Jan-Jakob Sonke

Respiratory correlated cone beam CT

A cone beam computed tomography (CBCT) scanner integrated with a linear accelerator is a powerful tool for image guided radiotherapy. Respiratory motion, however, induces artifacts in CBCT, while the respiratory correlated procedures, developed to reduce motion artifacts in axial and helical CT are not suitable for such CBCT scanners. We have developed an alternative respiratory correlated procedure for CBCT and evaluated its performance. This respiratory correlated CBCT procedure consists of retrospective sorting in projection space, yielding subsets of projections that each corresponds to a certain breathing phase. Subsequently, these subsets are reconstructed into a four-dimensional (4D) CBCT dataset. The breathing signal, required for respiratory correlation, was directly extracted from the 2D projection data, removing the need for an additional respiratory monitor system. Due to the reduced number of projections per phase, the contrast-to-noise ratio in a 4D scan reduced by a factor 2.6-3.7 compared to a 3D scan based on all projections. Projection data of a spherical phantom moving with a 3 and 5 s period with and without simulated breathing irregularities were acquired and reconstructed into 3D and 4D CBCT datasets. The positional deviations of the phantoms center of gravity between 4D CBCT and fluoroscopy were small: 0.13 +/- 0.09 mm for the regular motion and 0.39 +/- 0.24 mm for the irregular motion. Motion artifacts, clearly present in the 3D CBCT datasets, were substantially reduced in the 4D datasets, even in the presence of breathing irregularities, such that the shape of the moving structures could be identified more accurately. Moreover, the 4D CBCT dataset provided information on the 3D trajectory of the moving structures, absent in the 3D data. Considerable breathing irregularities, however, substantially reduces the image quality. Data presented for three different lung cancer patients were in line with the results obtained from the phantom study. In conclusion, we have successfully implemented a respiratory correlated CBCT procedure yielding a 4D dataset. With respiratory correlated CBCT on a linear accelerator, the mean position, trajectory, and shape of a moving tumor can be verified just prior to treatment. Such verification reduces respiration induced geometrical uncertainties, enabling safe delivery of 4D radiotherapy such as gated radiotherapy with small margins.

Frameless Stereotactic Body Radiotherapy for Lung Cancer Using Four-Dimensional Cone Beam CT Guidance

PURPOSE To quantify the localization accuracy and intrafraction stability of lung cancer patients treated with frameless, four-dimensional (4D) cone beam computed tomography (CBCT)-guided stereotactic body radiotherapy (SBRT) and to calculate and validate planning target volume (PTV) margins to account for the residual geometric uncertainties. MATERIALS AND METHODS Sixty-five patients with small peripheral lung tumors were treated with SBRT without a body frame to 54 Gy in three fractions. For each fraction, three 4D-CBCT scans were acquired: before treatment to measure and correct the time-weighted mean tumor position, after correction to validate the correction applied, and after treatment to estimate the intrafraction stability. Patient-specific PTV margins were computed and subsequently validated using Monte Carlo error simulations. RESULTS Systematic tumor localization inaccuracies (1 SD) were 0.8, 0.8, and 0.9 mm for the left-right, craniocaudal, and anteroposterior direction, respectively. Random localization inaccuracies were 1.1, 1.1, and 1.4 mm. Baseline variations were 1.8, 2.9, and 3.0 mm (systematic) and 1.1, 1.5, and 2.0 mm (random), indicating the importance of image guidance. Intrafraction stability of the target was 1.2, 1.2, and 1.8 mm (systematic) and 1.3, 1.5, and 1.8 mm (random). Monte Carlo error simulations showed that patient-specific PTV margins (5.8-10.5 mm) were adequate for 94% of the evaluated cases (2-28 mm peak-to-peak breathing amplitude). CONCLUSIONS Frameless SBRT can be safely administered using 4D-CBCT guidance. Even with considerable breathing motion, the PTV margins can safely be kept small, allowing patients with larger tumors to benefit from the advantages of SBRT. In case bony anatomy would be used as a surrogate for tumor position, considerably larger PTV margins would be required.

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.

Accurate two-dimensional IMRT verification using a back-projection EPID dosimetry method

The use of electronic portal imaging devices (EPIDs) is a promising method for the dosimetric verification of external beam, megavoltage radiation therapy-both pretreatment and in vivo. In this study, a previously developed EPID back-projection algorithm was modified for IMRT techniques and applied to an amorphous silicon EPID. By using this back-projection algorithm, two-dimensional dose distributions inside a phantom or patient are reconstructed from portal images. The model requires the primary dose component at the position of the EPID. A parametrized description of the lateral scatter within the imager was obtained from measurements with an ionization chamber in a miniphantom. In addition to point dose measurements on the central axis of square fields of different size, we also used dose profiles of those fields as reference input data for our model. This yielded a better description of the lateral scatter within the EPID, which resulted in a higher accuracy in the back-projected, two-dimensional dose distributions. The accuracy of our approach was tested for pretreatment verification of a five-field IMRT plan for the treatment of prostate cancer. Each field had between six and eight segments and was evaluated by comparing the back-projected, two-dimensional EPID dose distribution with a film measurement inside a homogeneous slab phantom. For this purpose, the y-evaluation method was used with a dose-difference criterion of 2% of dose maximum and a distance-to-agreement criterion of 2 mm. Excellent agreement was found between EPID and film measurements for each field, both in the central part of the beam and in the penumbra and low-dose regions. It can be concluded that our modified algorithm is able to accurately predict the dose in the midplane of a homogeneous slab phantom. For pretreatment IMRT plan verification, EPID dosimetry is a reliable and potentially fast tool to check the absolute dose in two dimensions inside a phantom for individual IMRT fields. Film measurements inside a phantom can therefore be replaced by EPID measurements.

The PET-boost randomised phase II dose-escalation trial in non-small cell lung cancer

PURPOSE The local site of relapse in non-small cell lung cancer (NSCLC) is primarily located in the high FDG uptake region of the primary tumour prior to treatment. A phase II PET-boost trial (NCT01024829) randomises patients between dose-escalation of the entire primary tumour (arm A) or to the high FDG uptake region inside the primary tumour (>50% SUV(max)) (arm B), whilst giving 66 Gy in 24 fractions to involved lymph nodes. We analysed the planning results of the first 20 patients for which both arms A and B were planned. METHODS Boost dose levels were escalated up to predefined normal tissue constraints with an equal mean lung dose in both arms. This also forces an equal mean PTV dose in both arms, hence testing pure dose-redistribution. Actual delivered treatment plans from the ongoing clinical trial were analysed. Patients were randomised between arms A and B if dose-escalation to the primary tumour in arm A of at least 72 Gy in 24 fractions could be safely planned. RESULTS 15/20 patients could be escalated to at least 72 Gy. Average prescribed fraction dose was 3.27±0.31 Gy [3.01-4.28 Gy] and 3.63±0.54 Gy [3.20-5.40 Gy] for arms A and B, respectively. Average mean total dose inside the PTV of the primary tumour was comparable: 77.3±7.9 Gy vs. 77.5±10.1 Gy. For the boost region dose levels of on average 86.9±14.9 Gy were reached. No significant dose differences between both arms were observed for the organs at risk. Most frequent observed dose-limiting constraints were the mediastinal structures (13/15 and 14/15 for arms A and B, respectively), and the brachial plexus (3/15 for both arms). CONCLUSION Dose-escalation using an integrated boost could be achieved to the primary tumour or high FDG uptake regions whilst keeping the pre-defined dose constraints.

Setup uncertainties of anatomical sub-regions in head-and-neck cancer patients after offline CBCT guidance

PURPOSE To quantify local geometrical uncertainties in anatomical sub-regions during radiotherapy for head-and-neck cancer patients. METHODS AND MATERIALS Local setup accuracy was analyzed for 38 patients, who had received intensity-modulated radiotherapy and were regularly scanned during treatment with cone beam computed tomography (CBCT) for offline patient setup correction. In addition to the clinically used large region of interest (ROI), we defined eight ROIs in the planning CT that contained rigid bony structures: the mandible, larynx, jugular notch, occiput bone, vertebrae C1-C3, C3-C5, and C5-C7, and the vertebrae caudal of C7. By local rigid registration to successive CBCT scans, the local setup accuracy of each ROI was determined and compared with the overall setup error assessed with the large ROI. Deformations were distinguished from rigid body movements by expressing movement relative to a reference ROI (vertebrae C1-C3). RESULTS The offline patient setup correction protocol using the large ROI resulted in residual systematic errors (1 SD) within 1.2 mm and random errors within 1.5 mm for each direction. Local setup errors were larger, ranging from 1.1 to 3.4 mm (systematic) and 1.3 to 2.5 mm (random). Systematic deformations ranged from 0.4 mm near the reference C1-C3 to 3.8 mm for the larynx. Random deformations ranged from 0.5 to 3.6 mm. CONCLUSION Head-and-neck cancer patients show considerable local setup variations, exceeding residual global patient setup uncertainty in an offline correction protocol. Current planning target volume margins may be inadequate to account for these uncertainties. We propose registration of multiple ROIs to drive correction protocols and adaptive radiotherapy to reduce the impact of local setup variations.

Adaptive Radiotherapy for Lung Cancer

Lung cancer radiation therapy (RT) is associated with complex geometrical uncertainties, such as respiratory motion, differential baseline shifts between primary tumor and involved lymph nodes, and anatomical changes due to treatment response. Generous safety margins required to account for these uncertainties limit the potential of dose escalation to improve treatment outcome. Four dimensional inverse planning incorporating pretreatment patient-specific respiratory motion information into the treatment plan already improves treatment plan quality. More importantly, repetitive imaging during treatment quantifies patient-specific intrafraction, interfraction, and progressive geometrical variations. These patient-specific parameters subsequently can drive adaptive plan modification correcting for systematic errors while incorporating random errors. Adaptive RT therefore has the potential to considerably improve the accuracy of RT, reducing the exposure of organs at risk, facilitating safe dose escalation, and improving local control as well as overall survival.

A Collaborative Analysis of Stereotactic Lung Radiotherapy Outcomes for Early-Stage Non–Small-Cell Lung Cancer Using Daily Online Cone-Beam Computed Tomography Image-Guided Radiotherapy

Introduction: We report lung stereotactic-body radiotherapy (SBRT) outcomes for a large pooled cohort treated using daily online cone-beam computed tomography. Methods: Five hundred and five stage I–IIB (T1-3N0M0) non–small-cell lung cancer (NSCLC) cases underwent SBRT using cone-beam computed tomography image guidance at five international institutions from 1998 to 2010. Median age was 74 years (range, 42–92) whereas median forced expiratory volume in 1 second/diffusing lung capacity for carbon monoxide were 1.4 liter (65%) and 10.8 ml/min/mmHg (53%). Of the 505 cases, 64% were biopsy proven and 87% medically inoperable. Staging was: IA 63%, IB 33%, IIA 2%, and recurrent 1%. Median max tumor dimension was 2.6 cm (range, 0.9–8.5). Median heterogeneously calculated volumetric prescription dose (PD) was 54 Gy (range, 20–64 Gy) in three fractions (range, 1–15) over 8 days (range, 1–27). Median biologically equivalent PD biological equivalent doses (BED10) was 132 Gy (range, 60–180). Results: With a median follow-up of 1.6 years (range, 0.1–7.3), the 2-year Kaplan–Meier local control (LC), regional control, and distant metastasis (DM) rates were 94%, 89%, and 20%, respectively, whereas cause-specific and overall survival were 87% and 60% (78% operable, 58% inoperable, p = 0.01), respectively. Stage, gross-tumor volume size (≥ 2.7 cm) and PD(BED10) predicted local relapse (LR) and DM. LR was 15% for BED10 less than 105 Gy versus 4% for BED10 of 105 Gy or more (p < 0.001); DM was 31% versus 18% for BED10 less than 105 versus 105 Gy or more (p = 0.01). On multivariate analysis, PD(BED10) and elapsed days during radiotherapy predicted LR; gross-tumor volume size predicted DM. Grade 2 or higher pneumonitis, rib fracture, myositis, and dermatitis were 7%, 3%, 1%, and 2%, respectively. Conclusions: In the largest early-stage NSCLC SBRT data set to date, a high rate of local control was achieved, which was correlated with a PD(BED10) of 105 Gy or more. Failures were primarily distant, severe toxicities were rare, and overall survival was encouraging in operable patients.

Quantifying Interfraction and Intrafraction Tumor Motion in Lung Stereotactic Body Radiotherapy Using Respiration-Correlated Cone Beam Computed Tomography

PURPOSE Stereotactic body radiation therapy (SBRT) is an effective treatment for medically inoperable Stage I non-small-cell lung cancer. However, changes in the patients breathing patterns during the course of SBRT may result in a geographic miss or an overexposure of healthy tissues to radiation. However, the precise extent of these changes in breathing pattern is not well known. We evaluated the inter- and intrafractional changes in tumor motion amplitude (DeltaM) over an SBRT course. METHODS AND MATERIALS Eighteen patients received image-guided SBRT delivered in three fractions; this therapy was done with abdominal compression in four patients. For each fraction, cone beam computed tomography (CBCT) was performed for tumor localization (+/- 3-mm tolerance) and then repeated to confirm geometric accuracy. Additional CBCT images were acquired at the midpoint and end of each SBRT fraction. Respiration-correlated CBCT (rcCBCT) reconstructions allowed retrospective assessment of inter- and intrafractional DeltaM by a comparison of tumor displacements in all four-dimensional CT and rcCBCT scans. The DeltaM was measured in mediolateral, superior-inferior, and anterior-posterior directions. RESULTS A total of 201 rcCBCT images were analyzed. The mean time from localization of the tumor to the end-fraction CBCT was 35 +/- 7 min. Compared with the motion recorded on four-dimensional CT, the mean DeltaM was 0.4, 1.0, and 0.4 mm, respectively, in the mediolateral, superior-inferior, and anterior-posterior directions. On treatment, the observed DeltaM was, on average, <1 mm; no DeltaM was statistically different with respect to the initial rcCBCT. However, patients in whom abdominal compression was used showed a statistically significant difference (p < 0.05) in the variance of DeltaM with respect to the initial rcCBCT in the superior-inferior direction. CONCLUSIONS The inter- and intrafractional DeltaM that occur during a course of lung SBRT are small. However, abdominal compression causes larger variations in the time spent on the treatment couch and in the inter- and intrafractional DeltaM values.

Radiation pneumonitis in patients treated for malignant pulmonary lesions with hypofractionated radiation therapy

PURPOSE We evaluated the relationship between the mean lung dose (MLD) and the incidence of radiation pneumonitis (RP) after stereotactic body radiation therapy (SBRT), and compared this with conventional fractionated radiation therapy (CFRT). MATERIALS AND METHODS For both SBRT (n=128) and CFRT (n=142) patients, RP grade > or = 2 was scored. Toxicity models predicting the probability of RP as a function of the MLD were fitted using maximum log likelihood analysis. The MLD was NTD (Normalized Total Dose) corrected using an alpha/beta ratio of 3 Gy. RESULTS SBRT patients were treated with 6-12 Gy per fraction with a median MLD of 6.4 Gy (range: 1.5-26.5 Gy). CFRT patients were treated with 2 Gy or 2.25 Gy per fraction, the median MLD was 13.2 Gy (range: 3.0-23.0 Gy). The crude incidence rates of RP were 10.9% and 17.6% for the SBRT and CFRT patients, respectively. A significant dose-response relationship for RP was found after SBRT, which was not significantly different from the dose-response relationship for CFRT (p=0.18). CONCLUSION We derived a significant dose-response relationship between the risk of RP and the MLD for SBRT from the clinical data. This relation was not significantly different from the dose-response relation for CFRT, although statistical analysis was hampered by the low number of patients in the high dose range.