Adaptive radiotherapy for breast cancer.

Research in the field of local and locoregional breast cancer radiotherapy aims to maintain excellent oncological outcomes while reducing treatment-related toxicity. Adaptive radiotherapy (ART) considers variations in target and organs at risk (OARs) anatomy occurring during the treatment course and integrates these in re-optimized treatment plans. Exploiting ART routinely in clinic may result in smaller target volumes and better OAR sparing, which may lead to reduction of acute as well as late toxicities. In this review MR-guided and CT-guided ART for breast cancer patients according to different clinical scenarios (neoadjuvant and adjuvant partial breast irradiation, whole breast, chest wall and regional nodal irradiation) are reviewed and their advantages as well as challenging aspects discussed.

Estimation of secondary cancer projected risk after partial breast irradiation at the 1.5 T MR-linac.

PURPOSE: For patients treated with partial breast irradiation (PBI), potential long-term treatment-related toxicities are important. The 1.5 T magnetic resonance guided linear accelerator (MRL) offers excellent tumor bed visualization and a daily treatment plan adaption possibility, but MRL-specific electron stream and return effects may cause increased dose deposition at air-tissue interfaces. In this study, we aimed to investigate the projected risk of radiation-induced secondary malignancies (RISM) in patients treated with PBI at the 1.5 T MRL. METHODS: Projected excess absolute risk values (EARs) for the contralateral breast, lungs, thyroid and esophagus were estimated for 11 patients treated with PBI at the MRL and compared to 11 patients treated with PBI and 11 patients treated with whole breast irradiation (WBI) at the conventional linac (CTL). All patients received 40.05 Gy in 15 fractions. For patients treated at the CTL, additional dose due to daily cone beam computed tomography (CBCT) was simulated. The t­test with Bonferroni correction was used for comparison. RESULTS: The highest projected risk for a radiation-induced secondary cancer was found for the ipsilateral lung, without significant differences between the groups. A lower contralateral breast EAR was found for MRL-PBI (EAR = 0.89) compared to CTL-PBI (EAR = 1.41, p = 0.01), whereas a lower thyroid EAR for CTL-PBI (EAR = 0.17) compared to MRL-PBI (EAR = 0.33, p = 0.03) and CTL-WBI (EAR = 0.46, p = 0.002) was observed. Nevertheless, when adding the CBCT dose no difference between thyroid EAR for CTL-PBI compared to MRL-PBI was detected. CONCLUSION: Better breast tissue visualization and the possibility for daily plan adaption make PBI at the 1.5 T MRL particularly attractive. Our simulations suggest that this treatment can be performed without additional projected risk of RISM.

Analysis of the electron-stream effect in patients treated with partial breast irradiation using the 1.5 T MR-linear accelerator.

INTRODUCTION: The hybrid magnetic resonance linear accelerator (MRL) has the potential to test novel concepts in breast cancer patients such as daily MR-guided real-time plan adaptation. Before starting clinical trials, preparatory studies for example of the MR-dependent electron stream effect (ESE) are necessary. MATERIAL AND METHODS: To prospectively investigate the ESE, data from 11 patients treated with partial breast irradiation (PBI) at the 1.5 T MRL were evaluated. A bolus was placed on the chin and in vivo dosimetry results were compared with the dose simulated by the treatment planning system (TPS). The same measurements were carried out for three patients treated at a conventional linac. Toxicity and cosmesis were evaluated. RESULTS: Median doses measured and simulated on top/ underneath the bolus were 1.91 / 0.62 Gy and 2.82 / 0.63 Gy, respectively. Median differences between calculations and measurements were 0.8 Gy and 0.1 Gy. At the conventional linac, median measured doses on top/ underneath the bolus were 0.98 and 1.37 Gy. No acute toxicity exceeding grade 2 was recorded. Cosmesis was good or excellent and patient reported outcome measures were mostly scored as none or mild. CONCLUSION: The dose due to the ESE is low, correctly predicted by the TPS and effectively minimized by a bolus.

Marker-less online MR-guided stereotactic body radiotherapy of liver metastases at a 1.5 T MR-Linac - Feasibility, workflow data and patient acceptance.

INTRODUCTION: Stereotactic body radiotherapy (SBRT) is an established ablative treatment for liver tumors with excellent local control rates. Magnetic resonance imaging guided radiotherapy (MRgRT) provides superior soft tissue contrast and may therefore facilitate a marker-less liver SBRT workflow. The goal of the present study was to investigate feasibility, workflow parameters, toxicity and patient acceptance of MRgSBRT on a 1.5 T MR-Linac. METHODS: Ten consecutive patients with liver metastases treated on a 1.5 T MR-Linac were included in this prospective trial. Tumor delineation was performed on four-dimensional computed tomography scans and both exhale triggered and free-breathing T2 MRI scans from the MR-Linac. An internal target volume based approach was applied. Organ at risk constraints were based on the UKSABR guidelines (Version 6.1). Patient acceptance regarding device specific aspects was assessed and toxicity was scored according to the common toxicity criteria of adverse events, version 5. RESULTS: Nine of ten tumors were clearly visible on the 1.5 T MR-Linac. No patient had fiducial markers placed for treatment. All patients were treated with three or five fractions. Median dose to 98% of the gross tumor volume was 38.5 Gy. The median time from "patient identity check" until "beam-off" was 31 min. Median beam on time was 9.6 min. Online MRgRT was well accepted in general and no treatment had to be interrupted on patient request. No event of symptomatic radiation induced liver disease was observed after a median follow-up of ten month (range 3-17 months). CONCLUSION: Our early experience suggests that online 1.5 T MRgSBRT of liver metastases represents a promising new non-invasive marker-free treatment modality based on high image quality, clinically reasonable in-room times and high patient acceptance. Further studies are necessary to assess clinical outcome, to validate advanced motion management and to explore the benefit of online response adaptive liver SBRT.

Development and validation of a 1.5 T MR-Linac full accelerator head and cryostat model for Monte Carlo dose simulations.

PURPOSE: To develop, implement, and validate a full 1.5 T/7 MV magnetic resonance (MR)-Linac accelerator head and cryostat model in EGSnrc for high precision dose calculations accounting for magnetic field effects that are independent from the vendor treatment planning system. METHODS: Primary electron beam parameters for the implemented model were adapted to be in accordance with measured dose profiles of the Elekta Unity (Elekta AB, Stockholm, Sweden). Parameters to be investigated were the mean electron energy as well as the Gaussian radial intensity and energy distributions. Energy tuning was done comparing depth dose profiles simulated with monoenergetic beams of varying energies to measurements. The optimum radial intensity distribution was found by varying the radial full width at half maximum (FWHM) and comparing simulated and measured lateral profiles. The influence of the energy distribution was investigated by comparing simulated lateral and depth dose profiles with varying energy spreads to measured data. Comparison of simulations and measurements was performed by calculating average and maximum local dose deviations. The model was validated recalculating a clinical intensity-modulated radiation therapy plan for the MR-Linac and comparing the resulting dose distribution with simulations from the commercial treatment planning system Monaco using the gamma criterion. RESULTS: Comparison of simulated and measured data showed that the optimum initial electron beam for MR-Linac simulations was monoenergetic with an electron energy of (7.4 ± 0.2) MeV. The optimum Gaussian radial intensity distribution has a FWHM of (2.2 ± 0.3) mm. The average relative deviations were smaller than 1% for all simulated profiles with optimum electron parameters, whereas the largest maximum deviation of 2.07% was found for the 22 × 22 cm 2 cross-plane profile. Profiles were insensitive to energy spread variations. The IMRT plan recalculated with the final MR-Linac model with optimized initial electron beam parameters showed a gamma pass rate of 99.83 % using a gamma criterion of 3%/3 mm. CONCLUSIONS: The EGSnrc MR-Linac model developed in this study showed good accordance with measurements and was successfully used to recalculate a first full clinical IMRT treatment plan. Thus, it shows the general possibility for future secondary dose calculations of full IMRT plans with EGSnrc, which needs further detailed investigations before clinical use.

Introducing FDG PET/CT-guided chemoradiotherapy for stage III NSCLC in low- and middle-income countries: preliminary results from the IAEA PERTAIN trial.

PURPOSE: Patients with stage III non-small-cell lung cancer (NSCLC) treated with chemoradiotherapy (CRT) in low- and middle-income countries (LMIC) continue to have a poor prognosis. It is known that FDG PET/CT improves staging, treatment selection and target volume delineation (TVD), and although its use has grown rapidly, it is still not widely available in LMIC. CRT is often used as sequential treatment, but is known to be more effective when given concurrently. The aim of the PERTAIN study was to assess the impact of introducing FDG PET/CT-guided concurrent CRT, supported by training and quality control (QC), on the overall survival (OS) and progression-free survival (PFS) of patients with stage III NSCLC. METHODS: The study included patients with stage III NSCLC from nine medical centres in seven countries. A retrospective cohort was managed according to local practices between January 2010 and July 2014, which involved only optional diagnostic FDG PET/CT for staging (not for TVD), followed by sequential or concurrent CRT. A prospective cohort between August 2015 and October 2018 was treated according to the study protocol including FDG PET/CT in treatment position for staging and multimodal TVD followed by concurrent CRT by specialists trained in protocol-specific TVD and with TVD QC. Kaplan-Meier analysis was used to assess OS and PFS in the retrospective and prospective cohorts. RESULTS: Guidelines for FDG PET/CT image acquisition and TVD were developed and published. All specialists involved in the PERTAIN study received training between June 2014 and May 2016. The PET/CT scanners used received EARL accreditation. In November 2018 a planned interim analysis was performed including 230 patients in the retrospective cohort with a median follow-up of 14 months and 128 patients in the prospective cohort, of whom 69 had a follow-up of at least 1 year. Using the Kaplan-Meier method, OS was significantly longer in the prospective cohort than in the retrospective cohort (23 vs. 14 months, p = 0.012). In addition, median PFS was significantly longer in the prospective cohort than in the retrospective cohort (17 vs. 11 months, p = 0.012). CONCLUSION: In the PERTAIN study, the preliminary results indicate that introducing FDG PET/CT-guided concurrent CRT for patients with stage III NSCLC in LMIC resulted in a significant improvement in OS and PFS. The final study results based on complete data are expected in 2020.

Precision of T2 TSE MRI-CT-image fusions based on gold fiducials and repetitive T2 TSE MRI-MRI-fusions for adaptive IGRT of prostate cancer by using phantom and patient data.

INTRODUCTION: To increase precision of radiation treatment (RT) delivery in prostate cancer, MRI-based RT as well as the use of fiducials like gold markers (GMs) have shown promising results. Their combined use is currently under investigation in clinical trials. Here, we aimed to evaluate a workflow of image registration based on GMs between CT and MRI as well as weekly MRI-MRI adaption based on T2 TSE sequence. MATERIAL AND METHODS: A gel-phantom with two inserted GMs was scanned with CT and three different MR-scanners of 1.5 and 3 T (T2 TSE and T1 VIBE-Dixon, isotropic, voxel size 2 × 2 × 2 mm). After image fusion, deviations for fiducial and gel match were measured and artifacts were evaluated. Additionally, CT-MRI-match deviations and MRI-MRI-match deviations of 10 Patients from the M-basePro study using GMs were assessed. RESULTS: GMs were visible in all imaging modalities. The outer gel contours were matched with <1 mm deviation, contour volumes varied between 0 and 1%. The deviations of the GMs were less than 2 mm in any direction of MRI/CT. Shifts of peripherally or centrally located GMs were randomly distributed. The average MRI-CT-match precision of 10 patients with GMs was 1.9 mm (range 1.1-3.1 mm). CONCLUSIONS: Match inaccuracies for GMs between reference CT and voxel-isotropic T2-TSE sequences are small. Spatial deviations of CT- and MR-contoured fiducials were less than 2 mm, i.e., below SLT of the applied modalities. In patients, the average CT-MRI-match precision for GMs was 1.9 mm supporting their use in MR-guided high precision RT.

Correlation of FMISO simulations with pimonidazole-stained tumor xenografts: A question of O2 consumption?

PURPOSE: To compare a dedicated simulation model for hypoxia PET against tumor microsections stained for different parameters of the tumor microenvironment. The model can readily be adapted to a variety of conditions, such as different human head and neck squamous cell carcinoma (HNSCC) xenograft tumors. METHODS: Nine different HNSCC tumor models were transplanted subcutaneously into nude mice. Tumors were excised and immunoflourescently labeled with pimonidazole, Hoechst 33342, and CD31, providing information on hypoxia, perfusion, and vessel distribution, respectively. Hoechst and CD31 images were used to generate maps of perfused blood vessels on which tissue oxygenation and the accumulation of the hypoxia tracer FMISO were mathematically simulated. The model includes a Michaelis-Menten relation to describe the oxygen consumption inside tissue. The maximum oxygen consumption rate M0 was chosen as the parameter for a tumor-specific optimization as it strongly influences tracer distribution. M0 was optimized on each tumor slice to reach optimum correlations between FMISO concentration 4 h postinjection and pimonidazole staining intensity. RESULTS: After optimization, high pixel-based correlations up to R(2) = 0.85 were found for individual tissue sections. Experimental pimonidazole images and FMISO simulations showed good visual agreement, confirming the validity of the approach. Median correlations per tumor model varied significantly (p < 0.05), with R(2) ranging from 0.20 to 0.54. The optimum maximum oxygen consumption rate M0 differed significantly (p < 0.05) between tumor models, ranging from 2.4 to 5.2 mm Hg/s. CONCLUSIONS: It is feasible to simulate FMISO distributions that match the pimonidazole retention patterns observed in vivo. Good agreement was obtained for multiple tumor models by optimizing the oxygen consumption rate, M0, whose optimum value differed significantly between tumor models.

Automatic delineation of tumor volumes by co-segmentation of combined PET/MR data.

Combined PET/MRI may be highly beneficial for radiotherapy treatment planning in terms of tumor delineation and characterization. To standardize tumor volume delineation, an automatic algorithm for the co-segmentation of head and neck (HN) tumors based on PET/MR data was developed. Ten HN patient datasets acquired in a combined PET/MR system were available for this study. The proposed algorithm uses both the anatomical T2-weighted MR and FDG-PET data. For both imaging modalities tumor probability maps were derived, assigning each voxel a probability of being cancerous based on its signal intensity. A combination of these maps was subsequently segmented using a threshold level set algorithm. To validate the method, tumor delineations from three radiation oncologists were available. Inter-observer variabilities and variabilities between the algorithm and each observer were quantified by means of the Dice similarity index and a distance measure. Inter-observer variabilities and variabilities between observers and algorithm were found to be comparable, suggesting that the proposed algorithm is adequate for PET/MR co-segmentation. Moreover, taking into account combined PET/MR data resulted in more consistent tumor delineations compared to MR information only.

Functional imaging for radiotherapy treatment planning: current status and future directions-a review.

In recent years, radiotherapy (RT) has been subject to a number of technological innovations. Today, RT is extremely flexible, allowing irradiation of tumours with high doses, whilst also sparing normal tissues from doses. To make use of these additional degrees of freedom, integration of functional image information may play a key role (i) for better staging and tumour detection, (ii) for more accurate RT target volume delineation, (iii) to assess functional information about biological characteristics and individual radiation resistance and (iv) to apply personalized dose prescriptions. In this article, we discuss the current status and future directions of different clinically available functional imaging modalities; CT, MRI, positron emission tomography (PET) as well as the hybrid imaging techniques PET/CT and PET/MRI and their potential for individualized RT.

Methodological aspects on hypoxia PET acquisition and image processing.

Tumor hypoxia is one of the main factors compromising the effectiveness of radiotherapy. As a consequence, non-invasive hypoxia imaging with positron emission tomography (PET) is very promising with regard to its potential to provide a functional basis for patient stratification or therapy modification. This review article aims at providing a comprehensive overview of different methodologies for hypoxia PET image acquisition protocols as well as data processing and analysis as used in recent studies and clinical trials. Furthermore, different physical and also technical aspects that may induce ambiguities and limitations into hypoxia PET image acquisition and interpretation are discussed in the context of this article. In the future, dedicated hypoxia PET image acquisition protocols and methodologies for processing, analysis and interpretation of hypoxia PET data are necessary to allow for comparison of hypoxia PET image data acquired in different study centers and enable for the definition of multicenter trials on hypoxia PET imaging and hypoxia-based treatment interventions.

Integration of FDG-PET/CT into external beam radiation therapy planning: technical aspects and recommendations on methodological approaches.

UNLABELLED: This work addresses the clinical adoption of FDG-PET/CT for image-guided radiation therapy planning (RTP). As such, important technical and methodological aspects of PET/CT-based RTP are reviewed and practical recommendations are given for routine patient management and clinical studies. First, recent developments in PET/CT hardware that are relevant to RTP are reviewed in the context of quality control and system calibration procedures that are mandatory for a reproducible adoption of PET/CT in RTP. Second, recommendations are provided on image acquisition and reconstruction to support the standardization of imaging protocols. A major prerequisite for routine RTP is a complete and secure data transfer to the actual planning system. Third, state-of-the-art tools for image fusion and co-registration are discussed briefly in the context of PET/CT imaging pre- and post-RTP. This includes a brief review of state-of-the-art image contouring algorithms relevant to PET/CT-guided RTP. Finally, practical aspects of clinical workflow and patient management, such as patient setup and requirements for staff training are emphasized. PET/CT-guided RTP mandates attention to logistical aspects, patient set-up and acquisition parameters as well as an in-depth appreciation of quality control and protocol standardization. CONCLUSION: Upon fulfilling the requirements to perform PET/CT for RTP, a new dimension of molecular imaging can be added to traditional morphological imaging. As a consequence, PET/CT imaging will support improved RTP and better patient care. This document serves as a guidance on practical and clinically validated instructions that are deemed useful to the staff involved in PET/CT-guided RTP.

Multi-centre calibration of an adaptive thresholding method for PET-based delineation of tumour volumes in radiotherapy planning of lung cancer.

PURPOSE: To evaluate the calibration of an adaptive thresholding algorithm (contrast-oriented algorithm) for FDG PET-based delineation of tumour volumes in eleven centres with respect to scanner types and image data processing by phantom measurements. METHODS: A cylindrical phantom with spheres of different diameters was filled with FDG realizing different signal-to-background ratios and scanned using 5 Siemens Biograph PET/CT scanners, 5 Philips Gemini PET/CT scanners, and one Siemens ECAT-ART PET scanner. All scans were analysed by the contrast-oriented algorithm implemented in two different software packages. For each site, the threshold SUVs of all spheres best matching the known sphere volumes were determined. Calibration parameters a and b were calculated for each combination of scanner and image-analysis software package. In addition, "scanner-type-specific" calibration curves were determined from all values obtained for each combination of scanner type and software package. Both kinds of calibration curves were used for volume delineation of the spheres. RESULTS: Only minor differences in calibration parameters were observed for scanners of the same type (Δa ≤4%, Δb ≤14%) provided that identical imaging protocols were used whereas significant differences were found comparing calibration parameters of the ART scanner with those of scanners of different type (Δa ≤60%, Δb ≤54%). After calibration, for all scanners investigated the calculated SUV thresholds for auto-contouring did not differ significantly (all p>0.58). The resulting sphere volumes deviated by less than -7% to +8% from the true values. CONCLUSION: After multi-centre calibration the use of the contrast-oriented algorithm for FDG PET-based delineation of tumour volumes in the different centres using different scanner types and specific imaging protocols is feasible.

Functional target volume delineation for radiation therapy on the basis of positron emission tomography and the correlation with histopathology.

Accurate target volume delineation becomes more and more important for modern high-precision radiotherapy. During the last years, molecular imaging using positron emission tomography (PET) has been shown to be of high clinical impact on diagnosis, staging and/or restaging of many malignancies. Therefore, the integration of PET-data into the radiotherapy planning process is of high interest in radio-oncology. During the last years a number of automatic and semi-automatic PET-based volume delineation methods have been developed which will be presented in this review. We will not only describe those algorithms currently used in clinical settings, but also present some of the latest developments in this highly dynamic field of research. Furthermore, validation of different segmentation approaches against histopathology is discussed.