M Metaxas

Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial

BACKGROUND After breast-conserving surgery, 90% of local recurrences occur within the index quadrant despite the presence of multicentric cancers elsewhere in the breast. Thus, restriction of radiation therapy to the tumour bed during surgery might be adequate for selected patients. We compared targeted intraoperative radiotherapy with the conventional policy of whole breast external beam radiotherapy. METHODS Having safely piloted the new technique of single-dose targeted intraoperative radiotherapy with Intrabeam, we launched the TARGIT-A trial on March 24, 2000. In this prospective, randomised, non-inferiority trial, women aged 45 years or older with invasive ductal breast carcinoma undergoing breast-conserving surgery were enrolled from 28 centres in nine countries. Patients were randomly assigned in a 1:1 ratio to receive targeted intraoperative radiotherapy or whole breast external beam radiotherapy, with blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy. Neither patients nor investigators or their teams were masked to treatment assignment. Postoperative discovery of predefined factors (eg, lobular carcinoma) could trigger addition of external beam radiotherapy to targeted intraoperative radiotherapy (in an expected 15% of patients). The primary outcome was local recurrence in the conserved breast. The predefined non-inferiority margin was an absolute difference of 2.5% in the primary endpoint. All randomised patients were included in the intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00983684. FINDINGS 1113 patients were randomly allocated to targeted intraoperative radiotherapy and 1119 were allocated to external beam radiotherapy. Of 996 patients who received the allocated treatment in the targeted intraoperative radiotherapy group, 854 (86%) received targeted intraoperative radiotherapy only and 142 (14%) received targeted intraoperative radiotherapy plus external beam radiotherapy. 1025 (92%) patients in the external beam radiotherapy group received the allocated treatment. At 4 years, there were six local recurrences in the intraoperative radiotherapy group and five in the external beam radiotherapy group. The Kaplan-Meier estimate of local recurrence in the conserved breast at 4 years was 1.20% (95% CI 0.53-2.71) in the targeted intraoperative radiotherapy and 0.95% (0.39-2.31) in the external beam radiotherapy group (difference between groups 0.25%, -1.04 to 1.54; p=0.41). The frequency of any complications and major toxicity was similar in the two groups (for major toxicity, targeted intraoperative radiotherapy, 37 [3.3%] of 1113 vs external beam radiotherapy, 44 [3.9%] of 1119; p=0.44). Radiotherapy toxicity (Radiation Therapy Oncology Group grade 3) was lower in the targeted intraoperative radiotherapy group (six patients [0.5%]) than in the external beam radiotherapy group (23 patients [2.1%]; p=0.002). INTERPRETATION For selected patients with early breast cancer, a single dose of radiotherapy delivered at the time of surgery by use of targeted intraoperative radiotherapy should be considered as an alternative to external beam radiotherapy delivered over several weeks. FUNDING University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research (BMBF).

Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial

BACKGROUND The TARGIT-A trial compared risk-adapted radiotherapy using single-dose targeted intraoperative radiotherapy (TARGIT) versus fractionated external beam radiotherapy (EBRT) for breast cancer. We report 5-year results for local recurrence and the first analysis of overall survival. METHODS TARGIT-A was a randomised, non-inferiority trial. Women aged 45 years and older with invasive ductal carcinoma were enrolled and randomly assigned in a 1:1 ratio to receive TARGIT or whole-breast EBRT, with blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy: randomisation occurred either before lumpectomy (prepathology stratum, TARGIT concurrent with lumpectomy) or after lumpectomy (postpathology stratum, TARGIT given subsequently by reopening the wound). Patients in the TARGIT group received supplemental EBRT (excluding a boost) if unforeseen adverse features were detected on final pathology, thus radiotherapy was risk-adapted. The primary outcome was absolute difference in local recurrence in the conserved breast, with a prespecified non-inferiority margin of 2·5% at 5 years; prespecified analyses included outcomes as per timing of randomisation in relation to lumpectomy. Secondary outcomes included complications and mortality. This study is registered with ClinicalTrials.gov, number NCT00983684. FINDINGS Patients were enrolled at 33 centres in 11 countries, between March 24, 2000, and June 25, 2012. 1721 patients were randomised to TARGIT and 1730 to EBRT. Supplemental EBRT after TARGIT was necessary in 15·2% [239 of 1571] of patients who received TARGIT (21·6% prepathology, 3·6% postpathology). 3451 patients had a median follow-up of 2 years and 5 months (IQR 12-52 months), 2020 of 4 years, and 1222 of 5 years. The 5-year risk for local recurrence in the conserved breast was 3·3% (95% CI 2·1-5·1) for TARGIT versus 1·3% (0·7-2·5) for EBRT (p=0·042). TARGIT concurrently with lumpectomy (prepathology, n=2298) had much the same results as EBRT: 2·1% (1·1-4·2) versus 1·1% (0·5-2·5; p=0·31). With delayed TARGIT (postpathology, n=1153) the between-group difference was larger than 2·5% (TARGIT 5·4% [3·0-9·7] vs EBRT 1·7% [0·6-4·9]; p=0·069). Overall, breast cancer mortality was much the same between groups (2·6% [1·5-4·3] for TARGIT vs 1·9% [1·1-3·2] for EBRT; p=0·56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1·4% [0·8-2·5] vs 3·5% [2·3-5·2]; p=0·0086), attributable to fewer deaths from cardiovascular causes and other cancers. Overall mortality was 3·9% (2·7-5·8) for TARGIT versus 5·3% (3·9-7·3) for EBRT (p=0·099). Wound-related complications were much the same between groups but grade 3 or 4 skin complications were significantly reduced with TARGIT (four of 1720 vs 13 of 1731, p=0·029). INTERPRETATION TARGIT concurrent with lumpectomy within a risk-adapted approach should be considered as an option for eligible patients with breast cancer carefully selected as per the TARGIT-A trial protocol, as an alternative to postoperative EBRT. FUNDING University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research.

Targeted intraoperative radiotherapy for breast cancer in patients in whom external beam radiation is not possible.

PURPOSE External beam radiation therapy (EBRT) following wide local excision of the primary tumor is the standard treatment in early breast cancer. In some circumstances this procedure is not possible or is contraindicated or difficult. The purpose of this study was to determine the safety and efficacy of targeted intraoperative radiotherapy (TARGIT) when EBRT is not feasible. METHODS AND MATERIALS We report our experience with TARGIT in three centers (Australia, Germany, and the United Kingdom) between 1999 and 2008. Patients at these centers received a single radiation dose of 20 Gy to the breast tissue in contact with the applicator (or 6 Gy at 1-cm distance), as they could not be given EBRT and were keen to avoid mastectomy. RESULTS Eighty patients were treated with TARGIT. Reasons for using TARGIT were 21 patients had previously received EBRT, and 31 patients had clinical reasons such as systemic lupus erythematosus, motor neuron disease, Parkinsons disease, ankylosing spondylitis, morbid obesity, and cardiovascular or severe respiratory disease. Three of these patients received percutaneous radiotherapy without surgery; 28 patients were included for compelling personal reasons, usually on compassionate grounds. After a median follow-up of 38 months, only two local recurrences were observed, an annual local recurrence rate of 0.75% (95% confidence interval, 0.09%-2.70%). CONCLUSIONS While we await the results of the randomized trial (over 2,000 patients have already been recruited), TARGIT is an acceptable option but only in highly selected cases that cannot be recruited in the trial and in whom EBRT is not feasible/possible.

Adaptive Imaging Using the I-ImaS X-Ray Imaging System

The I-ImaS (intelligent imaging sensors) is an European Union project whose objective is to design and develop intelligent imaging sensors and evaluate their use within an adaptive imaging system. The system employs an in-line scanning technology approach and use of CMOS active pixel sensors developed specifically for high spatial resolution, efficient light collection and large dynamic range. This paper discusses the principle of the data acquisition (DAQ) system and the characterisation of the I-ImaS sensors, both optically and using mono-energetic X-rays.

A Multi-Element Detector System for Intelligent Imaging: I-ImaS

I-ImaS is a European project aiming to produce new, intelligent X-ray imaging systems using novel APS sensors to create optimal diagnostic images. Initial systems concentrate on mammography and encephalography. Later development will yield systems for other types of radiography such as industrial QA and homeland security. The I-ImaS system intelligence, due to APS technology and FPGAs, allows real-time analysis of data during image acquisition, giving the capability to build a truly adaptive imaging system with the potential to create images with maximum diagnostic information within given dose constraints. A companion paper deals with the DAQ system and preliminary characterization. This paper considers the laboratory X-ray characterization of the detector elements of the I-ImaS system. The characterization of the sensors when tiled to form a strip detector will be discussed, along with the appropriate correction techniques formulated to take into account the misalignments between individual sensors within the array. Preliminary results show that the detectors have sufficient performance to be used successfully in the initial mammographic and encephalographic I-ImaS systems under construction and this paper will further discuss the testing of these systems and the iterative processes used for intelligence upgrade in order to obtain the optimal algorithms and settings.

Adaptive image content-based exposure control for scanning applications in radiography

I-ImaS (Intelligent Imaging Sensors) is a European project which has designed and developed a new adaptive X-ray imaging system using on-line exposure control, to create locally optimized images. The I-ImaS system allows for real-time image analysis during acquisition, thus enabling real-time exposure adjustment. This adaptive imaging system has the potential of creating images with optimal information within a given dose constraint and to acquire optimally exposed images of objects with variable density during one scan. In this paper we present the control system and results from initial tests on mammographic and encephalographic images. Furthermore, algorithms for visualization of the resulting images, consisting of unevenly exposed image regions, are developed and tested. The preliminary results show that the same image quality can be achieved at 30-70% lower dose using the I-ImaS system compared to conventional mammography systems.

A scanning system for intelligent imaging: I-ImaS

I-ImaS (Intelligent Imaging Sensors) is a European project aiming to produce adaptive x-ray imaging systems using Monolithic Active Pixel Sensors (MAPS) to create optimal diagnostic images. Initial systems concentrate on mammography and cephalography. The on-chip intelligence available to MAPS technology will allow real-time analysis of data during image acquisition, giving the capability to build a truly adaptive imaging system with the potential to create images with maximum diagnostic information within given dose constraints. In our system, the exposure in each image region is optimized and the beam intensity is a function not only of tissue thickness and attenuation, but also of local physical and statistical parameters found in the image itself. Using a linear array of detectors with on-chip intelligence, the system will perform an on-line analysis of the image during the scan and then will optimize the X-ray intensity in order to obtain the maximum diagnostic information from the region of interest while minimizing exposure of less important, or simply less dense, regions. This paper summarizes the testing of the sensors and their electronics carried out using synchrotron radiation, x-ray sources and optical measurements. The sensors are tiled to form a 1.5D linear array. These have been characterised and appropriate correction techniques formulated to take into account misalignments between individual sensors. Full testing of the mammography and cephalography I-ImaS prototypes is now underway and the system intelligence is constantly being upgraded through iterative testing in order to obtain the optimal algorithms and settings.

Design and Characterization of the I-ImaS Multi-Element X-Ray Detector System

I-ImaS (Intelligent Imaging Sensors) is a European project aiming to produce new, intelligent X-ray imaging systems using novel APS sensors to create optimal diagnostic images. Initial systems have been constructed for medical imaging; specifically mammography and dental encephalography. However, the I-ImaS system concept could be applied to all areas of X-ray imaging, including homeland security and industrial QA. The I-ImaS system intelligence is implemented by the use of APS technology and FPGAs, allowing real-time analysis of data during image acquisition. This gives the system the capability to perform as an on-the-fly adaptive imaging system, with the potential to create images with maximum diagnostic information within given dose constraints. The I-ImaS system uses a scanning linear array of scintillator-coupled 1.5-D CMOS Active Pixel Sensors to create a full 2-D X-ray image of an object. This paper describes the parameters considered when choosing the scintillator elements of the detectors. A study of the positioning of the sensors to form a linear detector is also considered, along with a discussion of the potential losses in image quality associated with creating a linear sensor by tiling many smaller sensors. Preliminary results show that the detectors have sufficient performance to be used successfully in the initial mammographic and encephalographic I-ImaS systems that are currently under construction.

Characterisation of the Components of a Prototype Scanning Intelligent Imaging System for Use in Digital Mammography: The I-ImaS System

The physical performance characteristics of a prototype scanning digital mammography (DM) system have been investigated. The I-ImaS system utilises CMOS MAPS technology promoting on-chip data processing; consequently statistical analysis is therefore achievable in real-time for the purpose of exposure modulation via a feedback mechanism during the image acquisition procedure. The imager employs a dual array of twenty CMOS APS sensing devices each individually coupled to a 100 mum thick thallium doped structured CsI scintillator. The X-ray performance of the sensors was characterised where the presampled modulation transfer function (MTF), normalised noise power spectrum (NNPS), and the detective quantum efficiency (DQE) was determined. The presampled MTF was measured utilising the slit technique and was found to be 0.1 at 6 lp/mm. The NNPS measured utilising a W/Al target/filter combination hardened with 38 mm PMMA was seen to decrease with increasing exposure as expected and the manifesting DQE was 0.30 at close to zero spatial frequency at an exposure of 1.75 mR. Preliminary image stitching of the individual steps acquired from the scanning system is presented. A conventionally acquired image that is without the implementation of beam modulation or off-line intelligence is compared and contrasted to an intelligently off-line processed image. Results indicate the implementation of real-time intelligence into the image acquisition phase of digital mammography is foreseeable.

Source location and dose verification for X-ray intra-operative radiotherapy (IORT)

A recent development in radiotherapy has been the introduction of the PRS Intrabeam system (Karl Zeiss LtD) for the treatment of both brain and breast tumours. This is essentially a miniaturized, electron-driven photon generator that allows high intensity, soft-energy x-rays to be delivered directly to the tumour site in a single fraction. The isotropical distribution of these photons about the tip of a magnetically shielded needle can be viewed as a point source buried in the body. This work has looked into ways of localizing the source in the body in an Emission Computerized Tomography (ECT) procedure. Various detection systems have been considered as possible candidates for this work. The accuracy with which the source can be localized has been investigated. Furthermore, Monte Carlo studies have been employed in order to extract information on the dosimetric aspect of the resulting image. The final goal of this work is to formulate a direct mathematical relation (Transform Map) between the image created by the escaping photons and the dose map as predicted by the theoretical model. This could allow for a real-time monitoring system of the radiation delivery during the treatment and provide dose verification maps for patient records