The Current Status and Future Potential of Theranostics to Diagnose and Treat Childhood Cancer

In theranostics (i.e., therapy and diagnostics) radiopharmaceuticals are used for both therapeutic and diagnostic purposes by targeting one specific tumor receptor. Biologically relevant compounds, e.g., receptor ligands or drugs, are labeled with radionuclides to form radiopharmaceuticals. The possible applications are multifold: visualization of biological processes or tumor biology in vivo, diagnosis and tumor staging, therapy planning, and treatment of specific tumors. Theranostics research is multidisciplinary and allows for the rapid translation of potential tumor targets from preclinical research to "first-in-man" clinical studies. In the last decade, the use of theranostics has seen an unprecedented value for adult cancer patients. Several radiopharmaceuticals are routinely used in clinical practice (e.g., [68Ga/177Lu]DOTATATE), and dozens are under (pre)clinical development. In contrast to these successes in adult oncology, theranostics have scarcely been developed to diagnose and treat pediatric cancers. To date, [123/131I]meta-iodobenzylguanidine ([123/131I]mIBG) is the only available and approved theranostic in pediatric oncology. mIBG targets the norepinephrine transporter, expressed by neuroblastoma tumors. For most pediatric tumors, including neuroblastoma, there is a clear need for novel and improved radiopharmaceuticals for imaging and therapy. The strategy of theranostics for pediatric oncology can be divided in (1) the improvement of existing theranostics, (2) the translation of theranostics developed in adult oncology for pediatric purposes, and (3) the development of novel theranostics for pediatric tumor-specific targets. Here, we describe the recent advances in theranostics development in pediatric oncology and shed a light on how this methodology can affect diagnosis and provide additional treatment options for these patients

Combined use of zoledronic acid and 153Sm-EDTMP in hormone-refractory prostate cancer patients with bone metastases

Purpose: 153Sm-ethylenediaminetetramethylenephosphonic acid (EDTMP; Quadramet®) is indicated for the treatment of painful bone metastases, whereas zoledronic acid (Zometa®) is indicated for the prevention of skeletal complications. Because of the different therapeutic effects, combining the treatments may be beneficial. Both, however, accumulate in areas with increased osteoblastic activity. Possible drug interactions were investigated. Methods: Patients with hormone-refractory prostate cancer were treated with 18.5 MBq/kg 153Sm-EDTMP in weeks 1 and 3 and with 37 MBq/kg in week 15. Treatment with 4 mg zoledronic acid began in week 3 and continued every 4 weeks through week 23. In weeks 3 and 15, zoledronic acid was administered 2 days before 153Sm-EDTMP treatment. Urine was collected 48 h after injection of 153Sm-EDTMP, and whole-body images were obtained 6, 24 and 48 h post-injection. The effect of zoledronic acid on total bone uptake of 153Sm-EDTMP was measured indirectly by the cumulative activity excreted in the urine in weeks 1, 3 and 15. Biodistribution, safety, tolerability and effect on prostate-specific antigen level were also studied. Results: The urinary excretion in week 3 divided by the urinary excretion in week 1 (baseline) times 100% was mean 98.4±11.6% (median 96.2%). From week 1 to 15, after four zoledronic acid treatments, the mean ratio was 101.9±10.7% (median 101.8%). Bioequivalence could be concluded by using a two-sample t test for both perprotocol (n=13) and full-analysis sets (n=18). Toxicity was comparable to of monotherapy with 153Sm-EDTMP. Conclusion: Zoledronic acid treatment does not influence 153Sm-EDTMP skeletal uptake. Combined treatment is feasible and safe

Interventional respiratory motion compensation by simultaneous fluoroscopic and nuclear imaging: a phantom study

Purpose A compact and mobile hybrid c-arm scanner, capable of simultaneously acquiring nuclear and fluoroscopic projections and SPECT/CBCT, was developed to aid fluoroscopy-guided interventional procedures involving the administration of radionuclides (e.g. hepatic radioembolization). However, as in conventional SPECT/CT, the acquired nuclear images may be deteriorated by patient respiratory motion. We propose to perform compensation for respiratory motion by extracting the motion signal from fluoroscopic projections so that the nuclear counts can be gated into motion bins. The purpose of this study is to quantify the performance of this motion compensation technique with phantom experiments. Methods Anthropomorphic phantom configurations that are representative of distributions obtained during the pre-treatment procedure of hepatic radioembolization were placed on a stage that translated with three different motion patterns. Fluoroscopic projections and nuclear counts were simultaneously acquired under planar and SPECT/CBCT imaging. The planar projections were visually assessed. The SPECT reconstructions were visually assessed and quantitatively assessed by calculating the activity recovery of the spherical inserts in the phantom. Results The planar nuclear projections of the translating anthropomorphic phantom were blurry when no motion compensation was applied. With motion compensation, the nuclear projections became representative of the stationary phantom nuclear projection. Similar behavior was observed for the visual quality of SPECT reconstructions. The mean error of the activity recovery in the uncompensated SPECT reconstructions was 15.8±0.9% for stable motion, 11.9±0.9% for small variations, and 11.0±0.9% for large variations. When applying motion compensation, the mean error decreased to 1.8±1.6% for stable motion, 2.2±1.5% for small variations, and 5.2±2.5% for large variations. Conclusion A compact and mobile hybrid c-arm scanner, capable of simultaneously acquiring nuclear and fluoroscopic projections, can perform compensation for respiratory motion. Such motion compensation results in sharper planar nuclear projections and increases the quantitative accuracy of the SPECT reconstructions

Biologicals as theranostic vehicles in paediatric oncology

Biologicals, such as antibodies or antibody-fragments e.g. nanobodies, have changed the landscape of cancer therapy and can be used in combination with traditional cancer treatments. They have been demonstrated to be excellent vehicles for molecular imaging. Several biologicals for nuclear imaging of adult cancer may be used in combination with (nuclear) therapy. Though it's great potential, molecular imaging using biologicals is rarely applied in paediatric oncology. This paper describes the current status of biologicals as radiopharmaceuticals for childhood cancer. Furthermore, the importance and potential for developing additional biological theranostics as opportunity to image and treat childhood cancer is discussed

Comparison of the Biograph Vision and Biograph mCT for quantitative Y-90 PET/CT imaging for radioembolisation

BACKGROUND: New digital PET scanners with improved time of flight timing and extended axial field of view such as the Siemens Biograph Vision have come on the market and are expected to replace current generation photomultiplier tube (PMT)-based systems such as the Siemens Biograph mCT. These replacements warrant a direct comparison between the systems, so that a smooth transition in clinical practice and research is guaranteed, especially when quantitative values are used for dosimetry-based treatment guidance. The new generation digital PET scanners offer increased sensitivity. This could particularly benefit 90Y imaging, which tends to be very noisy owing to the small positron branching ratio and high random fraction of 90Y. This study aims to determine the ideal reconstruction settings for the digital Vision for quantitative 90Y imaging and to evaluate the image quality and quantification of the digital Vision in comparison with its predecessor, the PMT-based mCT, for 90Y imaging in radioembolisation procedures. METHODS: The NEMA image quality phantom was scanned to determine the ideal reconstruction settings for the Vision. In addition, an anthropomorphic phantom was scanned with both the Vision and the mCT, mimicking a radioembolisation patient with lung, liver, tumour, and extrahepatic deposition inserts. Image quantification of the anthropomorphic phantom was assessed by the lung shunt fraction, the tumour to non-tumour ratio, the parenchymal dose, and the contrast to noise ratio of extrahepatic depositions. RESULTS: For the Vision, a reconstruction with 3 iterations, 5 subsets, and no post-reconstruction filter is recommended for quantitative 90Y imaging, based on the convergence of the recovery coefficient. Comparing both systems showed that the noise level of the Vision is significantly lower than that of the mCT (background variability of 14% for the Vision and 25% for the mCT at 2.5·103 MBq for the 37 mm sphere size). For quantitative 90Y measures, such as needed in radioembolisation, both systems perform similarly. CONCLUSIONS: We recommend to reconstruct 90Y images acquired on the Vision with 3 iterations, 5 subsets, and no post-reconstruction filter for quantitative imaging. The Vision provides a reduced noise level, but similar quantitative accuracy as compared with its predecessor the mCT

Automatic healthy liver segmentation for holmium-166 radioembolization dosimetry

BACKGROUND: For safe and effective holmium-166 ( 166Ho) liver radioembolization, dosimetry is crucial and requires accurate healthy liver definition. The current clinical standard relies on manual segmentation and registration of a separately acquired contrast enhanced CT (CECT), a prone-to-error and time-consuming task. An alternative is offered by simultaneous imaging of 166Ho and technetium-99m stannous-phytate accumulating in healthy liver cells ( 166Ho- 99mTc dual-isotope protocol). This study compares healthy liver segmentation performed with an automatic method using 99mTc images derived from a 166Ho- 99mTc dual-isotope acquisition to the manual segmentation, focusing on healthy liver dosimetry and corresponding hepatotoxicity. Data from the prospective HEPAR PLuS study were used. Automatic healthy liver segmentation was obtained by thresholding the 99mTc image (no registration step required). Manual segmentation was performed on CECT and then manually registered to the SPECT/CT and subsequently to the corresponding 166Ho SPECT to compute absorbed dose in healthy liver. RESULTS: Thirty-one patients (66 procedures) were assessed. Manual segmentation and registration took a median of 30 min per patient, while automatic segmentation was instantaneous. Mean ± standard deviation of healthy liver absorbed dose was 18 ± 7 Gy and 20 ± 8 Gy for manual and automatic segmentations, respectively. Mean difference ± coefficient of reproducibility between healthy liver absorbed doses using the automatic versus manual segmentation was 2 ± 6 Gy. No correlation was found between mean absorbed dose in the healthy liver and hepatotoxicity. CONCLUSIONS: 166Ho- 99mTc dual-isotope protocol can automatically segment the healthy liver without hampering the 166Ho dosimetry assessment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02067988. Registered 20 February 2014. https://clinicaltrials.gov/ct2/show/NCT02067988

Intra-arterial versus standard intravenous administration of lutetium-177-DOTA-octreotate in patients with NET liver metastases: study protocol for a multicenter, randomized controlled trial (LUTIA trial)

BACKGROUND: Lutetium-177-DOTA-octreotate (177Lu-DOTATATE) significantly increases survival and response rates in patients with grade I and grade II neuroendocrine tumors (NETs). However, survival and response rates are significantly lower in patients with bulky liver metastases. Increasing the tumor-absorbed dose in liver metastases may improve response to 177Lu-DOTATATE. The LUTIA (Lutetium Intra-Arterial) study aims to increase the tumor-absorbed dose in liver metastases by intra-arterial (IA) administration of 177Lu-DOTATATE, compared to conventional intravenous (IV) administration. METHODS: A multicenter, within-patient randomized controlled trial (RCT) in 26 patients with progressive, liver-dominant, unresectable grade I or grade II NET will be conducted. Patients with bilobar bulky disease will be randomly allocated to receive IA treatment into either the left or the right hepatic artery. Using this approach, one liver lobe will be treated intra-arterially (first-pass effect), while the contralateral lobe will receive an intravenous treatment as a second-pass effect. The primary endpoint of this study is the difference in tumor-to-non-tumor ratio of 177Lu-DOTATATE uptake between the two liver lobes on post-treatment SPECT/CT (IA versus IV). Secondary endpoints include absorbed dose in both liver lobes, tumor response, dose-response relationship, toxicity, uptake in extrahepatic lesions, and renal uptake. DISCUSSION: This multicenter, within-patient RCT will investigate whether IA administration of 177Lu-DOTATATE results in a higher activity concentration in liver metastases compared to IV administration. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03590119. Registered on 17 July 2018

Feasibility of imaging 90Y microspheres at diagnostic activity levels for hepatic radioembolization treatment planning

PURPOSE: Prior to 90 Y hepatic radioembolization, a dosage of 99m Tc-macroaggregated albumin ( 99m Tc-MAA) is administered to simulate the distribution of the 90 Y-loaded microspheres. This pretreatment procedure enables lung shunt estimation, detection of potential extrahepatic depositions, and estimation of the intrahepatic dose distribution. However, the predictive accuracy of the MAA particle distribution is often limited. Ideally, 90 Y microspheres would also be used for the pretreatment procedure. Based on previous research, the pretreatment activity should be limited to the estimated safety threshold of 100 MBq, making imaging challenging. The purpose of this study was to evaluate the quality of intra- and extrahepatic imaging of 90 Y-based pretreatment positron emission tomography/computed tomography (PET/CT) and quantitative single photon emission computed tomography (SPECT)/CT scans, by means of phantom experiments and a patient study. METHODS: An anthropomorphic phantom with three extrahepatic depositions was filled with 90 Y chloride to simulate a lung shunt fraction (LSF) of 5.3% and a tumor to nontumor ratio (T/N) of 7.9. PET /CT (Siemens Biograph mCT) and Bremsstrahlung SPECT/CT (Siemens Symbia T16) images were acquired at activities ranging from 1999 MBq down to 24 MBq, representing post- and pretreatment activities. PET/CT images were reconstructed with the clinical protocol and SPECT/CT images were reconstructed with a quantitative Monte Carlo-based reconstruction protocol. Estimated LSF, T/N, contrast to noise ratio of all extrahepatic depositions, and liver parenchymal and tumor dose were compared with the phantom ground truth. A clinically reconstructed SPECT/CT of 150 MBq 99m Tc represented the current clinical standard. In addition, a 90 Y pretreatment scan was simulated for a patient by acquiring posttreatment PET/CT and SPECT/CT data with shortened acquisition times. RESULTS: At an activity of 100 MBq 90 Y, PET/CT overestimated LSF [+10 percentage point (pp)], underestimated liver parenchymal dose (-3 Gy/GBq), and could not detect the extrahepatic depositions. SPECT/CT more accurately estimated LSF (-0.7 pp), parenchymal dose (-0.3 Gy/GBq) and could detect all three extrahepatic depositions. 99m Tc SPECT/CT showed similar accuracy as 90 Y SPECT/CT (LSF: +0.2 pp, parenchymal dose: +0.4 Gy/GBq, all extrahepatic depositions visible), although the noise level in the liver compartment was considerably lower for 99m Tc SPECT/CT compared to 90 Y SPECT/CT. The patient's SPECT/CT simulating a pretreatment 90 Y procedure accurately represented the posttreatment 90 Y microsphere distribution. CONCLUSIONS: Quantitative SPECT/CT of 100 MBq 90 Y could accurately estimate LSF, T/N, parenchymal and tumor dose, and visualize extrahepatic depositions

Mode of progression after radioembolization in patients with colorectal cancer liver metastases

BACKGROUND: Radioembolization is an established treatment modality in colorectal cancer patients with liver-dominant disease in a salvage setting. Selection of patients who will benefit most is of vital importance. The aim of this study was to assess response (and mode of progression) at 3 months after radioembolization and the impact of baseline characteristics. METHODS: Three months after radioembolization with either yttrium-90 resin/glass or holmium-166, anatomic response, according to RECIST 1.1, was evaluated in 90 patients. Correlations between baseline characteristics and efficacy were evaluated. For more detailed analysis of progressive disease as a dismal clinical entity, distinction was made between intra- and extrahepatic progression, and between progression of existing metastases and new metastases. RESULTS: Forty-two patients (47%) had extrahepatic disease (up to five ≥ 1 cm lung nodules, and ≤ 2 cm lymph nodes) at baseline. No patients showed complete response, 5 (5.5%) patients had partial response, 16 (17.8%) had stable disease, and 69 (76.7%) had progressive disease. Most progressive patients (67/69; 97%) had new metastases (intra-hepatic N = 11, extrahepatic N = 32; or both N = 24). Significantly fewer patients had progressive disease in the group of patients presenting without extrahepatic metastases at baseline (63% versus 93%; p = 0.0016). Median overall survival in patients with extrahepatic disease was 6.5 months, versus 10 months in patients without extrahepatic disease at baseline (hazard ratio 1.79, 95%CI 1.24-2.57). CONCLUSIONS: Response at 3-month follow-up and survival were heavily influenced by new metastases. Patients with extrahepatic disease at baseline had a worse outcome compared to patients without

Normal imaging findings after aortic valve implantation on 18F-Fluorodeoxyglucose positron emission tomography with computed tomography

Background: To determine the normal perivalvular 18F-Fluorodeoxyglucose (18F-FDG) uptake on positron emission tomography (PET) with computed tomography (CT) within one year after aortic prosthetic heart valve (PHV) implantation. Methods: Patients with uncomplicated aortic PHV implantation were prospectively included and underwent 18F-FDG PET/CT at either 5 (± 1) weeks (group 1), 12 (± 2) weeks (group 2) or 52 (± 8) weeks (group 3) after implantation. 18F-FDG uptake around the PHV was scored qualitatively (none/low/intermediate/high) and quantitatively by measuring the maximum Standardized Uptake Value (SUVmax) and target to background ratio (SUVratio). Results: In total, 37 patients (group 1: n = 12, group 2: n = 12, group 3: n = 13) (mean age 66 ± 8 years) were prospectively included. Perivalvular 18F-FDG uptake was low (8/12 (67%)) and intermediate (4/12 (33%)) in group 1, low (7/12 (58%)) and intermediate (5/12 (42%)) in group 2, and low (8/13 (62%)) and intermediate (5/13 (38%)) in group 3 (P = 0.91). SUVmax was 4.1 ± 0.7, 4.6 ± 0.9 and 3.8 ± 0.7 (mean ± SD, P = 0.08), and SUVratio was 2.0 [1.9 to 2.2], 2.0 [1.8 to 2.6], and 1.9 [1.7 to 2.0] (median [IQR], P = 0.81) for groups 1, 2, and 3, respectively. Conclusion: Non-infected aortic PHV have similar low to intermediate perivalvular 18F-FDG uptake with similar SUVmax and SUVratio at 5, 12, and 52 weeks after implantation