-Meier analysis. RESULTS: Fifty-one patients were analyzed with a median age of 70 years and World Health Organization (WHO) performance status ≤1 in 92.2%. Median follow-up was 36 months (interquartile range [IQR], 19.6-45.4) and median overall survival 48 months (IQR 21.5-59.3). In 15 patients (29.4%) bronchial stenosis was observed on follow-up computed tomography scan. Grade 1 stenosis was seen in 21.6% (n = 11), grade 2 in 7.8% (n = 4). No grade ≥3 stenosis was observed. Median time to stenosis was 9.6 months (IQR 4.4-19.2). Patients who developed stenosis had significantly larger gross tumor volume with a median of 19 cm3(IQR 7.7-63.2) versus 5.2 cm3 (IQR 1.7-11.3, P <.01). Prognostic factors in multivariate analysis for stenosis were age (P = .03; odds ratio [OR] 1.1), baseline dyspnea (P = .02 OR 7.7), and the mean lobar bronchus dose (P = .01; OR 1.1). CONCLUSIONS: Low-grade (≤2) lobar bronchial stenosis is a complication in approximately one-third of patients after SBRT for lung tumors with a PTV ≤2 cm from PBT. Prognostic risk factors were age, baseline dyspnea and mean dose on a lobar bronchus.

Heart dose associated with overall survival in locally advanced NSCLC patients treated with hypofractionated chemoradiotherapy.

Association of heart dose and overall survival was investigated in a cohort including 469 locally-advanced NSCLC patients receiving daily low-dose hypofractionated chemo-radiotherapy. Significant associations were found over a range of dose parameters. Multivariate analysis showed significant associations of heart_V2Gy:HR=1.007%-1 (95% CI:1.002-1.013; p=0.006), age:HR=1.026year-1 (1.011-1.042; p=0.001) and GTV volume:HR=1.001cc-1 (1.000-1.002; p=0.006) with overall survival.

Mitigating differential baseline shifts in locally advanced lung cancer patients using an average anatomy model.

BACKGROUND AND PURPOSE: Differential baseline shifts between primary tumor and involved lymph nodes in locally advanced lung cancer patients compromise the accuracy of radiotherapy. The purpose of this study was to evaluate the performance of an average anatomy model (AAM) derived from repeat imaging and deformable registration to reduce these geometrical uncertainties. METHODS AND MATERIALS: An in-house implementation of a B-Spline deformable image registration (DIR) algorithm was first validated using three different validation approaches: (a) a circle method to test the consistency of the DIR, (b) fiducial marker target registration error, and (c) the recovery of a known deformation vector field (DVF). Subsequently, AAM was generated by first averaging five DVFs resulting from cone beam CT (CBCT) to planning CT (pCT) DIR and second by applying the inverse of the average DVF to the pCT. The proposed method was evaluated on 15 locally advanced lung cancer patients receiving daily motion compensated CBCT and a repeat CT (rCT) for adaptive radiotherapy. Reduction of systematic baseline shifts of the primary tumor were quantified for the fractions used to build the AAM as well as over the whole treatment and compared to the performance of the rCT. RESULTS: The deformable registration accuracy was ≤ 2 mm vector length for the first two validation methods and about 3 mm for the third method. The systematic baseline shifts over the five fractions prior to the rCT used to build the AAM reduced from 5.9 mm vector length relative to the pCT to 2.3 and 4.2 mm relative to the AAM and rCT, respectively. The overall systematic errors in the left-right, cranio-caudal, and anterior-posterior directions were [3.4, 3.8, 3.3] mm, [2.3, 2.9, 2.6] mm, and [2.3, 3.1, 2.7] mm for the pCT, AAM, and rCT, respectively. CONCLUSIONS: The AAM mitigates systematic errors occurring during treatment due to differential baseline shifts between the primary tumor and involved lymph nodes similar to (or even better than) rCT. The superior performance of the AAM in terms of the systematic error derived from the initial fractions indicates that further analysis of the optimum intervention time is required. This model has the potential to be used as an efficient and accurate alternative for rCT in adaptive radiotherapy of locally advanced lung cancer patients, obviating the need for rescanning and recontouring.

Dose-effect analysis of radiation induced rib fractures after thoracic SBRT.

BACKGROUND AND PURPOSE: To determine a dose-effect relation for radiation induced rib fractures after stereotactic body radiation therapy (SBRT) in early stage non-small cell lung cancer (NSCLC). Automatic rib delineation has enabled the analysis of a large patient group. MATERIAL AND METHODS: Four-hundred and sixty-six patients with stage I/II NSCLC received SBRT with a median of 54Gy in 3 fractions. The optimal EQD2-corrected dose parameter to predict (a)symptomatic fractures was found using Cox regression. Three normal tissue complication probability (NTCP) models based on this optimal parameter were constructed: (1) at a median follow up (FU) of 26months, (2) for all data, with time to toxicity taken into account and (3) at a FU of 26months, excluding low dose ribs. RESULTS: The median time to fracture was 22 (range 5-51) months. Maximum rib dose best predicted fractures. The TD50 (dose with 50% complication) of the second NTCP model was 375Gy. The TD50 was significantly higher for the other models indicating an under-estimation of the dose effect at the median follow-up time and/or when excluding low dose ribs. CONCLUSIONS: The risk of symptomatic rib fractures after SBRT was significantly correlated to dose, and was <5% at 26months when Dmax<225Gy.

Intrafraction Motion in Stereotactic Body Radiation Therapy for Non-Small Cell Lung Cancer: Intensity Modulated Radiation Therapy Versus Volumetric Modulated Arc Therapy.

PURPOSE: Stereotactic body radiation therapy (SBRT) for early-stage inoperable non-small cell lung cancer (NSCLC) patients delivers high doses that require high-precision treatment. Typically, image guidance is used to minimize day-to-day target displacement, but intrafraction position variability is often not corrected. Currently, volumetric modulated arc therapy (VMAT) is replacing intensity modulated radiation therapy (IMRT) in many departments because of its shorter delivery time. This study aimed to evaluate whether intrafraction variation in VMAT patients is reduced in comparison with patients treated with IMRT. METHODS AND MATERIALS: NSCLC patients (197 IMRT and 112 VMAT) treated with a frameless SBRT technique to a prescribed dose of 3 × 18 Gy were evaluated. Image guidance for both techniques was identical: pretreatment cone beam computed tomography (CBCT) (CBCTprecorr) for setup correction followed immediately before treatment by postcorrection CBCT (CBCTpostcorr) for verification. Then, after either a noncoplanar IMRT technique or a VMAT technique, a posttreatment (CBCTpostRT) scan was acquired. The CBCTpostRT and CBCTpostcorr scans were then used to evaluate intrafraction motion. Treatment delivery times, systematic (Σ) and random (σ) intrafraction variations, and associated planning target volume (PTV) margins were calculated. RESULTS: The median treatment delivery time was significantly reduced by 20 minutes (range, 32-12 minutes) using VMAT compared with noncoplanar IMRT. Intrafraction tumor motion was significantly larger for IMRT in all directions up to 0.5 mm systematic (Σ) and 0.7 mm random (σ). The required PTV margins for IMRT and VMAT differed by less than 0.3 mm. CONCLUSION: VMAT-based SBRT for NSCLC was associated with significantly shorter delivery times and correspondingly smaller intrafraction motion compared with noncoplanar IMRT. However, the impact on the required PTV margin was small.

Validation of automatic segmentation of ribs for NTCP modeling.

BACKGROUND AND PURPOSE: Determination of a dose-effect relation for rib fractures in a large patient group has been limited by the time consuming manual delineation of ribs. Automatic segmentation could facilitate such an analysis. We determine the accuracy of automatic rib segmentation in the context of normal tissue complication probability modeling (NTCP). MATERIALS AND METHODS: Forty-one patients with stage I/II non-small cell lung cancer treated with SBRT to 54 Gy in 3 fractions were selected. Using the 4DCT derived mid-ventilation planning CT, all ribs were manually contoured and automatically segmented. Accuracy of segmentation was assessed using volumetric, shape and dosimetric measures. Manual and automatic dosimetric parameters Dx and EUD were tested for equivalence using the Two One-Sided T-test (TOST), and assessed for agreement using Bland-Altman analysis. NTCP models based on manual and automatic segmentation were compared. RESULTS: Automatic segmentation was comparable with the manual delineation in radial direction, but larger near the costal cartilage and vertebrae. Manual and automatic Dx and EUD were significantly equivalent. The Bland-Altman analysis showed good agreement. The two NTCP models were very similar. CONCLUSIONS: Automatic rib segmentation was significantly equivalent to manual delineation and can be used for NTCP modeling in a large patient group.

Alpha/beta ratio for normal lung tissue as estimated from lung cancer patients treated with stereotactic body and conventionally fractionated radiation therapy.

PURPOSE: To estimate the α/ß 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/ß ratios from 0 Gy to ∞ Gy. To test for which α/ß ratio both treatments have equal biological effect, a 5-parameter logistic model was optimized for both dose-effect relationships simultaneously. Beside the α/ß 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/ß 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/ß ratio equal to 1.3 Gy (0.5-2.1 Gy).

Differential motion between mediastinal lymph nodes and primary tumor in radically irradiated lung cancer patients.

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.

Microscopic disease extensions as a risk factor for loco-regional recurrence of NSCLC after SBRT.

PURPOSE: Stereotactic body radiotherapy (SBRT) is a highly conformal technique that allows a more accurate irradiation of lung tumors. However, a highly conformal dose distribution may underdose undetected microscopic disease extensions (MDE) near the tumor leading to loco-regional failure in tumor control. The purpose of the current work is to assess the risk of loco-regional failure in SBRT by analyzing pre-treatment scans. METHODS AND MATERIALS: A model to predict the risk of occurrence of MDE from pretreatment images was developed based on pathology samples of 47 lung cancer patients. This model was used to assess the outcome of 238 SBRT treatments. RESULTS: Patients with high risk of MDE presence showed significantly lower 2-year loco-regional control (82.0% vs. 91.8%) and shorter time to loco-regional failure (8.4 months vs. 20.7 months) than low risk patients. The minimum dose delivered in the volume surrounding the GTV affected the model predictive power. The model remained predictive for patients who received less than 31 Gy in that volume. For patients who received larger doses, the MDE risk classification was not significant. CONCLUSIONS: The results show that MDEs are, at least partially, responsible of loco-regional failure in highly conformal radiotherapy. This information could be used to optimize dose distributions.

Local dose-effect relations for lung perfusion post stereotactic body radiotherapy.

PURPOSE: To model the local dose-effect relation for lung perfusion reduction in lung cancer patients treated with stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: Forty-two patients having upper-lobe peripheral tumours <5 cm treated with SBRT (3×18 Gy) underwent single-photon emission computed-tomography (SPECT) scans to measure the lung perfusion 2 weeks pre-SBRT, 4-months post-SBRT, and for 8 patients 15-months post-SBRT. The relation between the calculated relative local perfusion reduction and the normalised total dose (α/ß=3 Gy) at 4-months post-SBRT was modeled by 3-parameter logistic model and 2-parameter linear-maximum model. RESULTS: The relation between local dose and perfusion reduction at 4-months post-SBRT showed a maximum effect of 42.6% at doses >100 Gy and was best described by the logistic model with parameters (95% CI): M=42.6% (40.7-44.6), D50=28.7 Gy (26.3-31.1) and k=2.2 (1.8-2.5). A significant increase of this maximum effect to 65.2% was found at 15-months post-SBRT. CONCLUSIONS: The relation between local dose and perfusion reduction in patients treated with SBRT can be modeled by a 3-parameter logistic model. This demonstrated relationship 4-months post-SBRT approaches a plateau for doses >100 Gy, where 90% of the maximum lung-perfusion reduction is observed at NTD=78 Gy. A further perfusion reduction compared to 4-months post-SBRT was observed fifteen months post-SBRT.

Mediastinal lymph node position variability in non-small cell lung cancer patients treated with radical irradiation.

BACKGROUND AND PURPOSE: Detailed knowledge on mediastinal lymph nodes position variability is lacking. In this study we quantified the variability over the irradiation course in non-small cell lung cancer (NSCLC) patients. METHODS: A 0.35×5 mm gold fiducial marker was inserted in mediastinal lymph nodes of 14 stage III NSCLC patients. A respiration correlated 4D-planning-CT (pCT) and daily 4D-Cone Beam (CB)CT-scans were acquired. To calculate the systematic and random baseline variations, and respiratory motion variability of the lymph nodes, all CBCT scans were registered to both the bony anatomy and marker in the pCT. Patient population statistics of the peak-to-peak amplitude and time averaged mean position relative to the bony anatomy were calculated. RESULTS: The average peak-to-peak amplitude was 0.21 cm, 0.52 cm and 0.20 cm in the Left-Right, Cranial-Caudal and Anterior-Posterior direction respectively, while the amplitude variability was ≤0.1 cm in each direction. Inter-fraction lymph node baseline variation was 0.21/0.2 cm, 0.34/0.23 cm, and 0.17/0.15 cm systematic/random. PTV margins for these variations were 0.92 cm, 1.24 cm, 0.82 cm for an online bone match and could be reduced to 0.77 cm, 0.82 cm and 0.86 cm for an online carina match. CONCLUSIONS: Substantial and anisotropic, systematic and random mediastinal lymph node baseline variations were found in NSCLC patients indicating that non-uniform margins could be beneficial.

Comparison of different strategies to use four-dimensional computed tomography in treatment planning for lung cancer 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.

Mid-ventilation CT scan construction from four-dimensional respiration-correlated CT scans for radiotherapy planning of lung cancer patients.

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.