Image guidance and interfractional anatomical variation in paediatric abdominal radiotherapy.

OBJECTIVES: To identify variables predicting interfractional anatomical variations measured with cone-beam CT (CBCT) throughout abdominal paediatric radiotherapy, and to assess the potential of surface-guided radiotherapy (SGRT) to monitor these changes. METHODS: Metrics of variation in gastrointestinal (GI) gas volume and separation of the body contour and abdominal wall were calculated from 21 planning CTs and 77 weekly CBCTs for 21 abdominal neuroblastoma patients (median 4 years, range: 2 - 19 years). Age, sex, feeding tubes, and general anaesthesia (GA) were explored as predictive variables for anatomical variation. Furthermore, GI gas variation was correlated with changes in body and abdominal wall separation, as well as simulated SGRT metrics of translational and rotational corrections between CT/CBCT. RESULTS: GI gas volumes varied 74 ± 54 ml across all scans, while body and abdominal wall separation varied 2.0 ± 0.7 mm and 4.1 ± 1.5 mm from planning, respectively. Patients < 3.5 years (p = 0.04) and treated under GA (p < 0.01) experienced greater GI gas variation; GA was the strongest predictor in multivariate analysis (p < 0.01). Absence of feeding tubes was linked to greater body contour variation (p = 0.03). GI gas variation correlated with body (R = 0.53) and abdominal wall (R = 0.63) changes. The strongest correlations with SGRT metrics were found for anterior-posterior translation (R = 0.65) and rotation of the left-right axis (R = -0.36). CONCLUSIONS: Young age, GA, and absence of feeding tubes were linked to stronger interfractional anatomical variation and are likely indicative of patients benefiting from adaptive/robust planning pathways. Our data suggest a role for SGRT to inform the need for CBCT at each treatment fraction in this patient group. ADVANCES IN KNOWLEDGE: This is the first study to suggest the potential role of SGRT for the management of internal interfractional anatomical variation in paediatric abdominal radiotherapy.

Deep learning based synthetic CT from cone beam CT generation for abdominal paediatric radiotherapy.

Objective. Adaptive radiotherapy workflows require images with the quality of computed tomography (CT) for re-calculation and re-optimisation of radiation doses. In this work we aim to improve the quality of on-board cone beam CT (CBCT) images for dose calculation using deep learning.Approach. We propose a novel framework for CBCT-to-CT synthesis using cycle-consistent Generative Adversarial Networks (cycleGANs). The framework was tailored for paediatric abdominal patients, a challenging application due to the inter-fractional variability in bowel filling and small patient numbers. We introduced to the networks the concept of global residuals only learning and modified the cycleGAN loss function to explicitly promote structural consistency between source and synthetic images. Finally, to compensate for the anatomical variability and address the difficulties in collecting large datasets in the paediatric population, we applied a smart 2D slice selection based on the common field-of-view (abdomen) to our imaging dataset. This acted as a weakly paired data approach that allowed us to take advantage of scans from patients treated for a variety of malignancies (thoracic-abdominal-pelvic) for training purposes. We first optimised the proposed framework and benchmarked its performance on a development dataset. Later, a comprehensive quantitative evaluation was performed on an unseen dataset, which included calculating global image similarity metrics, segmentation-based measures and proton therapy-specific metrics.Main results. We found improved performance for our proposed method, compared to a baseline cycleGAN implementation, on image-similarity metrics such as Mean Absolute Error calculated for a matched virtual CT (55.0 ± 16.6 HU proposed versus 58.9 ± 16.8 HU baseline). There was also a higher level of structural agreement for gastrointestinal gas between source and synthetic images measured using the dice similarity coefficient (0.872 ± 0.053 proposed versus 0.846 ± 0.052 baseline). Differences found in water-equivalent thickness metrics were also smaller for our method (3.3 ± 2.4% proposed versus 3.7 ± 2.8% baseline).Significance. Our findings indicate that our innovations to the cycleGAN framework improved the quality and structure consistency of the synthetic CTs generated.

Clinically Applicable Segmentation of Head and Neck Anatomy for Radiotherapy: Deep Learning Algorithm Development and Validation Study.

BACKGROUND: Over half a million individuals are diagnosed with head and neck cancer each year globally. Radiotherapy is an important curative treatment for this disease, but it requires manual time to delineate radiosensitive organs at risk. This planning process can delay treatment while also introducing interoperator variability, resulting in downstream radiation dose differences. Although auto-segmentation algorithms offer a potentially time-saving solution, the challenges in defining, quantifying, and achieving expert performance remain. OBJECTIVE: Adopting a deep learning approach, we aim to demonstrate a 3D U-Net architecture that achieves expert-level performance in delineating 21 distinct head and neck organs at risk commonly segmented in clinical practice. METHODS: The model was trained on a data set of 663 deidentified computed tomography scans acquired in routine clinical practice and with both segmentations taken from clinical practice and segmentations created by experienced radiographers as part of this research, all in accordance with consensus organ at risk definitions. RESULTS: We demonstrated the model's clinical applicability by assessing its performance on a test set of 21 computed tomography scans from clinical practice, each with 21 organs at risk segmented by 2 independent experts. We also introduced surface Dice similarity coefficient, a new metric for the comparison of organ delineation, to quantify the deviation between organ at risk surface contours rather than volumes, better reflecting the clinical task of correcting errors in automated organ segmentations. The model's generalizability was then demonstrated on 2 distinct open-source data sets, reflecting different centers and countries to model training. CONCLUSIONS: Deep learning is an effective and clinically applicable technique for the segmentation of the head and neck anatomy for radiotherapy. With appropriate validation studies and regulatory approvals, this system could improve the efficiency, consistency, and safety of radiotherapy pathways.

Risk of radiation-induced second malignant neoplasms from photon and proton radiotherapy in paediatric abdominal neuroblastoma.

BACKGROUND AND PURPOSE: State-of-the-art radiotherapy modalities have the potential of reducing late effects of treatment in childhood cancer survivors. Our aim was to investigate the carcinogenic risk associated with 3D conformal (photon) radiation (3D-CRT), intensity modulated arc therapy (IMAT) and pencil beam scanning proton therapy (PBS-PT) in the treatment of paediatric abdominal neuroblastoma. MATERIALS AND METHODS: The risk of radiation-induced second malignant neoplasm (SMN) was estimated using the concept of organ equivalent dose (OED) for eleven organs (lungs, rectum, colon, stomach, small intestine, liver, bladder, skin, central nervous system (CNS), bone, and soft tissues). The risk ratio (RR) between radiotherapy modalities and lifetime absolute risks (LAR) were reported for twenty abdominal neuroblastoma patients (median, 4y; range, 1-9y) historically treated with 3D-CRT that were also retrospectively replanned for IMAT and PBS-PT. RESULTS: The risk of SMN due to primary radiation was reduced in PBS-PT against 3D-CRT and IMAT for most patients and organs. The RR across all organs ranged from 0.38 ± 0.22 (bladder) to 0.98 ± 0.04 (CNS) between PBS-PT and IMAT, and 0.12 ± 0.06 (rectum and bladder) to 1.06 ± 0.43 (bone) between PBS-PT and 3D-CRT. The LAR for most organs was within 0.01-1% (except the colon) with a cumulative risk of 21 ± 13%, 35 ± 14% and 35 ± 16% for PBS-PT, IMAT and 3D-CRT, respectively. CONCLUSIONS: PBS-PT was associated with the lowest risk of radiation-induced SMN compared to IMAT and 3D-CRT in abdominal neuroblastoma treatment. Other clinical endpoints and plan robustness should also be considered for optimal plan selection.

Atlas construction and spatial normalisation to facilitate radiation-induced late effects research in childhood cancer.

Reducing radiation-induced side effects is one of the most important challenges in paediatric cancer treatment. Recently, there has been growing interest in using spatial normalisation to enable voxel-based analysis of radiation-induced toxicities in a variety of patient groups. The need to consider three-dimensional distribution of doses, rather than dose-volume histograms, is desirable but not yet explored in paediatric populations. In this paper, we investigate the feasibility of atlas construction and spatial normalisation in paediatric radiotherapy. We used planning computed tomography (CT) scans from twenty paediatric patients historically treated with craniospinal irradiation to generate a template CT that is suitable for spatial normalisation. This childhood cancer population representative template was constructed using groupwise image registration. An independent set of 53 subjects from a variety of childhood malignancies was then used to assess the quality of the propagation of new subjects to this common reference space using deformable image registration (i.e. spatial normalisation). The method was evaluated in terms of overall image similarity metrics, contour similarity and preservation of dose-volume properties. After spatial normalisation, we report a dice similarity coefficient of 0.95 ± 0.05, 0.85 ± 0.04, 0.96 ± 0.01, 0.91 ± 0.03, 0.83 ± 0.06 and 0.65 ± 0.16 for brain and spinal canal, ocular globes, lungs, liver, kidneys and bladder. We then demonstrated the potential advantages of an atlas-based approach to study the risk of second malignant neoplasms after radiotherapy. Our findings indicate satisfactory mapping between a heterogeneous group of patients and the template CT. The poorest performance was for organs in the abdominal and pelvic region, likely due to respiratory and physiological motion and to the highly deformable nature of abdominal organs. More specialised algorithms should be explored in the future to improve mapping in these regions. This study is the first step toward voxel-based analysis in radiation-induced toxicities following paediatric radiotherapy.

Impact of varying planning parameters on proton pencil beam scanning dose distributions in four commercial treatment planning systems.

PURPOSE: In pencil beam scanning proton therapy, target coverage is achieved by scanning the pencil beam laterally in the x- and y-directions and delivering spots of dose to positions at a given radiological depth (layer). Dose is delivered to the spots on different layers by pencil beams of different energy until the entire volume has been irradiated. The aim of this study is to investigate the implementation of proton planning parameters (spot spacing, layer spacing and margins) in four commercial proton treatment planning systems (TPSs): Eclipse, Pinnacle3 , RayStation and XiO. MATERIALS AND METHODS: Using identical beam data in each TPS, plans were created on uniform material synthetic phantoms with cubic targets. The following parameters were systematically varied in each TPS to observe their different implementations: spot spacing, layer spacing and margin. Additionally, plans were created in Eclipse to investigate the impact of these parameters on plan delivery and optimal values are suggested. RESULTS: It was found that all systems except Eclipse use a variable layer spacing per beam, based on the Bragg peak width of each energy layer. It is recommended that if this cannot be used, then a constant value of 5 mm will ensure good dose homogeneity. Only RayStation varies the spot spacing according to the variable spot size with depth. If a constant spot spacing is to be used, a value of 5 mm is recommended as a good compromise between dose homogeneity, plan robustness and planning time. It was found that both Pinnacle3 and RayStation position spots outside of the defined volume (target plus margin). CONCLUSIONS: All four systems are capable of delivering uniform dose distributions to simple targets, but their implementation of the various planning parameters is different. In this paper comparisons are made between the four systems and recommendations are made as to the values that will provide the best compromise in dose homogeneity and planning time.

Novel horizontal and vertical integrated bioethics curriculum for medical courses.

Studies conducted by the University of Haifa, Israel in 2001, evaluating the effectiveness of bioethics being taught in medical colleges, suggested that there was a significant lack of translation in clinical care. Analysis also revealed, ineffectiveness with the teaching methodology used, lack of longitudinal integration of bioethics into the undergraduate medical curriculum, and the limited exposure to the technology in decision making when confronting ethical dilemmas. A modern novel bioethics curriculum and innovative methodology for teaching bioethics for the medical course was developed by the UNESCO Chair in Bioethics, Haifa. The horizontal (subject-wise) curriculum was vertically integrated seamlessly through the entire course. An innovative bioethics teaching methodology was employed to implement the curriculum. This new curriculum was piloted in a few medical colleges in India from 2011 to 2015 and the outcomes were evaluated. The evaluation confirmed gains over the earlier identified translation gap with added high student acceptability and satisfaction. This integrated curriculum is now formally implemented in the Indian program's Health Science Universities which is affiliated with over 200 medical schools in India. This article offers insights from the evaluated novel integrated bioethics curriculum and the innovative bioethics teaching methodology that was used in the pilot program.

A generalized framework unifying image registration and respiratory motion models and incorporating image reconstruction, for partial image data or full images.

Surrogate-driven respiratory motion models relate the motion of the internal anatomy to easily acquired respiratory surrogate signals, such as the motion of the skin surface. They are usually built by first using image registration to determine the motion from a number of dynamic images, and then fitting a correspondence model relating the motion to the surrogate signals. In this paper we present a generalized framework that unifies the image registration and correspondence model fitting into a single optimization. This allows the use of 'partial' imaging data, such as individual slices, projections, or k-space data, where it would not be possible to determine the motion from an individual frame of data. Motion compensated image reconstruction can also be incorporated using an iterative approach, so that both the motion and a motion-free image can be estimated from the partial image data. The framework has been applied to real 4DCT, Cine CT, multi-slice CT, and multi-slice MR data, as well as simulated datasets from a computer phantom. This includes the use of a super-resolution reconstruction method for the multi-slice MR data. Good results were obtained for all datasets, including quantitative results for the 4DCT and phantom datasets where the ground truth motion was known or could be estimated.

Inter-comparison of relative stopping power estimation models for proton therapy.

Theoretical stopping power values were inter-compared for the Bichsel, Janni, ICRU and Schneider relative stopping power (RSP) estimation models, for a variety of tissues and tissue substitute materials taken from the literature. The RSPs of eleven plastic tissue substitutes were measured using Bragg peak shift measurements in water in order to establish a gold standard of RSP values specific to our centre's proton beam characteristics. The theoretical tissue substitute RSP values were computed based on literature compositions to assess the four different computation approaches. The Bichsel/Janni/ICRU approaches led to mean errors in the RSP of -0.1/+0.7/-0.8%, respectively. Errors when using the Schneider approach, with I-values from the Bichsel, Janni and ICRU sources, followed the same pattern but were generally larger. Following this, the mean elemental ionisation energies were optimized until the differences between theoretical RSP values matched measurements. Failing to use optimized I-values when applying the Schneider technique to 72 human tissues could introduce errors in the RSP of up to -1.7/+1.1/-0.4% when using Bichsel/Janni/ICRU I-values, respectively. As such, it may be necessary to introduce an additional step in the current stoichiometric calibration procedure in which tissue insert RSPs are measured in a proton beam. Elemental I-values can then optimized to match these measurements, reducing the uncertainty when calculating human tissue RSPs.

Validation of clinical acceptability of an atlas-based segmentation algorithm for the delineation of organs at risk in head and neck cancer.

PURPOSE: The aim of this study was to assess whether clinically acceptable segmentations of organs at risk (OARs) in head and neck cancer can be obtained automatically and efficiently using the novel "similarity and truth estimation for propagated segmentations" (STEPS) compared to the traditional "simultaneous truth and performance level estimation" (STAPLE) algorithm. METHODS: First, 6 OARs were contoured by 2 radiation oncologists in a dataset of 100 patients with head and neck cancer on planning computed tomography images. Each image in the dataset was then automatically segmented with STAPLE and STEPS using those manual contours. Dice similarity coefficient (DSC) was then used to compare the accuracy of these automatic methods. Second, in a blind experiment, three separate and distinct trained physicians graded manual and automatic segmentations into one of the following three grades: clinically acceptable as determined by universal delineation guidelines (grade A), reasonably acceptable for clinical practice upon manual editing (grade B), and not acceptable (grade C). Finally, STEPS segmentations graded B were selected and one of the physicians manually edited them to grade A. Editing time was recorded. RESULTS: Significant improvements in DSC can be seen when using the STEPS algorithm on large structures such as the brainstem, spinal canal, and left/right parotid compared to the STAPLE algorithm (all p < 0.001). In addition, across all three trained physicians, manual and STEPS segmentation grades were not significantly different for the brainstem, spinal canal, parotid (right/left), and optic chiasm (all p > 0.100). In contrast, STEPS segmentation grades were lower for the eyes (p < 0.001). Across all OARs and all physicians, STEPS produced segmentations graded as well as manual contouring at a rate of 83%, giving a lower bound on this rate of 80% with 95% confidence. Reduction in manual interaction time was on average 61% and 93% when automatic segmentations did and did not, respectively, require manual editing. CONCLUSIONS: The STEPS algorithm showed better performance than the STAPLE algorithm in segmenting OARs for radiotherapy of the head and neck. It can automatically produce clinically acceptable segmentation of OARs, with results as relevant as manual contouring for the brainstem, spinal canal, the parotids (left/right), and optic chiasm. A substantial reduction in manual labor was achieved when using STEPS even when manual editing was necessary.

A comparison of the dose distributions from three proton treatment planning systems in the planning of meningioma patients with single-field uniform dose pencil beam scanning.

With the number of new proton centers increasing rapidly, there is a need for an assessment of the available proton treatment planning systems (TPSs). This study compares the dose distributions of complex meningioma plans produced by three proton TPSs: Eclipse, Pinnacle3, and XiO. All three systems were commissioned with the same beam data and, as best as possible, matched configuration settings. Proton treatment plans for ten patients were produced on each system with a pencil beam scanning, single-field uniform dose approach, using a fixed horizontal beamline. All 30 plans were subjected to identical dose constraints, both for the target coverage and organ at risk (OAR) sparing, with a consistent order of priority. Beam geometry, lateral field margins, and lateral spot resolutions were made consistent across all systems. Few statistically significant differences were found between the target coverage and OAR sparing of each system, with all optimizers managing to produce plans within clinical tolerances (D2 < 107% of prescribed dose, D5 < 105%, D95 > 95%, D99 > 90%, and OAR maximum doses) despite strict constraints and overlapping structures.

Evolving surgical prosthetic rehabilitation protocol for success of dental implant placed in distracted alveolar ridge.

BACKGROUND: Remodelling of bone in the form of resorption generally follows the extraction of a tooth. During all stages of atrophy of the alveolar ridge, characteristic shapes result from the resorptive process, as influenced by anatomic alterations in the alveolar bone. Various ridge augmentation procedures have been documented as predictable means of establishing new vital bone for implant placement, out of which distraction osteogenesis is one such modality. Hence the following study has been conducted to evolve a surgico- prosthetic rehabilitation protocol in grossly atrophic alveolar ridge by distraction osteogenesis and subsequent implant placement and to provide an effective alternative to lost dental tissue to serving soldiers, their families and ex-servicemen of the Indian Army in a cost effective manner. METHODS: A total of 30 patients with ridge defects in age group between 18 to 70 years were selected for the study. The net success rate of distraction procedure was 93.33% (100% in maxilla and 80% in mandible) with 2 cases deemed as failures out of a total of 30 cases. The average amount of defect compensated was 76.1% (85.1% and 59.5% in maxilla and mandible respectively). RESULTS: For the implant surgical procedure the success rate was 100% and subsequently prosthetic rehabilitation on implants was proved to be successful. CONCLUSION: Distraction ostoeogenesis of an atrophied ridge for further implant placement certainly proves to be successful procedure by this study. Further studies in the same procedure using a larger sample size will definitely be more beneficial.

Imaging Cerenkov emission as a quality assurance tool in electron radiotherapy.

A new potential quality assurance (QA) method is explored (including assessment of depth dose, dose linearity, dose rate linearity and beam profile) for clinical electron beams based on imaging Cerenkov light. The potential of using a standard commercial camera to image Cerenkov light generated from electrons in water for fast QA measurement of a clinical electron beam was explored and compared to ionization chamber measurements. The new method was found to be linear with dose and independent of dose rate (to within 3%). The uncorrected practical range measured in Cerenkov images was found to overestimate the actual value by 3 mm in the worst case. The field size measurements underestimated the dose at the edges by 5% without applying any correction factor. Still, the measured field size could be used to monitor relative changes in the beam profile. Finally, the beam-direction profile measurements were independent of the field size within 2%. A simulation was also performed of the deposited energy and of Cerenkov production in water using GEANT4. Monte Carlo simulation was used to predict the measured light distribution around the water phantom, to reproduce Cerenkov images and to find the relation between deposited energy and Cerenkov production. The camera was modelled as a pinhole camera in GEANT4, to attempt to reproduce Cerenkov images. Simulations of the deposited energy and the Cerenkov light production agreed with each other for a pencil beam of electrons, while for a realistic field size, Cerenkov production in the build-up region overestimated the dose by +8%.

Toward adaptive radiotherapy for head and neck patients: Feasibility study on using CT-to-CBCT deformable registration for "dose of the day" calculations.

PURPOSE: The aim of this study was to evaluate the appropriateness of using computed tomography (CT) to cone-beam CT (CBCT) deformable image registration (DIR) for the application of calculating the "dose of the day" received by a head and neck patient. METHODS: NiftyReg is an open-source registration package implemented in our institution. The affine registration uses a Block Matching-based approach, while the deformable registration is a GPU implementation of the popular B-spline Free Form Deformation algorithm. Two independent tests were performed to assess the suitability of our registrations methodology for "dose of the day" calculations in a deformed CT. A geometric evaluation was performed to assess the ability of the DIR method to map identical structures between the CT and CBCT datasets. Features delineated in the planning CT were warped and compared with features manually drawn on the CBCT. The authors computed the dice similarity coefficient (DSC), distance transformation, and centre of mass distance between features. A dosimetric evaluation was performed to evaluate the clinical significance of the registrations errors in the application proposed and to identify the limitations of the approximations used. Dose calculations for the same intensity-modulated radiation therapy plan on the deformed CT and replan CT were compared. Dose distributions were compared in terms of dose differences (DD), gamma analysis, target coverage, and dose volume histograms (DVHs). Doses calculated in a rigidly aligned CT and directly in an extended CBCT were also evaluated. RESULTS: A mean value of 0.850 in DSC was achieved in overlap between manually delineated and warped features, with the distance between surfaces being less than 2 mm on over 90% of the pixels. Deformable registration was clearly superior to rigid registration in mapping identical structures between the two datasets. The dose recalculated in the deformed CT is a good match to the dose calculated on a replan CT. The DD is smaller than 2% of the prescribed dose on 90% of the body's voxels and it passes a 2% and 2 mm gamma-test on over 95% of the voxels. Target coverage similarity was assessed in terms of the 95%-isodose volumes. A mean value of 0.962 was obtained for the DSC, while the distance between surfaces is less than 2 mm in 95.4% of the pixels. The method proposed provided adequate dose estimation, closer to the gold standard than the other two approaches. Differences in DVH curves were mainly due to differences in the OARs definition (manual vs warped) and not due to differences in dose estimation (dose calculated in replan CT vs dose calculated in deformed CT). CONCLUSIONS: Deforming a planning CT to match a daily CBCT provides the tools needed for the calculation of the "dose of the day" without the need to acquire a new CT. The initial clinical application of our method will be weekly offline calculations of the "dose of the day," and use this information to inform adaptive radiotherapy (ART). The work here presented is a first step into a full implementation of a "dose-driven" online ART.

Intensity-modulated arc therapy to improve radiation dose delivery in the treatment of abdominal neuroblastoma.

The standard European radiotherapy technique for children with neuroblastoma is a conventional parallel opposed pair. This frequently results in compromise on planning target volume coverage to stay within normal tissue tolerances. This study investigates the use of an intensity-modulated arc therapy (IMAT) technique to improve dose distribution and allow better protocol compliance. Among 20 previously treated patients, ten had received the full prescribed dose with conventional planning (protocol compliant) and ten had a compromise on planning target volume coverage (protocol noncompliant). All patients were replanned with IMAT. Dosimetric parameters of the conventional radiotherapy and IMAT were compared. The dose received by 98% of the planning target volume, homogeneity and conformity indices were all improved with IMAT (p < 0.001). IMAT would have enabled delivery of the full protocol dose in eight out of ten protocol-noncompliant patients. IMAT may improve outcomes through improved protocol compliance and better dose distributions.

177Lu-DOTATATE molecular radiotherapy for childhood neuroblastoma.

UNLABELLED: This study tested the principle that (68)Ga-DOTATATE PET/CT may be used to select children with primary refractory or relapsed high-risk neuroblastoma for treatment with (177)Lu-DOTATATE and evaluated whether this is a viable therapeutic option for those children. METHODS: Between 2008 and 2010, 8 children with relapsed or refractory high-risk neuroblastoma were studied with (68)Ga-DOTATATE PET/CT. The criterion of eligibility for (177)Lu-DOTATATE therapy was uptake on the diagnostic scan equal to or higher than that of the liver. RESULTS: Of the 8 children imaged, 6 had abnormally high uptake on the (68)Ga-DOTATATE PET/CT scan and proceeded to treatment. Patients received 2 or 3 administrations of (177)Lu-DOTATATE at a median interval of 9 wk and a median administered activity of 7.3 GBq. Of the 6 children treated, 5 had stable disease by the response evaluation criteria in solid tumors (RECIST). Of these 5 children, 2 had an initial metabolic response and reduction in the size of their lesions, and 1 patient had a persistent partial metabolic response and reduction in size of the lesions on CT, although the disease was stable by RECIST. One had progressive disease. Three children had grade 3 and 1 child had grade 4 thrombocytopenia. No significant renal toxicity has been seen. CONCLUSION: (68)Ga-DOTATATE can be used to image children with neuroblastoma and identify those suitable for molecular radiotherapy with (177)Lu-DOTATATE. We have shown, for what is to our knowledge the first time, that treatment with (177)Lu-DOTATATE is safe and feasible in children with relapsed or primary refractory high-risk neuroblastoma. We plan to evaluate this approach formally in a phase I-II clinical trial.

TARGeted Intraoperative radiotherapy (TARGIT): an innovative approach to partial-breast irradiation.

A revolution is challenging the dogma that local treatment for all patients with breast cancer treated with breast conservation therapy must include postoperative radiotherapy delivered to the whole breast. Such prolonged postoperative radiotherapy is a burden to patients and hospitals and forces many women to chose mastectomy instead. Furthermore, for patients receiving chemotherapy, the start of conventional radiotherapy may be delayed so long as to increase the risk of local relapse. These problems might be eliminated if effective radiotherapy could be given as a single treatment intraoperatively, immediately after the surgery. Local recurrence after breast-conserving surgery usually occurs in the portion of the breast in the immediate proximity of the tumor, even when radiotherapy is omitted. Therefore, it should usually be possible to restrict radiotherapy to only the area adjacent to the tumor in selected women. Based on this premise, we have devised a new technique of partial breast irradiation, with the intention of completing all local treatment in a single session. In this article, we elaborate on the rationale and on the different methods of delivering intraoperative radiotherapy. If this approach is validated in ongoing randomized trials, it could save time, money, and breasts.

Intraoperative radiotherapy for breast cancer.

Postoperative radiotherapy, which forms part of breast-conserving therapy, may not need to encompass the whole breast. Apart from the consumption of huge resources and patients' time, postoperative radiotherapy deters many women from receiving the benefits of breast-conserving surgery, forcing them to choose a mastectomy instead. If radiotherapy could be given in the operating theatre immediately after surgery, many of these disadvantages could be overcome. One striking fact about local recurrence after breast-conserving surgery is that most occurs in the area of breast immediately next to the primary tumour; this is despite the finding that two-thirds of mastectomy samples have microscopic tumours distributed throughout the breast, even when radiotherapy is omitted. Thus, only the area adjacent to the tumour may need treatment with radiotherapy. On the basis of this premise, clinical scientists have used new technology to administer radiotherapy to the area at greatest risk of local recurrence, with the aim of completing the whole local treatment in one sitting. In this review, we have elaborated on the rationale and different methods of delivery of intraoperative radiotherapy. If this approach is validated by the results of current randomised trials, it could save time, money, and breasts.

The novel technique of delivering targeted intraoperative radiotherapy (Targit) for early breast cancer.

AIM: We believe that conservative treatment of early breast cancer may not require radiotherapy that encompasses the whole breast in all patients. We have developed a novel therapeutic approach that allows targeted intraoperative radiotherapy (Targit) to be safely and accurately delivered in a standard operating theatre. We are currently recruiting for a randomized trial testing whether Targit can replace the whole 6 weeks of post-operative radiotherapy after breast conserving surgery. METHODS: This paper describes the operative technique. It employs a miniature electron-beam-driven X-ray source called INTRABEAM (PeC) that emits soft X-rays (50 kV) from within the breast. The X-rays are emitted from the tip of a 10 cm x 3.2 mm diameter probe, that is enclosed in a spherical applicator (available in 2.5-5 cm diameter sizes), which in turn is inserted in the tumour bed and intraoperative radiotherapy is delivered in about 25 min. The prescribed dose is 5 and 20 Gy at 1 cm and 0.2 cm respectively, from the tumour bed. RESULTS: The biologically effective dose is 7-53 Gy for alpha/beta=10 and 20-120 Gy for alpha/beta=1.5. The quick attenuation of the radiation reduces the damage to normal tissues and allows radiotherapy to be delivered in a standard operating theatre. Tungsten impregnated rubber sheets, cut to size, are placed on the chest wall to protect the heart/lungs and over the wound to stop stray radiation. The skin dose is monitored with thermoluminescent detectors (TLDs). After wide local excision of the tumour and good haemostasis, a spherical applicator is inserted in the tumour bed and the target breast tissues are wrapped around it with a purse-string suture. Thus, true conformation of the target around the applicator source is achieved in real time. CONCLUSION: As a tumour bed boost, this technique has the potential to reduce local recurrence by avoiding geographical misses and achieving excellent dosimetry. In patients with low risk of local recurrence, it has the potential to replace the full 6 weeks of post-operative radiotherapy with considerable implications to patients and hospitals.