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Purpose: Organ-at-risk contouring is still a bottleneck in radiotherapy, with many deep learning methods falling short of promised results when evaluated on clinical data. We investigate the accuracy and time-savings resulting from the use of an interactive-machine-learning method for an organ-at-risk contouring task. Methods: We implement an open-source interactive-machine-learning software application that facilitates corrective-annotation for deep-learning generated contours on X-ray CT images. A trained-physician contoured 933 hearts using our software by delineating the first image, starting model training, and then correcting the model predictions for all subsequent images. These corrections were added into the training data, which was used for continuously training the assisting model. From the 933 hearts, the same physician also contoured the first 10 and last 10 in Eclipse (Varian) to enable comparison in terms of accuracy and duration. Results: We find strong agreement with manual delineations, with a dice score of 0.95. The annotations created using corrective-annotation also take less time to create as more images are annotated, resulting in substantial time savings compared to manual methods. After 923 images had been delineated, hearts took 2 min and 2 s to delineate on average, which includes time to evaluate the initial model prediction and assign the needed corrections, compared to 7 min and 1 s when delineating manually. Conclusions: Our experiment demonstrates that interactive-machine-learning with corrective-annotation provides a fast and accessible way for non computer-scientists to train deep-learning models to segment their own structures of interest as part of routine clinical workflows.

To benefit from modern radiation therapy characterized by highly conformal dose distribution and steep dose gradients, high quality imaging is required for precise tumor delineation. The standard imaging for radiation therapy planning (RTP) remains the acquisition of a dedicated planning computed tomography (CT). Recent advances in combined functional and structural imaging, e.g. hybrid positron emission tomography and CT (PET/CT) have led to progress in management of cancer patients. As PET/CT has become widely available it is increasingly being incorporated into routine RTP. PET/CT in RTP is a multidisciplinary task involving the expertise in radiation oncology, radiology, nuclear medicine and medical physics. Imaging protocols and tumor delineation methods for PET/CT in RT planning should be well-defined and rigorously applied to guarantee reproducibility. The most often used radiotracer for PET/CT in RTP is the glucose analog [18F]FDG, depicting cell metabolism with high sensitivity but low specificity as it is not a specific tumor tracer. PET-based RTP can improve local tumor control by reducing target volume and using dose escalation, with fewer side effects by restricting RT to [18F]FDG avid volumes. Applications of functional imaging are continuously evolving with development of novel PET tracers aimed at specific biological processes. As personalized medicine has become a true force in modern medicine, the individualization of treatment strategies in RTP will require functional imaging in the tailoring of RT for each patient. Novel approaches in radiation therapy delivery, such as dose painting using PET/CT, have been suggested as methods to reduce risk of local recurrence. Equally important, is minimizing radiation toxicity to normal tissue by using PET/CT with breath hold techniques. Furthermore, PET/CT is increasingly used to predict and evaluate response to RT to optimize treatment strategy.

Aim: To explore [fluorine-18]-fluoro-2-deoxy-d-glucose positron-emission-tomography/computed tomography (18FDG-PET/CT) in patients where standard investigations were non-diagnostic. Methods: We reviewed medical records of previously healthy children who had 18FDG-PET/CT performed at Copenhagen University Hospital in 2015–2020 due to unexplained fever. Results: Thirty-five of 819 paediatric 18FDG-PET/CT were performed due to unexplained fever. The final diagnoses were malignancy (11%), infections (23%), inflammatory diseases (43%) and miscellaneous (26%). 18FDG-PET/CT was diagnostic in six cases with Takayasu's arteritis, tuberculosis, Langerhans cell histiocytosis and Ewing sarcoma. Sixteen cases had focal 18FDG-uptake, but 18FDG-PET/CT could only differentiate malignancy, infection and inflammation in three cases. In six cases with inflammatory diseases and no focal signs, PET/CT was normal except increased non-specific 18FDG-uptake in bone marrow and spleen in five cases. One case was false positive (suspicion of appendicitis) and two false negative (leukaemia and inflammatory disease). Conclusion: 18FDG-PET/CT was diagnostic, or contributed to the diagnosis, in several children with unexplained fever referred to a tertiary centre. Challenges comprised (i) only increased non-specific 18FDG-uptake in bone marrow and spleen in half of cases with inflammatory diseases, (ii) no differentiation between complicated infections, malignancy and inflammation in most cases with focal processes and (iii) a small risk of false positive and false negative results.

Background: Consolidation radiotherapy for advanced Hodgkin lymphoma (AHL) is controversial. Precise knowledge of the most likely relapse location is crucial for radiotherapy planning. We performed detailed patterns of relapse analyses and evaluated if initial bulky disease, initial 18F-fluoro-deoxy-glucose (FDG)-avidity and/or a residual mass on computed tomography (CT)-scan after chemotherapy are sites with a high risk of relapse. This information could provide guidance for optimal use of radiotherapy in AHL. Material and methods: We included 133 patients treated with curatively intended chemotherapy for AHL. 23 patients received consolidation radiotherapy. For relapsed patients, imaging from diagnosis, response evaluation, relapse, and any radiotherapy planning, were retrieved and co-registered to determine the exact site(s) of relapse relative to initial site(s), residual mass(es) and to any irradiated volumes. Size and FDG-avidity of initial sites with later relapse, and residual CT-abnormalities after chemotherapy in these sites were registered. Survival analyses were done using the Kaplan–Meier method. Results: Nine (6.8%) patients relapsed, eight in initially involved sites. One relapse was in an initially irradiated site (as well as other sites). Initial bulky disease, high initial FDG-uptake, and/or residual masses on CT-scan after chemotherapy did not predict sites with a high risk of relapse. Overall survival was 79.6% (95% CI, 72.7–86.5%) and 70.6% (95% CI, 62.4–78.8%) at 5 and 10 years, respectively. Time to progression analysis showed 91.8% (95% CI, 86.9–96.7%) and 90.7% (95% CI, 85.4–96.0%) without progression at 5 and 10 years, respectively. Conclusion: Current treatment strategies for AHL provide excellent disease control. Neither initial bulk, high initial FDG-uptake, nor a residual CT-abnormality post-chemotherapy seem to indicate sites with a high risk of relapse.

Tissue factor (TF) expression in cancers correlates with poor prognosis. Recently, the first TF-targeted therapy was approved by the US Food and Drug Administration for cervical cancer. To unfold the potential of TF-targeted therapies, correct stratification and selection of patients eligible for treatments may become important for optimization of patient outcomes. TF-targeted PET imaging based on 18F-radiolabeled active-site inhibited versions of the TF natural ligand coagulation factor VII (18F-ASIS) has in preclinical models convincingly demonstrated its use for non-invasive quantitative measurements of TF expression in tumor tissue. 18F-ASIS PET imaging thus has the potential to act as a diagnostic companion for TF-targeted therapies in the clinical setting. Methods: In this first-in-human trial we included 10 cancer patients (4 pancreatic, 3 breast, 2 lung, and 1 cervical cancer patient) for 18F-ASIS PET imaging. The mean and standard deviation of administered 18F-ASIS activity was 157 ± 35 MBq (range, 93-198 MBq). PET/CT acquisition was performed after 1, 2, and 4 hours. The primary objectives were to establish the safety, biodistribution, pharmacokinetics, and dosimetry of 18F-ASIS. Secondary objectives included quantitative measurements of standardized uptake values (SUV) in tumor tissue with PET and evaluation of the correlation (Pearson correlation) between tumor SUVmax and ex vivo TF expression in tumor tissue. Results: Administration of 18F-ASIS was safe, and no adverse events were observed. No clinically significant changes in vital signs, electrocardiograms, or blood parameters were observed following injection of 18F-ASIS. Mean 18F-ASIS plasma half-life was 3.2 hours, and the radiotracer was predominantly excreted in the urine. For an administered dose of 200 MBq of 18F-ASIS, effective whole-body dose was 4 mSv and no prohibitive organ-specific absorbed doses were found. Heterogeneous radiotracer uptake was observed across patients and within tumor

The clinical course for patients with neuroendocrine neoplasms (NENs) ranges from indolent to highly aggressive. Non-invasive tools to improve prognostication and guide decisions on treatment are warranted. Expression of urokinase plasminogen activator receptor (uPAR) is present in many cancer types and associated with a poor outcome. Therefore, using an in-house developed uPAR PET tracer (68Ga-NOTA-AE105) we aimed to assess uPAR expression in NENs. We hypothesized that uPAR expression was detectable in a significant proportion of patients and associated with a poorer outcome. In addition, as uPAR-targeted radionuclide therapy has previously proven effective in preclinical models, the study would also indicate the potential for uPAR-targeted radionuclide therapy in NEN patients. METHODS: In a prospective clinical phase II trial, we included 120 patients with NENs of all grades of whom 96 subsequently had uPAR PET/CT performed with evaluable lesions. PET/CT was acquired 20 minutes after injection of approximately 200 MBq 68Ga-NOTA-AE105. uPAR target-to-liver ratio (uPAR TLR) was used to define lesions as uPAR positive when lesion SUVmax /liver SUVmean ≥ 2. Patients were followed for at least 1 year to assess progression-free survival (PFS) and overall survival (OS). RESULTS: The majority of patients had small intestinal NEN (n = 61) and metastatic disease (n = 86). uPAR positive lesions were seen in 68% (n = 65) of all patients and in 75% (n = 18) of patients with high grade disease (NEN G3). During follow-up (median 28 months), 59 patients (62%) experienced progressive disease and 28 patients (30%) died. High uPAR expression, defined as uPAR TLR above median, had a hazard ratio (95% confidence interval) of 1.87 (1.11-3.17) and 2.64 (1.19-5.88) for PFS and OS, respectively (p<0.05 for both). CONCLUSION: Using 68Ga-NOTA-AE105 PET for imaging uPAR in patients with NEN, uPAR positive lesions were seen in the majority of patients and most notably in patients with both

Purpose: Whole-body FDG-PET-CT is widely used at diagnosis of squamous cell carcinoma of the head and neck (SCCHN) but may identify suspicious lesions outside the neck that require investigation. This study evaluated the impact of smoking and P16-status on the incidence of malignant disease outside the head and neck region in newly diagnosed patients with SCCHN. Methods: All PET-positive foci outside the head–neck area were registered in 1069 patients planned for postoperative or curative intent radiotherapy with whole-body FDG-PET/CT from 2006 to 2012. All patient files were retrospectively investigated and clinical parameters, tobacco use, HPV (P16)-status and subsequent malignant disease registered. Results: Malignancy outside the neck was diagnosed in 9% of smokers, 2% of never-smokers, and 5% of patients with P16-positive oropharyngeal squamous cell carcinoma (OPSCC). Clinically suspicious PET-positive foci outside the head–neck were malignant in 55% of smokers, 34% of never-smokers, and in 38% of P16-pos OPSCC. All but two patients with cancer occurring outside the head and neck region were smokers. Conclusion: Malignancy outside the neck at diagnosis was more frequent in smokers compared to non-smokers or P16-pos OPSCC. A high proportion of clinically suspicious PET-positive foci were non-malignant.

Introduction: The prospective TEDDI protocol investigates the feasibility of radiotherapy delivery in deep inspiration breath-hold (DIBH) for pediatric patients. To secure optimal radiotherapy planning, a diagnostic baseline FDG PET/CT in free breathing (FB) and DIBH was acquired. The anatomical changes in the mediastinum and the effect on PET metrics between the two breathing conditions were assessed for pediatric patients with mediastinal lymphoma. Material and methods: Ten patients aged 5–17 were included and had a PET/CT in FB and DIBH. Metabolic active lymphoma volumes were manually delineated with a visually based segmentation method and the PET metrics were extracted. The anatomical lymphoma, lung and heart volumes were delineated on CT. Results: The lung volume increased while the heart was displaced caudally and separated from the lymphoma in DIBH compared to FB. Both the anatomical and the metabolically active lymphoma volumes appeared different regarding shape and configuration in the two breathing conditions. The image quality of the DIBH PET was equal to the FB PET regarding interpretation and delineation of lymphoma lesions. All PET metrics increased on the DIBH PET compared to the FB PET with the highest increase observed for the maximum standardized uptake value (33%, range 7–56%). Conclusion: Diminished respiratory motion together with anatomical changes within the lymphoma increased all PET metrics in DIBH compared to FB. The anatomical changes observed in DIBH compared to FB are expected to reduce radiation doses to the heart and lungs in pediatric patients with mediastinal lymphoma referred for radiotherapy delivery in DIBH and, thereby, reduce their risk of late effects. Trial registration: The Danish Ethical Committee (H-16035870, approved November 24th 2016), the Danish Data Protection Agency (2012-58-0004, approved 1 January 2017). Registered retrospectively at clinicaltrials.gov (NCT03315546, 20 October 2017).

64Cu-DOTATATE PET/CT imaging 1 hour (h) post-injection (p.i.) is excellent for lesion detection in patients with neuroendocrine neoplasms (NEN). We hypothesized that the imaging time window can be extended up to 3h p.i. without significant differences in the number of lesions detected. Methods From a prospective study, we compared, on a head-to-head basis, sets of 64Cu-DOTATATE PET/CT images from 35 patients with NEN scanned 1h and 3h p.i. of 200 MBq 64Cu-DOTATATE. The number of lesions on both scans were counted and grouped according to organs or regions and compared with negative binomial regression. Discordant lesions (visible on the 1h or 3h p.i. 64Cu-DOTATATE PET but not the other) were considered true if found on simultaneous CT or later MR, CT or somatostatin receptor imaging. We measured lesion maximal standardized uptake values (SUVmax), reference normal organ or tissue mean SUV (SUVmean) and tumor-to-normal tissue ratios (TTN) calculated from SUVmax/ SUVmeanResults We found 822 concordant lesions (visible on both the 1h and 3h p.i. 64Cu-DOTATATE PET) and five discordant lesions of which four were considered true. One discordant case in one patient involved a discordant organ system (lymph node) detected on the 3h p.i. but not the 1h p.i. 64Cu-DOTATATE PET that did not alter the patient's disease stage (stage IV) because the patient had 11 additional concordant liver lesions. We found no significant differences between the number of lesions detected on the 1h and 3h p.i. 64Cu-DOTATATE PET. Throughout the 1-3 h p.i. imaging window, TTN (mean [95% confidence interval]) remained high in all key organs: Liver (1h p.i.: 12.6 [10.2; 14.9] , 3h p.i.: 11.0 [8.7; 13.4]), intestines (1h p.i.: 24.2 [14.9; 33.4], 3h p.i.: 28.2 [16.5; 40.0]), pancreas (1h p.i.: 42.4 [12.3; 72.5], 3h p.i.: 41.1 [8.7; 73.4]) and bone (1h p.i.: 103.0 [38.6; 167.4], 3h p.i.: 124.2 [57.1; 191.2]). Conclusion The imaging time window of 64Cu-DOTATATE PET/CT of patients with NEN can be expan

Background: Pediatric Hodgkin lymphoma (pHL) is highly curable. However, a minority experience relapse and are subjected to toxic salvage regimens. Investigating the patterns of relapse could help to select the patients and/or the involved sites that would benefit from consolidating radiotherapy. Material and methods: The Danish Childhood Cancer Registry was used to identify children <18 years with relapsed pHL from 1990–2018. The lymphoma volumes involved at diagnosis and at relapse were contoured on the patients’ original scans. Rigid image co-registration was used to merge the scans enabling a visual assessment of the anatomical relapse localization relative to the initially involved lymph nodes, and if irradiated, to the radiotherapy field. Results: From 185 patients with pHL, 24 patients with relapse were available for analysis. All patients received combination chemotherapy and seven had consolidating radiotherapy. Relapses exclusively in initially involved sites occurred in 14 patients. Relapses exclusively in new sites were rare and only observed in three irradiated patients. Seven patients relapsed in both initially involved and new sites. The median time to relapse was 6 months (range 2–59 months), however, in-field relapses in irradiated patients occurred later (54 months, range 10–59 months). Neither risk group, initial bulky disease, early response, or metabolic activity seemed to be associated with the site of a later relapse. Conclusion: The number of relapses were small, and conclusions regarding the selection of patients for radiotherapy could not be drawn. Relapse exclusively in initially involved sites were the most common, most often in the exact same initially involved lymph nodes. Hence, modern involved site radiotherapy, focusing on the initially involved lymphoma volume and minimizing the radiation doses to normal tissues, should be applied when consolidating radiotherapy is used in patients with pHL.

Background: Radiotherapy (RT) planning for cervical cancer patients entails the acquisition of both Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). Further, molecular imaging by Positron Emission Tomography (PET) could contribute to target volume delineation as well as treatment response monitoring. The objective of this study was to investigate the feasibility of a PET/MRI-only RT planning workflow of patients with cervical cancer. This includes attenuation correction (AC) of MRI hardware and dedicated positioning equipment as well as evaluating MRI-derived synthetic CT (sCT) of the pelvic region for positioning verification and dose calculation to enable a PET/MRI-only setup. Material and methods: 16 patients underwent PET/MRI using a dedicated RT setup after the routine CT (or PET/CT), including eight pilot patients and eight cervical cancer patients who were subsequently referred for RT. Data from 18 patients with gynecological cancer were added for training a deep convolutional neural network to generate sCT from Dixon MRI. The mean absolute difference between the dose distributions calculated on sCT and a reference CT was measured in the RT target volume and organs at risk. PET AC by sCT and a reference CT were compared in the tumor volume. Results: All patients completed the examination. sCT was inferred for each patient in less than 5 s. The dosimetric analysis of the sCT-based dose planning showed a mean absolute error (MAE) of 0.17 ± 0.12 Gy inside the planning target volumes (PTV). PET images reconstructed with sCT and CT had no significant difference in quantification for all patients. Conclusions: These results suggest that multiparametric PET/MRI can be successfully integrated as a one-stop-shop in the RT workflow of patients with cervical cancer.

Diagnosing relapse after radiotherapy for lung cancer is challenging. The specificity of both CT and 2-deoxy-2-[18F]fluoro-D-glucose (FDG)-PET/CT is low due to radiation-induced changes. 3'-deoxy-3'-[18F]fluorothymidine (FLT)-PET has previously demonstrated higher specificity for malignancy than FDG-PET. We investigated the value of FLT-PET/CT for diagnosing relapse in irradiated lung cancer. Methods: Patients suspected for relapse of lung cancer after definitive radiotherapy (conventional fractionated radiotherapy (cRT) or stereotactic radiotherapy (SBRT)) were included. Sensitivity and specificity were analysed within the irradiated high-dose volume (HDV) and patient-based. Marginal differences and inter-observer agreement were assessed. Results: Sixty-three patients who had received radiotherapy in 70 HDVs (34 cRT; 36 SBRT) were included. The specificity of FLT-PET/CT was higher than FDG-PET/CT (HDV: 96% [87-100] vs. 71% [57-83]; P = 0.0039; patient-based (90 % [73-98] vs. 55% [36-74]; P = 0.0020)). The difference between specificity of FLT-PET/CT and FDG-PET/CT was higher after cRT compared with SBRT. Sensitivity of FLT-PET/CT was lower than FDG-PET/CT (HDV: 69% [41-89] vs. 94% [70-100]; P = 0.1250; patient-based: 70% [51-84] vs. 94% [80-99]; P = 0.0078). Adding FLT-PET/CT when FDG-PET/CT was positive or inconclusive improved diagnostic value compared with FDG-PET/CT only. In cRT-HDVs, the probability of malignancy increased from 67% for FDG-PET/CT alone to 100% when both PETs were positive. Conclusion: FLT-PET/CT adds diagnostic value to FDG-PET/CT in patients with suspected relapse. The diagnostic impact of FLT-PET/CT was highest after cRT. We suggest adding FLT-PET/CT when FDG-PET/CT is inconclusive or positive within the previously irradiated volume to improve diagnostic value in patients where histological confirmation is not easily obtained.

LESSONS LEARNED: It is possible to plan and treat some patients with stereotactic body radiotherapy (SBRT) in a timely fashion in an acute setting.Advanced and, in some indications, already implemented technologies such as SBRT are difficult to test in a randomized trial.BACKGROUND: Stereotactic body radiotherapy (SBRT) in metastatic spinal cord compression (MSCC) could be an alternative to decompressive surgery followed by fractionated radiotherapy.METHODS: In a randomized, single-institution, noninferiority trial, patients with MSCC were assigned to stereotactic body radiotherapy of 16 Gy in 1 fraction or decompression surgery followed by fractionated radiotherapy of 30 Gy in 10 fractions. Primary endpoint was ability to walk by EQ5D-5L questionnaire. Based on power calculations, 130 patients had to be included to be 89% sure that a 15% difference between the treatment arm and the experimental arm could be detected.RESULTS: Ten patients were accrued in 23 months, with six patients allocated to surgery and four patients to stereotactic body radiotherapy. The trial was closed prematurely because of poor accrual. One patient undergoing surgery and one patient undergoing stereotactic body radiotherapy were unable to walk at 6 weeks. Two patients were not evaluable at 6 weeks.CONCLUSION: A randomized, phase II, clinical trial comparing surgery followed by fractionated radiotherapy or image-guided SBRT of MSCC was initiated. SBRT was shown to be feasible, with three out of four patients retaining walking function. The trial was determined futile as a result of low accrual.

Involved node radiation therapy for lymphoma was introduced with the aim of using the smallest effective treatment volume, individualized to the patient's disease distribution, to avoid the potentially unnecessary normal tissue exposure and toxicity risks associated with traditional involved field radiation therapy. The successful implementation of involved node radiation therapy requires optimal imaging and precise coregistration of baseline imaging with the radiation therapy planning computed tomography scan. Limitations of baseline imaging, changes in patient position, and anatomic changes after chemotherapy may make this difficult in routine practice. Involved site radiation therapy (ISRT) was introduced by the International Lymphoma Radiation Oncology Group as a slightly larger treated volume, intended to allow for commonly encountered uncertainties. In addition to imaging considerations, the optimal ISRT treatment volume also depends on disease histology, stage, nodal or extranodal location, and the type and efficacy of systemic therapy, which in turn influence the distribution of macroscopic and potential subclinical disease. This article presents a systematic overview of ISRT, updating key evidence and highlighting differences in the application of ISRT across the lymphoma clinical spectrum.

Overexpression of somatostatin receptors in patients with neuroendocrine neoplasms (NEN) is utilized for both diagnosis and treatment. Receptor density may reflect tumor differentiation and thus be associated with prognosis. Non-invasive visualization and quantification of somatostatin receptor density is possible by somatostatin receptor imaging (SRI) using positron emission tomography (PET). Recently, we introduced 64Cu-DOTATATE for SRI and we hypothesized that uptake of this tracer could be associated with overall (OS) and progression-free survival (PFS). Methods: We evaluated patients with NEN that had a 64Cu-DOTATATE PET/CT SRI performed in two prospective studies. Tracer uptake was determined as the maximal standardized uptake value (SUVmax) for each patient. Kaplan-Meier analysis with log-rank was used to determine the predictive value of 64Cu-DOTATATE SUVmax for OS and PFS. Specificity, sensitivity and accuracy was calculated for prediction of outcome at 24 months after 64Cu-DOTATATE PET/CT. Results: A total of 128 patients with NEN were included and followed for a median of 73 (1-112) months. During follow-up, 112 experienced disease progression and 69 patients died. The optimal cutoff for 64Cu-DOTATATE SUVmax was 43.3 for prediction of PFS with a hazard ratio of 0.56 (95% CI: 0.38-0.84) for patients with SUVmax > 43.3. However, no significant cutoff was found for prediction of OS. In multiple Cox regression adjusted for age, sex, primary tumor site and tumor grade, the SUVmax cutoff hazard ratio was 0.50 (0.32-0.77) for PFS. The accuracy was moderate for predicting PFS (57%) at 24 months after 64Cu-DOTATATE PET/CT. Conclusion: In this first study to report the association of 64Cu-DOTATATE PET/CT and outcome in patients with NEN, tumor somatostatin receptor density visualized with 64Cu-DOTATATE PET/CT was prognostic for PFS but not OS. However, the accuracy of prediction of PFS at 24 months after 64Cu-DOTATATE PET/CT SRI was moderate limiting the valu