Treating patients with real-time tumor tracking using the Vero gimbaled linac system: Implementation and first review

Purpose

To report on the first clinical application of a real-time tumor tracking (RTTT) solution based on the Vero SBRT gimbaled linac system for treatment of moving tumors.

Methods and materials

A first group of 10 SBRT patients diagnosed with NSCLC or oligometastatic disease in lung or liver was treated with the RTTT technique. The PTV volumes and OAR exposure were benchmarked against the widely used ITV approach. Based on data acquired during execution of RTTT treatments, a first review was performed of the process.

Results

The 35% PTV volume reduction with RTTT of the studied single lesions SBRT irradiations of small target volumes is expected to result in a small (<1%) reduction of lung or liver NTCP. A GTV–PTV margin of 5.0 mm was applied for treatment planning of RTTT. From patient data on residual geometric uncertainties, a CTV–PTV margin of 3.2 mm was calculated. Reduction of the GTV–PTV margin below 5.0 mm without better understanding of biological definition of tumor boundaries was discouraged. Total treatment times were reduced to 34.4 min on average.

Conclusion

A considerable PTV volume reduction was achieved applying RTTT and time efficiency for respiratory correlated SBRT was reestablished with Vero RTTT.     

Improving the intra-fraction update efficiency of a correlation model used for internal motion estimation during real-time tumor tracking for SBRT patients: Fast update or no update?

Background and purpose

For tumor tracking, a correlation model is used to estimate internal tumor position based on external surrogate motion. When patients experience an internal/external surrogate drift, an update of the correlation model is required to continue tumor tracking. In this study, the accuracy of the internal tumor position estimation for both the clinical available update at discrete points in time (rebuild) and an in-house developed non-clinical online update approach was investigated.

Methods

A dynamic phantom with superimposed baseline drifts and 14 SBRT patients, treated with real-time tumor tracking (RTTT) on the Vero system, were retrospectively simulated for three update scenarios, respectively no update, clinical rebuild and 0.5 Hz automated online update of the correlation model. By comparing the target positions based on 0.5 Hz verification X-ray images with the estimated internal tumor positions regarding all three update scenarios, 95th percentile modeling errors (ME₉₅), incidences of full geometrical coverage of the CTV by a 5 mm extended PTV (P_5mm) and population-based PTV margins were calculated. Further, the treatment time reduction was estimated when switching from the clinical rebuild approach to the online correlation model update.

Results

For dynamic phantom motion with baseline drifts up to 0.4 mm/min, a 0.5 Hz intra-fraction update showed a similar accuracy in terms of ME₉₅ and P_5mm compared to clinical rebuild. For SBRT patients treated on Vero with RTTT, accuracy was improved by 0.5 Hz online update compared to the clinical rebuild protocol, yielding smaller PTV margins (from 3.2 mm to 2.7 mm), reduced ME_95,3D (from 4.1 mm to 3.4 mm) and an increased 5th percentile P_5mm (from 90.7% to 96.1%) for the entire patient group. Further, 80% of treatment sessions were reduced in time with on average 5.5 ± 4.1 (1 SD) min.

Conclusion

With a fast (0.5 Hz) automated online update of the correlation model, an efficient RTTT workflow with improved geometrical accuracy was obtained.     

Imaging dose assessment for IGRT in particle beam therapy

Introduction

Image-guided advanced photon and particle beam treatments are promising options for improving lung treatments. Extensive use of imaging increases the overall patient dose. The aim of this study was to determine the imaging dose for different IGRT solutions used in photon and particle beam therapy.

Material and methods

Measurements were performed in an Alderson phantom with TLDs. Clinically applied protocols for orthogonal planar kV imaging, stereoscopic imaging, CT scout views, fluoroscopy, CT, 4D-CT and CBCT were investigated at five ion beam centers and one conventional radiotherapy department. The overall imaging dose was determined for a patient undergoing a lung tumor irradiation with institute specific protocols.

Results

OAR doses depended on imaging modality and OAR position. Dose values were in the order of 1 mGy for planar and stereoscopic imaging and 10–50 mGy for volumetric imaging, except for one CBCT device leading to lower doses. The highest dose per exam (up to 150 mGy to the skin) was recorded for a 3-min fluoroscopy.

Discussion

Modalities like planar kV or stereoscopic imaging result in very low doses (∼1 mGy) to the patient. Imaging a moving target during irradiation, low-dose protocols and protocol optimization can reduce the imaging dose to the patient substantially.     

3D dose delivery verification using repeated cone-beam imaging and EPID dosimetry for stereotactic body radiotherapy of non-small cell lung cancer

Purpose

To implement a 3D dose verification procedure, based on in-room cone-beam CT imaging and portal dosimetry, for lung cancer patients treated with stereotactic body radiotherapy (SBRT).

Materials and methods

MV cone-beam CT scans were made for patient positioning and calibrated for dose calculation purposes. Prior to treatment, the treatment fields were captured using a calibrated electronic portal imaging device (EPID). A Monte Carlo dose reconstruction model was used to estimate the 3D dose delivered to the patient inside the cone-beam CT images. The planned and delivered dose distributions were compared for 4 patients and 10 treatment fractions using dose-volume histograms and gamma analysis.

Results

The gamma analysis showed a good agreement between the planned and delivered dose distributions for patients without changes in anatomy. The delivered mean dose per fraction inside the target volume deviated on average 1.1 ± 1.4% from the planned dose. For the critical organs, only minor differences were observed between the reconstructed and planned dose.

Conclusions

A method was presented that allows verification of the dose delivered in 3D for lung cancer patients treated with SBRT. The procedure is independent of the treatment planning system and uses in-room MV cone-beam CT imaging and portal dosimetry.     

Geometric accuracy of a novel gimbals based radiation therapy tumor tracking system

Purpose

VERO is a novel platform for image guided stereotactic body radiotherapy. Orthogonal gimbals hold the linac-MLC assembly allowing real-time moving tumor tracking. This study determines the geometric accuracy of the tracking.

Materials and methods

To determine the tracking error, an 1D moving phantom produced sinusoidal motion with frequencies up to 30 breaths per minute (bpm). Tumor trajectories of patients were reproduced using a 2D robot and pursued with the gimbals tracking system prototype. Using the moving beam light field and a digital-camera-based detection unit tracking errors, system lag and equivalence of pan/tilt performance were measured.

Results

The system lag was 47.7 ms for panning and 47.6 ms for tilting. Applying system lag compensation, sinusoidal motion tracking was accurate, with a tracking error 90% percentile E_90% < 0.82 mm and similar performance for pan/tilt. Systematic tracking errors were below 0.14 mm. The 2D tumor trajectories were tracked with an average E_90% of 0.54 mm, and tracking error standard deviations of 0.20 mm for pan and 0.22 mm for tilt.

Conclusions

In terms of dynamic behavior, the gimbaled linac of the VERO system showed to be an excellent approach for providing accurate real-time tumor tracking in radiation therapy.     

Intra- and interfractional variations in geometric arrangement between lung tumours and implanted markers

Purpose

To quantify the intra- and interfractional variations between lung tumours and implanted markers.

Materials and methods

Gold markers were implanted transbronchially around a lung tumour in fifteen patients. They underwent four-dimensional computed tomography scans twice, and the centroids of the tumour and markers were determined. Intrafractional variations were defined as the residual tumour motions relative to the markers due to respiration from the end-exhale phase. Interfractional variations were defined as the residual setup errors after correction for the position of the implanted markers in end-exhale phase images.

Results

The intrafractional variations differed between patients. The root mean squares of standard deviations for each phase were 0.6, 0.9, and 1.5 mm in the right–left, anterior–posterior, and superior–inferior directions, respectively. The maximum difference in intrafractional variation among 10 phases was correlated with the amplitude of tumour motion in all directions and the tumour-marker distance in the anterior–posterior and superior–inferior directions. The interfractional variations were within 2.5 mm.

Conclusions

The intrafractional variations differed according to the amount of tumour motion and the tumour-marker distance. Additionally, interfractional variations of up to 2.5 mm were observed. Thus, a corresponding margin should be considered during implanted marker-based beam delivery to account for these variations.     

Radiation exposure to patients from image guidance procedures and techniques to reduce the imaging dose

Purpose

To compare imaging doses from MV images, kV radiographs, and kV-CBCT and describe methods to reduce the dose to patient’s organs using existing on-board imaging devices.

Method and materials

Monte Carlo techniques were used to simulate kV X-ray sources. The kV image doses to a variety of patient anatomies were calculated by using the simulated realistic sources to deposit dose in patient CT images. For MV imaging, the doses for the same patients were calculated using a commercial treatment planning system.

Results

Portal imaging results in the largest dose to anatomic structures, followed by Varian OBI CBCT, Varian TrueBeam CBCT and then kV radiographs. The imaging doses for the 50% volume from the DVHs, D50, to the eyes for representative head images are 4.3–4.8 cGy; 0.05–0.06 cGy; 0.04–0.05 cGy; and, 0.12 cGy; D50 to the bladder for representative pelvis images are 3.3 cGy; 1.6 cGy; 1.0 cGy; and, 0.07 cGy; while D50 to the heart for representative thorax images are 3.5 cGy; 0.42 cGy; 0.2 cGy; and, 0.07 cGy; when using portal imaging, OBI kV-CBCT scans, TrueBeam kV-CBCT scans and kV radiographs, respectively. The orientation of the kV beam can affect organ dose. For example, D50 to the eyes can be reduced from 0.12 cGy using AP and right lateral radiographs to 0.008–0.017 cGy when using PA and right lateral radiographs. In addition, organ exposures can be further reduced to 15–70% of their original values with the use of a full-fan, bow-tie filter for kV radiographs. In contrast, organ doses increase by a factor of ∼2–4 if bow-tie filters are not used during kV-CBCT acquisitions.

Conclusion

Current on-board kV imaging devices result in much lower imaging doses compared to MV imagers even taking into account of higher bone dose from kV X-rays. And a variety of approaches are available to significantly reduce the image doses.     

Frequency filtering based analysis on the cardiac induced lung tumor motion and its impact on the radiotherapy management

Purpose/objectives

Lung tumor motion may be impacted by heartbeat in addition to respiration. This study seeks to quantitatively analyze heart-motion-induced tumor motion and to evaluate its impact on lung cancer radiotherapy.

Methods/materials

Fluoroscopy images were acquired for 30 lung cancer patients. Tumor, diaphragm, and heart were delineated on selected fluoroscopy frames, and their motion was tracked and converted into temporal signals based on deformable registration propagation. The clinical relevance of heart impact was evaluated using the dose volumetric histogram of the redefined target volumes.

Results

Correlation was found between tumor and cardiac motion for 23 patients. The heart-induced motion amplitude ranged from 0.2 to 2.6 mm. The ratio between heart-induced tumor motion and the tumor motion was inversely proportional to the amplitude of overall tumor motion. When the heart motion impact was integrated, there was an average 9% increase in internal target volumes for 17 patients. Dose coverage decrease was observed on redefined planning target volume in simulated SBRT plans.

Conclusions

The tumor motion of thoracic cancer patients is influenced by both heart and respiratory motion. The cardiac impact is relatively more significant for tumor with less motion, which may lead to clinically significant uncertainty in radiotherapy for some patients.     

Use of megavoltage cine-images for studying intra-thoracic motion during radiotherapy for locally advanced lung cancer

Background and purpose

Use of planning 4-dimensional CT (4DCT) scans often permits use of smaller target volumes for thoracic tumors but this assumes a reproducible pattern of motion during radiotherapy. We compared cranio-caudal (CC) motion on MV cine-images acquired during treatment with that seen on planning 4DCT.

Methods and materials

A pre-programmable respiratory motion phantom and a software tool for motion assessment were used to validate the use of MV cine-images for motion detection. MV cine-images acquired in 20 patients with node-positive lung cancer were analyzed using the same software. Intra-fraction CC motion on 6 MV cine-images from each patient was compared with CC motion on their planning 4DCT.

Results

Software-based motion measurement on MV cine-images from the phantom corresponded to actual motion. Mean CC motion of primary tumor, carina and hilus on 4DCT was 7.3 mm (range 2-13.8 mm), 6.8 mm (1.8-21.2) and 11.0 mm (4.2-15.1), respectively. Corresponding intra-fraction motion on MV cine was 4.1 mm (0.6-13.6 mm); 2.7 mm (0-10 mm) and 6.0 mm (1.8-14.4 mm), respectively. The tumor, hilus and carina could be tracked in 95%, 88% and 38% of the MV cine-images, respectively.

Conclusions

Intra-fraction motion can be reliably measured using MV-cine images from a phantom. Motion discrepancies identified on MV cine-images can identify patients in whom planning 4DCT scans are not representative.     

The accuracy of frameless stereotactic intracranial radiosurgery

Purpose

To determine the accuracy of frameless stereotactic radiosurgery using the BrainLAB ExacTrac system and robotic couch by measuring the individual contributions such as the accuracy of the imaging and couch correction system, the linkage between this system and the linac isocenter and the possible intrafraction motion of the patient in the frameless mask.

Materials and methods

An Alderson head phantom with hidden marker was randomly positioned 31 times. Automated 6D couch shifts were performed according to ExacTrac and the deviation with respect to the linac isocenter was measured using the hidden marker. ExacTrac-based set-up was performed for 46 patients undergoing hypofractionated stereotactic radiotherapy for 135 fractions, followed by verification X-rays. Forty-three of these patients received post-treatment X-ray verification for 79 fractions to determine the intrafraction motion.

Results

The hidden target test revealed a systematic error of 1.5 mm in one direction, which was corrected after replacement of the system calibration phantom. The accuracy of the ExacTrac positioning is approximately 0.3 mm in each direction, 1 standard deviation. The intrafraction motion was 0.35 ± 0.21 mm, maximum 1.15 mm.

Conclusion

Intrafraction motion in the BrainLAB frameless mask is very small. Users are strongly advised to perform an independent verification of the ExacTrac isocenter in order to avoid systematic deviations.     

Intensity modulated radiosurgery of brain metastases with flattening filter-free beams

Purpose

Flattening filter free (FFF) irradiation potentially reduces treatment delivery time in radiosurgery thus eliminating intrafraction motion and increasing patient comfort. We compared plan quality and efficiency of VMAT and IMRT plans for FFF- and standard delivery for brain metastases with single fraction doses of 20 Gy and validated the dosimetric accuracy of the FFF delivery.

Material and Methods

CT data of 15 patients with brain metastases were included in this study. For every patient, 2 IMRT- and 2 VMAT-plans were created using a high-resolution MLC with two different delivery modes (6 MV standard vs. 6 MV FFF). Plan quality and efficiency was assessed by analysis of conformity, homogeneity, dose gradients, treatment delivery time and number of monitor units (MU). Dosimetric evaluation was performed for 10 FFF plans with radiochromic film and ion chamber.

Results

Plan quality was similar for both approaches. FFF provided a mean treatment time reduction of 51.5% with similar MU for VMAT and IMRT for this low-modulation paradigm. The dosimetric validations showed an absolute dose deviation of +0.93 ± 0.99% and γ-index analysis (3%/3 mm and 3%/1 mm) resulted in agreement of 99.08 ± 1.58% respectively 93.46 ± 2.41%.

Conclusion

FFF radiosurgery is an efficient technique for intensity modulated hypofractionated or single fraction treatments with similar plan quality when compared to flattened beams at reduced treatment time.     

Detector comparison for small field output factor measurements in flattening filter free photon beams

Purpose

The applicability of various detectors for small field dosimetry and whether there are differences in the detector response when irradiated with FF- and FFF-beams was investigated.

Materials and methods

Output factors of 6 and 10 MV FF- and FFF-beams were measured with 14 different online detectors using field sizes between 10 × 10 and 0.6 × 0.6 cm² at a depth of 5 cm of water in isocentric conditions. Alanine pellets with a diameter of 5 and 2.5 mm were used as reference dosimeters for field sizes down to 1.2 × 1.2 and 0.6 × 0.6 cm², respectively. The ratio of the relative output measured with the online detectors to the relative output measured with alanine was evaluated (referred to as dose response ratio).

Results

The dose response ratios of two different shielded diodes measured with 10 MV FF-beams deviated substantially by 2–3% compared to FFF-beams at a field size of 0.6 × 0.6 cm². This difference was less pronounced for 6MV FF- and FFF-beams. For all other detectors the dose response ratios of FF- and FFF-beams showed no significant difference.

Conclusion

The dose response ratios of the majority of the detectors agreed within the measurement uncertainty when irradiated with FF- and FFF-beams. Of all investigated detectors, the microDiamond and the unshielded diodes would require only small corrections which make them suitable candidates for small field dosimetry in FF- and FFF-beams.     

Potential of image-guidance, gating and real-time tracking to improve accuracy in pulmonary stereotactic body radiotherapy

Purpose

To evaluate the potential of image-guidance, gating and real-time tumor tracking to improve accuracy in pulmonary stereotactic body radiotherapy (SBRT).

Materials and methods

Safety margins for compensation of inter- and intra-fractional uncertainties of the target position were calculated based on SBRT treatments of 43 patients with pre- and post-treatment cone-beam CT imaging. Safety margins for compensation of breathing motion were evaluated for 17 pulmonary tumors using respiratory correlated CT, model-based segmentation of 4D-CT images and voxel-based dose accumulation; the target in the mid-ventilation position was the reference.

Results

Because of large inter-fractional base-line shifts of the tumor, stereotactic patient positioning and image-guidance based on the bony anatomy required safety margins of 12 mm and 9 mm, respectively. Four-dimensional image-guidance targeting the tumor itself and intra-fractional tumor tracking reduced margins to <5 mm and <3 mm, respectively. Additional safety margins are required to compensate for breathing motion. A quadratic relationship between tumor motion and margins for motion compensation was observed: safety margins of 2.4 mm and 6 mm were calculated for compensation of 10 mm and 20 mm motion amplitudes in cranio-caudal direction, respectively.

Conclusion

Four-dimensional image-guidance with pre-treatment verification of the target position and online correction of errors reduced safety margins most effectively in pulmonary SBRT.     

Role of endorectal MR imaging and MR spectroscopic imaging in defining treatable intraprostatic tumor foci in prostate cancer: Quantitative analysis of imaging contour compared to whole-mount histopathology

Purpose

To investigate the role of endorectal MR imaging and MR spectroscopic imaging in defining the contour of treatable intraprostatic tumor foci in prostate cancer, since targeted therapy requires accurate target volume definition.

Materials and methods

We retrospectively identified 20 patients with prostate cancer who underwent endorectal MR imaging and MR spectroscopic imaging prior to radical prostatectomy and subsequent creation of detailed histopathological tumor maps from whole-mount step sections. Two experienced radiologists independently reviewed all MR images and electronically contoured all suspected treatable (?0.5 cm³) tumor foci. Deformable co-registration in MATLAB was used to calculate the margin of error between imaging and histopathological contours at both capsular and non-capsular surfaces and the treatment margin required to ensure at least 95% tumor coverage.

Results

Histopathology showed 17 treatable tumor foci in 16 patients, of which 8 were correctly identified by both readers and an additional 2 were correctly identified by reader 2. For all correctly identified lesions, both readers accurately identified that tumor contacted the prostatic capsule, with no error in contour identification. On the non-capsular border, the median distance between the imaging and histopathological contour was 1.4 mm (range, 0–12). Expanding the contour by 5 mm at the non-capsular margin included 95% of tumor volume not initially covered within the MR contour.

Conclusions

Endorectal MR imaging and MR spectroscopic imaging can be used to accurately contour treatable intraprostatic tumor foci; adequate tumor coverage is achieved by expanding the treatment contour at the non-capsular margin by 5 mm.     

Kilovoltage intrafraction motion monitoring and target dose reconstruction for stereotactic volumetric modulated arc therapy of tumors in the liver

Purpose

To use intrafraction kilovoltage (kV) imaging during liver stereotactic body radiotherapy (SBRT) delivered by volumetric modulated arc therapy (VMAT) to estimate the intra-treatment target motion and to reconstruct the delivered target dose.

Methods

Six liver SBRT patients with 2–3 implanted gold markers received SBRT in three fractions of 18.75 Gy or 25 Gy. CTV-to-PTV margins of 5 mm in the axial plane and 10 mm in the cranio-caudal directions were applied. A VMAT plan was designed to give minimum target doses of 95% (CTV) and 67% (PTV). At each fraction, the 3D marker trajectory was estimated by fluoroscopic kV imaging throughout treatment delivery and used to reconstruct the actually delivered CTV dose. The reduction in D₉₅ (minimum dose to 95% of the CTV) relative to the planned D₉₅ was calculated.

Results

The kV position estimation had mean root-mean-square errors of 0.36 mm and 0.47 mm parallel and perpendicular to the kV imager, respectively. Intrafraction motion caused a mean 3D target position error of 2.9 mm and a mean D₉₅ reduction of 6.0%. The D₉₅ reduction correlated with the mean 3D target position error during a fraction.

Conclusions

Kilovoltage imaging for detailed motion monitoring with dose reconstruction of VMAT-based liver SBRT was demonstrated for the first time showing large dosimetric impact of intrafraction tumor motion.     

Intra-fraction motion of the prostate during treatment with helical tomotherapy

Background and purpose

To measure the geometric uncertainty resulting from intra-fraction motion and intra-observer image matching, for patients having image-guided prostate radiotherapy on TomoTherapy.

Material and methods

All patients had already been selected for prostate radiotherapy on TomoTherapy, with daily MV-CT imaging. The study involved performing an additional MV-CT image at the end of treatment, on 5 occasions during the course of 37 treatments. 54 patients were recruited to the study. A new formula was derived to calculate the PTV margin for intra-fraction motion.

Results

The mean values of the intra-fraction differences were 0.0 mm, 0.5 mm, 0.5 mm and 0.0° for LR, SI, AP and roll, respectively. The corresponding standard deviations were 1.1 mm, 0.8 mm, 0.8 mm and 0.6° for systematic uncertainties (Σ), 1.3 mm, 2.0 mm, 2.2 mm and 0.3° for random uncertainties (σ). This intra-fraction motion requires margins of 2.2 mm in LR, 2.1 mm in SI and 2.1 mm in AP directions. Inclusion of estimates of the effect of rotations and matching errors increases these margins to approximately 4 mm in LR and 5 mm in SI and AP directions.

Conclusions

A new margin recipe has been developed to calculate margins for intra-fraction motion. This recipe is applicable to any measurement technique that is based on the difference between images taken before and after treatment.     

Use of bioluminescence imaging to detect enhanced hepatic and systemic tumor growth following partial hepatectomy in mice

Background

The impact of partial hepatectomy on intra-hepatic and distant tumor growth is a matter of controversy. Utilizing a highly sensitive tumor imaging strategy, we sought to demonstrate whether this growth-acceleration occurs, and to develop an animal model with which to investigate potential therapeutic strategies.

Methods

Mice bearing constitutively-active luciferase-expressing tumor cells were subjected to either 70% partial hepatectomy (PH; n = 10) or a sham operation (n = 11). Mice were sacrificed 14 days later and remnant livers (or anatomic equivalents in the control group) and lungs harvested for bioluminescence detection.

Results

Remnant liver weights were significantly increased in PH compared to equivalent lobes in sham-operated animals (t-test; p = 0.005). Tumor burden as measured by bioluminescence was significantly higher in both liver and lung specimens in the PH group (Wilcoxon's Rank Sum test; p = 0.01 and 0.004, respectively).

Conclusions

Following PH, enhanced metastatic growth was depicted regionally and systemically with bioluminescence imaging providing an objective measure of tumor burden. This preclinical model can help to identify adjuvant therapies that can influence both tumor growth and liver regeneration.     

Brain metastases following radical surgical treatment of non-small cell lung cancer: Is preoperative brain imaging important?

Objectives

There is a lack of good quality evidence or a clear consensus of opinion internationally regarding who should receive preoperative imaging of the brain prior to radical treatment for non-small cell lung cancer (NSCLC). We aimed to establish the proportion of patients who developed brain metastases following curative surgery and to estimate how many could have been detected by preoperative magnetic resonance imaging (MR).

Methods

We performed a retrospective analysis of 646 patients who underwent surgery for lung cancer with curative intent at a regional thoracic surgical centre in the United Kingdom. We identified those who developed brain metastases in the postoperative period and, by using volume doubling times, estimated the size of the metastasis at the time of surgery. We then determined the proportion of metastases that would have been seen on preoperative MR brain at detection thresholds of 2 and 5 mm diameter.

Results

There was a 6.3% incidence of postoperative brain metastases, with the majority occurring within 12 months of surgery. Those who developed metastases were more likely to have adenocarcinoma and the majority had early stage malignancy (73% stage I or stage II).We estimate that 71% of those who developed cerebral metastases might have been detected had they undergone MR brain as part of their staging (4.4% of all patients).

Conclusion

Based on our findings we suggest that, in addition to standard staging investigations, patients have brain imaging (MR or equivalent) prior to curative surgery in NSCLC regardless of preoperative stage.