Holmium-166 radioembolisation in patients with unresectable, chemorefractory liver metastases (HEPAR trial): a phase 1, dose-escalation study

Smits, Maarten L. J.; Nijsen, J. Frank W.; Bosch, Maurice A.A.J. van den; Lam, Marnix G. E. H.; Vente, M. A. D.; Mali, Wptm; Schip, Alfred D. van het; Zonnenberg, Bernard A.

doi:10.1016/s1470-2045(12)70334-0

Cited by 155 publications

(122 citation statements)

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“…Treatment with 166 Ho radioembolization can be preceded by a different scout dose used during the pretreatment session (7). This scout dose consists of a small batch of microspheres (250 MBq), identical to the treatment 166 Ho microspheres.…”

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confidence: 99%

Safety of a Scout Dose Preceding Hepatic Radioembolization with ¹⁶⁶Ho Microspheres

et al. 2015

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Before 166 Ho radioembolization, a small batch of the same type of microspheres is administered as a scout dose instead of the conventional 99m Tc-macroaggregated albumin ( 99m Tc-MAA). The 166 Ho scout dose provides a more accurate and precise lung shunt assessment. However, in contrast to 99m Tc-MAA, an unintended extrahepatic deposition of this β-emitting scout dose could inflict radiation damage, the extent of which we aimed to quantify in this study. Methods: All patients eligible for radioembolization in our institute between January 2011 and March 2014 were reviewed. Of the extrahepatic depositions of 99m Tc-MAA on SPECT, the amount and volume were measured. These were used to calculate the theoretic absorbed dose in the case a 166 Ho scout dose had been used. The extrahepatic activity was measured as the sum of all voxels of the deposition. Volumes were measured using a threshold technique including all voxels from the maximum voxel intensity up to a certain percentage. The threshold needed to obtain the true volume was studied in a phantom study. Results: In the phantom study, a threshold of 40% was found to overestimate the volume, with the consequence of underestimating the absorbed dose. Of 160 patients, 32 patients (34 cases) of extrahepatic deposition were identified. The depositions contained a median of 1.3% (range, 0.1%-19.5%) of the administered activity in a median volume of 6.8 mL (range, 1.1-42 mL). The use of a scout dose of 250 MBq of 166 Ho microspheres in these cases would theoretically have resulted in a median absorbed dose of 6.0 Gy (range, 0.9-374 Gy). The dose exceeded a limit of 49 Gy (reported in 2013) in 2 of 34 cases (5.9%; 95% confidence interval, 0.7%-20.1%) or 2 of 160 (1.3%; 95% confidence interval, 0.1%-4.7%) of all patients. In these 2 patients with a large absorbed dose (112 and 374 Gy), the culprit vessel was identified in 1 case. Conclusion: Extrahepatic deposition of a 166 Ho scout dose seems to be theoretically safe in most patients. Its safety in clinical practice is being evaluated in ongoing clinical trials. Radi oembolization is a minimally invasive treatment for hepatic malignancies. Millions of radioactive microspheres are injected in the hepatic artery to radiate and embolize malignancies (1). Deposition of microspheres in gastrointestinal organs can result in ulceration or inflammation of tissue by a combination of embolization and radiation damage (2-4). To prevent this, vessels leading to gastrointestinal organs may be coil-embolized in patients scheduled for radioembolization treatment, during a pretreatment session using contrastenhanced images (i.e., digital subtraction angiography complemented by C-arm CT) to identify the culprit vessel (5). 99m Tc-macroaggregated albumin ( 99m Tc-MAA) is administered in this pretreatment session to simulate intrahepatic treatment biodistribution and to assess lung shunting and the possibility of extrahepatic deposition of the microspheres (6). This procedure is safe because 99m Tc-MAA emits 140-keV g photons (detecta...

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confidence: 99%

Safety of a Scout Dose Preceding Hepatic Radioembolization with ¹⁶⁶Ho Microspheres

et al. 2015

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“…As 166 Ho-PLLA microspheres are paramagnetic, they can also be observed on MR imaging via the microsphere induced change in relaxation rates per mg/ml from a baseline scan acquired before therapy [137]. Activity quantitation was achieved using the specific activity of the spheres, and a good correlation (R 2 =0.91) was shown between MR and SPECT calculated dosimetry to liver segments determined from a convolution with a DVK [138].…”

Section: Other Treatment Isotopesmentioning

confidence: 99%

“…The results of the HEPAR trial (15 patients) [137], show the maximum tolerated radiation dose to the whole liver for the cohort to be 60 Gy (toxicity occurred in 2 of 3 patients receiving 80 Gy), and proposed this as an endpoint for a phase 2 trial.…”

Section: Other Treatment Isotopesmentioning

confidence: 99%

A review of 3D image-based dosimetry, technical considerations and emerging perspectives in 90Y microsphere therapy

Doherty¹

2015

J Diagn Imaging Ther

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Yttrium-90 radioembolization ( 90 Y-RE) is a well-established therapy for the treatment of hepatocellular carcinoma (HCC) and also of metastatic liver deposits from other malignancies. Nuclear Medicine and Cath Lab diagnostic imaging takes a pivotal role in the success of the treatment, and in order to fully exploit the efficacy of the technique and provide reliable quantitative dosimetry that are related to clinical endpoints in the era of personalized medicine, technical challenges in imaging need to be overcome. In this paper, the extensive literature of current 90 Y-RE techniques and challenges facing it in terms of quantification and dosimetry are reviewed, with a focus on the current generation of 3D dosimetry techniques. Finally, new emerging techniques are reviewed which seek to overcome these challenges, such as highresolution imaging, novel surgical procedures and the use of other radiopharmaceuticals for therapy and pre-therapeutic planning.

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“…[48,49,50] Furthermore, our institute has developed holmium-166 ( 166 Ho) poly (Llactic acid) microspheres to allow for quantitative imaging of microsphere distribution. [51,52] In addition to high-energy beta radiation, 166 Ho also emits gamma-radiation and thereby facilitates imaging by gamma scintigraphy and SPECT. [53,54] Moreover, the distribution of 166 Ho-microspheres can be visualized by MRI due to its highly paramagnetic properties.…”

Section: Author (Year)mentioning

confidence: 99%

The effect of intra-arterial angiotensin II on the hepatic tumor to non-tumor blood flow ratio for radioembolization: a systematic review

Hoven

Smits

Rosenbaum

et al. 2014

Journal of Vascular and Interventional Radiology

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Purpose: Treatment efficacy of intra-arterial radioembolization for liver tumors depends on the selective targeting of tumorous tissue. Recent investigations have demonstrated that tumors may receive inadequate doses of radioactivity after radioembolization, due to unfavorable tumor to non-tumor (T/N) uptake ratios of radioactive microspheres. Hepatic arterial infusion of the vasoconstrictor angiotensin II (AT-II) is reported to increase the T/N blood flow ratio. The purpose of this systematic review was to provide a comprehensive overview of the effect of hepatic arterial AT-II on T/N blood flow ratio in patients with hepatic malignancies, and determine its clinical value for radioembolization.Methods: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and MetaAnalyses guidelines. A structured search was performed in the PubMed, EMBASE and Cochrane databases. Only studies that presented data on T/N ratios before and after infusion of AT-II into the hepatic artery, in human patients with hepatic malignancies, were selected. Median T/N ratios before, during and after AT-II infusion, and the median T/N ratio improvement factor were extracted from the selected articles. All data on systemic blood pressure measurements and clinical symptoms were also extracted. Results:The search identified 524 titles of which 5 studies, including a total of 71 patients were considered relevant. Median T/N ratios before infusion of AT-II ranged from 0.4 to 3.4. All studies observed a substantial improvement of the T/N ratio after AT-II infusion, with median improvement factors ranging from 1.8 to 3.1. A transitory increase of systemic blood pressure was observed during AT-II infusion.Conclusions: Infusion of AT-II into the hepatic artery leads to an increase of the tumor to non-tumor blood flow ratio, as measured by T/N uptake ratios. Clinical trials are warranted to assess safety aspects, optimal administration strategy and impact on treatment efficacy during radioembolization.

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Holmium-166 radioembolisation in patients with unresectable, chemorefractory liver metastases (HEPAR trial): a phase 1, dose-escalation study

Cited by 155 publications

References 33 publications

Safety of a Scout Dose Preceding Hepatic Radioembolization with ¹⁶⁶Ho Microspheres

Safety of a Scout Dose Preceding Hepatic Radioembolization with ¹⁶⁶Ho Microspheres

A review of 3D image-based dosimetry, technical considerations and emerging perspectives in 90Y microsphere therapy

The effect of intra-arterial angiotensin II on the hepatic tumor to non-tumor blood flow ratio for radioembolization: a systematic review

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Holmium-166 radioembolisation in patients with unresectable, chemorefractory liver metastases (HEPAR trial): a phase 1, dose-escalation study

Cited by 155 publications

References 33 publications

Safety of a Scout Dose Preceding Hepatic Radioembolization with 166Ho Microspheres

Safety of a Scout Dose Preceding Hepatic Radioembolization with 166Ho Microspheres

A review of 3D image-based dosimetry, technical considerations and emerging perspectives in 90Y microsphere therapy

The effect of intra-arterial angiotensin II on the hepatic tumor to non-tumor blood flow ratio for radioembolization: a systematic review

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Safety of a Scout Dose Preceding Hepatic Radioembolization with ¹⁶⁶Ho Microspheres

Safety of a Scout Dose Preceding Hepatic Radioembolization with ¹⁶⁶Ho Microspheres