Advances in Radionuclide Therapies for Patients with Neuro-endocrine Tumors.

PURPOSE OF REVIEW: To provide insights into the role of peptide receptor radionuclide therapy (PRRT) in patients with advanced neuroendocrine tumors (NET) and an overview of possible strategies to combine PRRT with locoregional and systemic anticancer treatments. RECENT FINDINGS: Research on combining PRRT with other treatments encompasses a wide variety or treatments, both local (transarterial radioembolization) and systemic therapies, chemotherapy (i.e., capecitabine and temozolomide), targeted therapies (i.e., olaparib, everolimus, and sunitinib), and immunotherapies (e.g., nivolumab and pembrolizumab). Furthermore, PRRT shows promising first results as a treatment prior to surgery. There is great demand to enhance the efficacy of PRRT through combination with other anticancer treatments. While research in this area is currently limited, the field is rapidly evolving with numerous ongoing clinical trials aiming to address this need and explore novel therapeutic combinations.

[18F]mFBG PET-CT for detection and localisation of neuroblastoma: a prospective pilot study.

PURPOSE: Meta-[18F]fluorobenzylguanidine ([18F]mFBG) is a positron emission tomography (PET) radiotracer that allows for fast and high-resolution imaging of tumours expressing the norepinephrine transporter. This pilot study investigates the feasibility of [18F]mFBG PET-CT for imaging in neuroblastoma. METHODS: In a prospective, single-centre study, we recruited children with neuroblastoma, referred for meta-[123I]iodobenzylguanidine ([123I]mIBG) scanning, consisting of total body planar scintigraphy in combination with single-photon emission computed tomography-CT (SPECT-CT). Within two weeks of [123I]mIBG scanning, total body PET-CTs were performed at 1 h and 2 h after injection of [18F]mFBG (2 MBq/kg). Detected tumour localisations on scan pairs were compared. Soft tissue disease was quantified by number of lesions and skeletal disease by SIOPEN score. RESULTS: Twenty paired [123I]mIBG and [18F]mFBG scans were performed in 14 patients (median age 4.9 years, n = 13 stage 4 disease and n = 1 stage 4S). [18F]mFBG injection was well tolerated and no related adverse events occurred in any of the patients. Mean scan time for [18F]mFBG PET-CT (9.0 min, SD 1.9) was significantly shorter than for [123I]mIBG scanning (84.5 min, SD 10.5), p < 0.01. Most tumour localisations were detected on the 1 h versus 2 h post-injection [18F]mFBG PET-CT. Compared to [123I]mIBG scanning, [18F]mFBG PET-CT detected a higher, equal, and lower number of soft tissue lesions in 40%, 55%, and 5% of scan pairs, respectively, and a higher, equal, and lower SIOPEN score in 55%, 30%, and 15% of scan pairs, respectively. On average, two more soft tissue lesions and a 6-point higher SIOPEN score were detected per patient on [18F]mFBG PET-CT compared to [123I]mIBG scanning. CONCLUSION: Results of this study demonstrate feasibility of [18F]mFBG PET-CT for neuroblastoma imaging. More neuroblastoma localisations were detected on [18F]mFBG PET-CT compared to [123I]mIBG scanning. [18F]mFBG PET-CT shows promise for future staging and response assessment in neuroblastoma. TRIAL REGISTRATION: Dutch Trial Register NL8152.

Tolerability of concurrent external beam radiotherapy and [177Lu]Lu-PSMA-617 for node-positive prostate cancer in treatment naïve patients, phase I study (PROQURE-I trial).

BACKGROUND: Prostate cancer patients with locoregional lymph node disease at diagnosis (N1M0) still have a limited prognosis despite the improvements provided by aggressive curative intent multimodal locoregional external beam radiation therapy (EBRT) with systemic androgen deprivation therapy (ADT). Although some patients can be cured and the majority of patients have a long survival, the 5-year biochemical failure rate is currently 29-47%. [177Lu]Lu-PSMA-617 has shown impressive clinical and biochemical responses with low toxicity in salvage setting in metastatic castration-resistant prostate cancer. This study aims to explore the combination of standard EBRT and ADT complemented with a single administration of [177Lu]Lu-PSMA-617 in curative intent treatment for N1M0 prostate cancer. Hypothetically, this combined approach will enhance EBRT to better control macroscopic tumour localizations, and treat undetected microscopic disease locations inside and outside EBRT fields. METHODS: The PROQURE-I study is a multicenter prospective phase I study investigating standard of care treatment (7 weeks EBRT and 3 years ADT) complemented with one concurrent cycle (three, six, or nine GBq) of systemic [177Lu]Lu-PSMA-617 administered in week two of EBRT. A maximum of 18 patients with PSMA-positive N1M0 prostate cancer will be included. The tolerability of adding [177Lu]Lu-PSMA-617 will be evaluated using a Bayesian Optimal Interval (BOIN) dose-escalation design. The primary objective is to determine the maximum tolerated dose (MTD) of a single cycle [177Lu]Lu-PSMA-617 when given concurrent with EBRT + ADT, defined as the occurrence of Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 grade three or higher acute toxicity. Secondary objectives include: late toxicity at 6 months, dosimetric assessment, preliminary biochemical efficacy at 6 months, quality of life questionnaires, and pharmacokinetic modelling of [177Lu]Lu-PSMA-617. DISCUSSION: This is the first prospective study to combine EBRT and ADT with [177Lu]Lu-PSMA-617 in treatment naïve men with N1M0 prostate cancer, and thereby explores the novel application of [177Lu]Lu-PSMA-617 in curative intent treatment. It is considered likely that this study will confirm tolerability as the combined toxicity of these treatments is expected to be limited. Increased efficacy is considered likely since both individual treatments have proven high anti-tumour effect as mono-treatments. TRIAL REGISTRATION: ClinicalTrials, NCT05162573 . Registered 7 October 2021.

Dose finding study for unilobar radioembolization using holmium-166 microspheres to improve resectability in patients with HCC: the RALLY protocol.

BACKGROUND: High dose unilobar radioembolization (also termed 'radiation lobectomy')-the transarterial unilobar infusion of radioactive microspheres as a means of controlling tumour growth while concomitantly inducing future liver remnant hypertrophy-has recently gained interest as induction strategy for surgical resection. Prospective studies on the safety and efficacy of the unilobar radioembolization-surgery treatment algorithm are lacking. The RALLY study aims to assess the safety and toxicity profile of holmium-166 unilobar radioembolization in patients with hepatocellular carcinoma ineligible for surgery due to insufficiency of the future liver remnant. METHODS: The RALLY study is a multicenter, interventional, non-randomized, open-label, non-comparative safety study. Patients with hepatocellular carcinoma who are considered ineligible for surgery due to insufficiency of the future liver remnant (< 2.7%/min/m2 on hepatobiliary iminodiacetic acid scan will be included. A classical 3 + 3 dose escalation model will be used, enrolling three to six patients in each cohort. The primary objective is to determine the maximum tolerated treated non-tumourous liver-absorbed dose (cohorts of 50, 60, 70 and 80 Gy). Secondary objectives are to evaluate dose-response relationships, to establish the safety and feasibility of surgical resection following unilobar radioembolization, to assess quality of life, and to generate a biobank. DISCUSSION: This will be the first clinical study to assess the unilobar radioembolization-surgery treatment algorithm and may serve as a stepping stone towards its implementation in routine clinical practice. TRIAL REGISTRATION: Netherlands Trial Register NL8902 , registered on 2020-09-15.

Imaging in rhabdomyosarcoma: a patient journey.

Rhabdomyosarcoma, although rare, is the most frequent soft tissue sarcoma in children and adolescents. It can present as a mass at nearly any site in the body, with most common presentations in the head and neck, genitourinary tract and extremities. The optimal diagnostic approach and management of rhabdomyosarcoma require a multidisciplinary team with multimodal treatment, including chemotherapy and local therapy. Survival has improved over the last decades; however, further improvement in management is essential with current 5-year overall survival ranging from 35% to 100%, depending on disease and patient characteristics. In the full patient journey, from diagnosis, staging, management to follow-up after therapy, the paediatric radiologist and nuclear physician are essential members of the multidisciplinary team. Recently, guidelines of the European paediatric Soft tissue sarcoma Study Group, the Cooperative Weichteilsarkom Studiengruppe and the Oncology Task Force of the European Society of Paediatric Radiology (ESPR), in an ongoing collaboration with the International Soft-Tissue Sarcoma Database Consortium, provided guidance for high-quality imaging. In this educational paper, given as a lecture during the 2022 postgraduate ESPR course, the multi-disciplinary team of our national paediatric oncology centre presents the journey of two patients with rhabdomyosarcoma and discusses the impact on and considerations for the clinical (paediatric) radiologist and nuclear physician. The key learning points of the guidelines and their implementation in clinical practice are highlighted and up-to-date insights provided for all aspects from clinical suspicion of rhabdomyosarcoma and its differential diagnosis, to biopsy, staging, risk stratification, treatment response assessment and follow-up.

Dose-response relationship after yttrium-90-radioembolization with glass microspheres in patients with neuroendocrine tumor liver metastases.

BACKGROUND: In radioembolization, response is achieved through the irradiation and damaging of tumor DNA. For hepatic metastases of neuroendocrine tumors, a dose-response relationship has not been established yet. This study assesses whether increasing tumor-absorbed doses lead to increased response rates. METHODS: We included all patients who underwent yttrium-90 (90Y) glass microspheres radioembolization in our center if both pre- and post-treatment contrast-enhanced CT and post-injection PET/CT were available. Up to five hepatic tumors and the healthy hepatic tissue were delineated, and absorbed dose was quantified using post-injection PET/CT. Response was measured according to RECIST 1.1 on patient and tumor level. Linear mixed models were used to study the relationship between absorbed dose and response on tumor level. Logistic regression analysis was used on patient level to study dose-response and hepatic dose-toxicity relationships. RESULTS: A total of 128 tumors in 26 patients (31 procedures) were included in the response analysis. While correcting for confounding by tumor volume, a significant effect of response on dose was found (p = 0.0465). Geometric mean of absorbed dose for responding tumors was 170 Gy, for stable disease 101 Gy, and for progressive disease 67 Gy. No significant dose-toxicity relationship could be identified. CONCLUSION: In patients with neuroendocrine tumor liver metastases, treated with 90Y-radioembolization, a clear dose-response relationship was found. We propose to perform 90Y-radioembolization with an absolute minimum planned tumor-absorbed dose of 150 Gy.

A compact and mobile hybrid C-arm scanner for simultaneous nuclear and fluoroscopic image guidance.

PURPOSE: This study evaluates the performance of a mobile and compact hybrid C-arm scanner (referred to as IXSI) that is capable of simultaneous acquisition of 2D fluoroscopic and nuclear projections and 3D image reconstruction in the intervention room. RESULTS: The impact of slightly misaligning the IXSI modalities (in an off-focus geometry) was investigated for the reduction of the fluoroscopic and nuclear interference. The 2D and 3D nuclear image quality of IXSI was compared with a clinical SPECT/CT scanner by determining the spatial resolution and sensitivity of point sources and by performing a quantitative analysis of the reconstructed NEMA image quality phantom. The 2D and 3D fluoroscopic image of IXSI was compared with a clinical CBCT scanner by visualizing the Fluorad A+D image quality phantom and by visualizing a reconstructed liver nodule phantom. Finally, the feasibility of dynamic simultaneous nuclear and fluoroscopic imaging was demonstrated by injecting an anthropomorphic phantom with a mixture of iodinated contrast and 99mTc. CONCLUSION: Due to the divergent innovative hybrid design of IXSI, concessions were made to the nuclear and fluoroscopic image qualities. Nevertheless, IXSI realizes unique image guidance that may be beneficial for several types of procedures. KEY POINTS: • IXSI can perform time-resolved planar (2D) simultaneous fluoroscopic and nuclear imaging. • IXSI can perform SPECT/CBCT imaging (3D) inside the intervention room.

Use of an anti-reflux catheter to improve tumor targeting for holmium-166 radioembolization-a prospective, within-patient randomized study.

PURPOSE: The objective of this study was to investigate whether the use of an anti-reflux catheter improves tumor targeting for colorectal cancer patients with unresectable, chemorefractory liver metastases (mCRC) treated with holmium-166 (166Ho)-radioembolization. MATERIALS AND METHODS: In this perspective, within-patient randomized study, left and right hepatic perfusion territories were randomized between infusion with a Surefire® anti-reflux catheter or a standard microcatheter. The primary outcome was the difference in tumor to non-tumor (T/N) activity distribution. Secondary outcomes included the difference in infusion efficiency, absorbed doses, predictive value of 166Ho-scout, dose-response relation, and survival. RESULTS: Twenty-one patients were treated in this study (the intended number of patients was 25). The median T/N activity concentration ratio with the use of the anti-reflux catheter was 3.2 (range 0.9-8.7) versus 3.6 (range 0.8-13.3) with a standard microcatheter. There was no difference in infusion efficiency (0.04% vs. 0.03% residual activity for the standard microcatheter and anti-reflux catheter, respectively) (95%CI - 0.05-0.03). No influence of the anti-reflux catheter on the dose-response rate was found. Median overall survival was 7.8 months (95%CI 6-13). CONCLUSION: Using a Surefire® anti-reflux catheter did not result in a higher T/N activity concentration ratio in mCRC patients treated with 166Ho-radioembolization, nor did it result in improved secondary outcomes measures. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT02208804.

Additional holmium-166 radioembolisation after lutetium-177-dotatate in patients with neuroendocrine tumour liver metastases (HEPAR PLuS): a single-centre, single-arm, open-label, phase 2 study.

BACKGROUND: In patients with metastatic neuroendocrine neoplasms, the liver is the most commonly affected organ and a crucial factor for prognosis and survival. Peptide receptor radionuclide therapy can prolong progression-free survival in these patients. Additional treatment of liver disease might further improve outcomes. We aimed to investigate the safety and efficacy of additional holmium-166 (166Ho) radioembolisation after peptide receptor radionuclide therapy in patients with metastatic liver neuroendocrine neoplasms. METHODS: The Holmium Embolization Particles for Arterial Radiotherapy Plus 177Lu-Dotatate in Salvage Neuroendocrine Tumour Patients (HEPAR PLuS) study was a single-centre, phase 2 study done at the University Medical Center Utrecht (Utrecht, Netherlands). Patients, aged at least 18 years, with histologically proven grade 1 or 2 neuroendocrine neoplasms of all origins, an Eastern Cooperative Oncology Group performance status of 0-2, and three or more measurable liver metastases according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 criteria received 166Ho-radioembolisation within 20 weeks after four cycles of peptide receptor radionuclide therapy (lutetium-177-dotatate [177Lu-dotatate]). The primary endpoint was objective liver tumour response in the treated liver volume, defined as complete response (disappearance of all lesions) or partial response (≥30% decrease in the sum of the longest diameters of the target lesions, compared with baseline measurements), according to RECIST 1.1, analysed per protocol at 3 months. Safety was assessed in all patients who received treatment. This study is registered with ClinicalTrials.gov, NCT02067988. Recruitment is completed and long-term follow-up is ongoing. FINDINGS: From Oct 15, 2014, to Sept 12, 2018, 34 patients were assessed for eligibility. 31 patients received treatment and 30 (97%) patients were available for primary endpoint assessment and completed 6 months of follow-up. Three (9%) patients were excluded at screening and one (3%) patient was treated and died before the primary endpoint and was replaced. According to the per-protocol analysis 13 (43%; 95% CI 26-63) of 30 patients achieved an objective response in the treated volume. The most frequently reported Common Terminology Criteria for Adverse Events (CTCAE) grade 3-4 clinical and laboratory toxicities within 6 months included abdominal pain (three [10%] of 31 patients), increased γ-glutamyl transpeptidase (16 [54%]), and lymphocytopenia (seven [23%]). One (3%) fatal treatment-related serious adverse event occurred (radioembolisation-induced liver disease). Two (6%) patients had serious adverse events deemed to be unrelated to treatment (gastric ulcer and perforated cholecystitis). INTERPRETATION: 166Ho-radioembolisation, as an adjunct to peptide receptor radionuclide therapy in patients with neuroendocrine neoplasm liver metastases, is safe and efficacious. Radioembolisation can be considered in patients with bulky liver disease, including after peptide receptor radionuclide therapy. A future randomised, controlled study should investigate the added benefit of this treatment on progression-free survival. FUNDING: None.

Prospective Validation of Gallium-68 Prostate Specific Membrane Antigen-Positron Emission Tomography/Computerized Tomography for Primary Staging of Prostate Cancer.

PURPOSE: Prospective validation of 68Ga prostate specific membrane antigen positron emission tomography/computerized tomography is lacking in initial staging of prostate cancer. In this study we evaluated the diagnostic accuracy of 68Ga prostate specific membrane antigen positron emission tomography/computerized tomography for detecting lymph node metastasis in patients with intermediate-high risk prostate cancer. MATERIALS AND METHODS: Patients with newly diagnosed prostate cancer and negative bone scan findings at greater than 10% MSKCC (Memorial Sloan Kettering Cancer Center) risk for lymph node metastasis were prospectively included in study from October 2017 to October 2018. In candidates for extended pelvic lymph node dissection 68Ga prostate specific membrane antigen positron emission tomography/computerized tomography was performed prior to planned surgery. Scan results were evaluated in a second tumor board meeting to assess a potential change of management. Sensitivity, specificity, and positive and negative predictive value for detecting lymph node metastasis were calculated per patient and per resection template using histopathology as the reference. A positron emission tomography based change of management was also reported. RESULTS: A total of 103 patients were eligible for analysis and 97 extended pelvic lymph node dissections were performed. In 41 patients (42.3%) there was a total of 85 lymph node metastases. Positron emission tomography was positive in 17 patients, resulting in 41.5% patient based sensitivity (95% CI 26.7-57.8) for detecting lymph node metastasis. The patient based specificity rate was 90.9% (95% CI 79.3-96.6), and positive and negative predictive values were 77.3% (95% CI 54.2-91.3) and 67.6% (95% CI 55.6-77.7), respectively. A positron emission tomography based change of treatment was observed in 13 patients (12.6%). CONCLUSIONS: In patients with newly diagnosed prostate cancer at greater than 10% MSKCC risk for lymph node involvement 68Ga prostate specific membrane antigen positron emission tomography/computerized tomography detected lymph node metastasis with high specificity and moderate sensitivity. This led to a treatment change in 12.6% of patients.

The superior predictive value of 166Ho-scout compared with 99mTc-macroaggregated albumin prior to 166Ho-microspheres radioembolization in patients with liver metastases.

PURPOSE: As an alternative to technetium-99m-macroaggregated albumin (99mTc-MAA), a scout dose of holmium-166 (166Ho) microspheres can be used prior to 166Ho-radioembolization. The use of identical particles for pre-treatment and treatment procedures may improve the predictive value of pre-treatment analysis of distribution. The aim of this study was to analyze the agreement between 166Ho-scout and 166Ho-therapeutic dose in comparison with the agreement between 99mTc-MAA and 166Ho-therapeutic dose. METHODS: Two separate scout dose procedures were performed (99mTc-MAA and 166Ho-scout) before treatment in 53 patients. First, qualitative assessment was performed by two blinded nuclear medicine physicians who visually rated the agreement between the 99mTc-MAA, 166Ho-scout, and 166Ho-therapeutic dose SPECT-scans (i.e., all performed in the same patient) on a 5-point scale. Second, agreement was measured quantitatively by delineating lesions and normal liver on FDG-PET/CT. These volumes of interest (VOIs) were co-registered to the SPECT/CT images. The predicted absorbed doses (based on 99mTc-MAA and 166Ho-scout) were compared with the actual absorbed dose on post-treatment SPECT. RESULTS: A total of 23 procedures (71 lesions, 22 patients) were included for analysis. In the qualitative analysis, 166Ho-scout was superior with a median score of 4 vs. 2.5 for 99mTc-MAA (p < 0.001). The quantitative analysis showed significantly narrower 95%-limits of agreement for 166Ho-scout in comparison with 99mTc-MAA when evaluating lesion absorbed dose (- 90.3 and 105.3 Gy vs. - 164.1 and 197.0 Gy, respectively). Evaluation of normal liver absorbed dose did not show difference in agreement between both scout doses and 166Ho-therapeutic dose (- 2.9 and 5.5 Gy vs - 3.6 and 4.1 Gy for 99mTc-MAA and 166Ho-scout, respectively). CONCLUSIONS: In this study, 166Ho-scout was shown to have a superior predictive value for intrahepatic distribution in comparison with 99mTc-MAA.

Evaluation of the Safety and Feasibility of Same-Day Holmium-166 -Radioembolization Simulation and Treatment of Hepatic Metastases.

PURPOSE: To evaluate the safety and feasibility of same-day treatment, including the simulation procedure for assessment of intrahepatic and extrahepatic distribution of the microspheres, with holmium-166 (166Ho)-radioembolization. MATERIALS AND METHODS: This was a secondary analysis of patients included in the 4 prospective studies (HEPAR I, HEPAR II, HEPAR PLuS, and SIM) on 166Ho-radioembolization. The technical success rate of the same-day treatment protocol, defined as the number of patients who completed the same-day treatment, was measured. Total in-room time, duration of the scout procedure, time to imaging, and duration of the treatment procedure were recorded. Reasons for discontinuation or adjustment of treatment were identified. Adverse events that occurred during the treatment day were recorded. RESULTS: One hundred five of 120 scheduled patients completed the same-day treatment with 166Ho-radioembolization (success rate, 88%). After the simulation procedure, treatment was cancelled in 15 patients because of extrahepatic deposition (n = 8), suboptimal tumor targeting (n = 1), unanticipated vascular anatomy (n = 5), and dissection (n = 1). In another 14 patients, the treatment plan was adjusted. The median total procedure time (ie, simulation, imaging, and treatment) was 6:39 hours:minutes (range, 3:58-9:17 hours:minutes). Back pain was a major same-day treatment-related complaint (n = 28). CONCLUSION: 166Ho-radioembolization as a same-day treatment procedure is feasible in most selected patients, although treatment was adjusted in 12% of patients and cancelled in 12% of patients. This approach might be beneficial for a select patient population, such as patients needing a radiation segmentectomy.

Yttrium-90 Radioembolization in Intrahepatic Cholangiocarcinoma: A Multicenter Retrospective Analysis.

PURPOSE: To report outcomes of yttrium-90 (90Y) radioembolization in patients with unresectable intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS: Retrospective review was performed of 115 patients at 6 tertiary care centers; 92 were treated with resin microspheres (80%), 22 were treated with glass microspheres (19%), and 1 was treated with both. Postintervention outcomes were compared between groups with χ2 tests. Survival after diagnosis and after treatment was assessed by Kaplan-Meier method. RESULTS: Grade 3 laboratory toxicity was observed in 4 patients (4%); no difference in toxicity profile between resin and glass microspheres was observed (P = .350). Clinical toxicity per Society of Interventional Radiology criteria was noted in 29 patients (25%). Partial response per Response Evaluation Criteria In Solid Tumors 1.1 was noted in 25% of patients who underwent embolization with glass microspheres and 3% of patients who were treated with resin microspheres (P = .008). Median overall survival (OS) from first diagnosis was 29 months (95% confidence interval [CI], 21-37 mo) for all patients, and 1-, 3-, and 5-year OS rates were 85%, 31%, and 8%, respectively. Median OS after treatment was 11 months (95% CI, 8-13 mo), and 1- and 3-year OS rates were 44% and 4%, respectively. These estimates were not significantly different between resin and glass microspheres (P = .730 and P = .475, respectively). Five patients were able to undergo curative-intent resection after 90Y radioembolization (4%). CONCLUSIONS: This study provides observational data of treatment outcomes after 90Y radioembolization in patients with unresectable ICC.

Radioembolisation with 90Y microspheres for neuroendocrine liver metastases: an institutional case series, systematic review and meta-analysis.

BACKGROUND: Neuroendocrine liver metastases are clinically challenging due to their frequent disseminated distribution. This study aims to present a British experience with an emerging modality, radioembolisation with yttrium-90 labelled microspheres, and embed this within a meta-analysis of response and survival outcomes. METHODS: A retrospective case series of patients treated with SIR-Spheres (radiolabelled resin microspheres) was performed. Results were included in a systematic review and meta-analysis of published results with glass or resin microspheres. Objective response rate (ORR) was defined as complete or partial response. Disease control rate (DCR) was defined as complete/partial response or stable disease. RESULTS: Twenty-four patients were identified. ORR and DCR in the institutional series was 14/24 and 21/24 at 3 months. Overall survival and progression-free survival at 3-years was 77.6% and 50.4%, respectively. There were no grade 3/4 toxicities post-procedure. A fixed-effects pooled estimate of ORR of 51% (95% CI: 47%-54%) was identified from meta-analysis of 27 studies. The fixed-effects weighted average DCR was 88% (95% CI: 85%-90%, 27 studies). CONCLUSION: Current data demonstrate evidence of the clinical effectiveness and safety of radioembolisation for neuroendocrine liver metastases. Prospective randomised studies to compare radioembolisation with other liver directed treatment modalities are needed.

Safety analysis of holmium-166 microsphere scout dose imaging during radioembolisation work-up: A cohort study.

OBJECTIVE: Radioembolisation is generally preceded by a scout dose of technetium-99m-macroaggregated albumin to estimate extrahepatic shunting of activity. Holmium-166 microspheres can be used as a scout dose (±250 MBq) and as a therapeutic dose. The general toxicity of a holmium-166 scout dose (166Ho-SD) and safety concerns of an accidental extrahepatic deposition of 166Ho-SD were investigated. METHODS: All patients who received a 166Ho-SD in our institute were reviewed for general toxicity and extrahepatic depositions. The absorbed dose in extrahepatic tissue was calculated on SPECT/CT and correlated to clinical toxicities. RESULTS: In total, 82 patients were included. No relevant clinical toxicity occurred. Six patients had an extrahepatic deposition of 166Ho-SD (median administered activity 270 MBq). The extrahepatic depositions (median activity 3.7 MBq) were located in the duodenum (3x), gastric fundus, falciform ligament and the lesser curvature of the stomach, and were deposited in a median volume of 15.3 ml, which resulted in an estimated median absorbed dose of 3.6 Gy (range 0.3-13.8 Gy). No adverse events related to the extrahepatic deposition of the 166Ho-SD occurred after a median follow-up of 4 months (range 1-12 months). CONCLUSION: These results support the safety of 250 MBq 166Ho-SD in a clinical setting. KEY POINTS: • A holmium-166 scout dose is safe in a clinical setting. • Holmium-166 scout dose is a safe alternative for 99m Tc-MAA for radioembolisation work-up. • Holmium-166 scout dose potentially has several benefits over 99m Tc-MAA for radioembolisation work-up.

Additional hepatic 166Ho-radioembolization in patients with neuroendocrine tumours treated with 177Lu-DOTATATE; a single center, interventional, non-randomized, non-comparative, open label, phase II study (HEPAR PLUS trial).

BACKGROUND: Neuroendocrine tumours (NET) consist of a heterogeneous group of neoplasms with various organs of origin. At diagnosis 21% of the patients with a Grade 1 NET and 30% with a Grade 2 NET have distant metastases. Treatment with peptide receptor radionuclide therapy (PRRT) shows a high objective response rate and long median survival after treatment. However, complete remission is almost never achieved. The liver is the most commonly affected organ in metastatic disease and is the most incriminating factor for patient survival. Additional treatment of liver disease after PRRT may improve outcome in NET patients. Radioembolization is an established therapy for liver metastasis. To investigate this hypothesis, a phase 2 study was initiated to assess effectiveness and toxicity of holmium-166 radioembolization (166Ho-RE) after PRRT with lutetium-177 (177Lu)-DOTATATE. METHODS: The HEPAR PLUS trial ("Holmium Embolization Particles for Arterial Radiotherapy Plus 177 Lu-DOTATATE in Salvage NET patients") is a single centre, interventional, non-randomized, non-comparative, open label study. In this phase 2 study 30-48 patients with > 3 measurable liver metastases according to RECIST 1.1 will receive additional 166Ho-RE within 20 weeks after the 4th and last cycle of PRRT with 7.4 GBq 177Lu-DOTATATE. Primary objectives are to assess tumour response, complete and partial response according to RECIST 1.1, and toxicity, based on CTCAE v4.03, 3 months after 166Ho-RE. Secondary endpoints include biochemical response, quality of life, biodistribution and dosimetry. DISCUSSION: This is the first prospective study to combine PRRT with 177Lu-DOTATATE and additional 166Ho-RE in metastatic NET. A radiation boost on intrahepatic disease using 166Ho-RE may lead to an improved response rate without significant additional side-effects. TRIAL REGISTRATION: Clinicaltrials.gov NCT02067988 , 13 February 2014. Protocol version: 6, 30 november 2016.