www.thelancet.com/oncology Vol 13 October 2012 1025 Articles Lancet Oncol 2012; 13: 1025–34 Published Online August 22, 2012 http://dx.doi.org/10.1016/ S1470-2045(12)70334-0 This online publication has been corrected. The corrected version first appeared at thelancet.com/oncology on October 29, 2012 See Comment page 965 Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht, Netherlands (M L J Smits MD, J F W Nijsen PhD, Prof M A A J van den Bosch PhD, M G E H Lam PhD, M A D Vente PhD, Prof W P T M Mali PhD, A D van het Schip PhD, B A Zonnenberg PhD) Correspondence to: Dr Bernard A Zonnenberg, Department of Radiology and Nuclear Medicine, Room E.01.132, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, Netherlands b.zonnenberg@umcutrecht.nl Holmium-166 radioembolisation in patients with unresectable, chemorefractory liver metastases (HEPAR trial): a phase 1, dose-escalation study Maarten L J Smits, Johannes F W Nijsen, Maurice A A J van den Bosch, Marnix G E H Lam, Maarten A D Vente, Willem P T M Mali, Alfred D van het Schip, Bernard A Zonnenberg Summary Background The efficacy of radioembolisation for the treatment of liver tumours depends on the selective distribution of radioactive microspheres to tumorous tissue. The distribution of holmium-166 (¹⁶⁶Ho) poly(L-lactic acid) microspheres can be visualised in vivo by both single-photon-emission CT (SPECT) and MRI. In this phase 1 clinical trial, we aimed to assess the safety and the maximum tolerated radiation dose (MTRD) of ¹⁶⁶Ho-radioembolisation in patients with liver metastases. Methods Between Nov 30, 2009, and Sept 19, 2011, patients with unresectable, chemorefractory liver metastases were enrolled in the Holmium Embolization Particles for Arterial Radiotherapy (HEPAR) trial. Patients were treated with intra-arterial ¹⁶⁶Ho-radioembolisation in cohorts of three patients, with escalating aimed whole-liver absorbed doses of 20, 40, 60, and 80 Gy. Cohorts were extended to a maximum of six patients if dose-limiting toxicity occurred. Patients were assigned a dose in the order of study entry, with dose escalation until dose-limiting toxicity was encountered in at least two patients of a dose cohort. Clinical or laboratory toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 3.0. The primary endpoint was the MTRD. Analyses were per protocol. This study is registered with ClinicalTrials.gov, number NCT01031784. Findings 15 patients underwent ¹⁶⁶Ho-radioembolisation at doses of 20 Gy (n=6), 40 Gy (n=3), 60 Gy (n=3), and 80 Gy (n=3). Mean estimated whole-liver absorbed doses were 18 Gy (SD 2) for the 20 Gy cohort, 35 Gy (SD 1) for the 40 Gy cohort, 58 Gy (SD 3) for the 60 Gy cohort, and 73 Gy (SD 4) for the 80 Gy cohort. The 20 Gy cohort was extended to six patients because of the occurrence of dose-limiting toxicity in one patient (pulmonary embolism). In the 80 Gy cohort, dose-limiting toxicity occurred in two patients: grade 4 thrombocytopenia, grade 3 leucopenia, and grade 3 hypoalbuminaemia in one patient, and grade 3 abdominal pain in another patient. The MTRD was identified as 60 Gy. The most frequently encountered laboratory toxicities (including grade 1) were lymphocytopenia, hypoalbuminaemia, raised alkaline phosphatase, raised aspartate aminotransferase, and raised gamma-glutamyltransferase, which were all noted in 12 of 15 patients. Stable disease or partial response regarding target lesions was achieved in 14 of 15 patients (93%, 95% CI 70–99) at 6 weeks and nine of 14 patients (64%, 95% CI 39–84) at 12 weeks after radioembolisation. Compared with baseline, the average global health status and quality of life scale score at 6 weeks after treatment had decreased by 13 points (p=0·053) and by 14 points at 12 weeks (p=0·048). In all patients, technetium-99m (⁹⁹ m Tc)-macro- aggregated albumin SPECT, ¹⁶⁶Ho scout dose SPECT, and ¹⁶⁶Ho treatment dose SPECT showed similar patterns of the presence or absence of extrahepatic deposition of activity. Interpretation ¹⁶⁶Ho-radioembolisation is feasible and safe for the treatment of patients with unresectable and chemorefractory liver metastases and enables image-guided treatment. Clinical ¹⁶⁶Ho-radioembolisation should be done with an aimed whole-liver absorbed dose of 60 Gy. Funding Dutch Cancer Society, Dutch Technology Foundation STW. Introduction Radioembolisation using yttrium-90 (⁹⁰Y) microspheres is increasingly used to selectively target liver metastases as first-line or salvage treatment in patients with unresectable hepatic tumours. 1,2 The rationale behind this treatment is that blood from the hepatic artery flows preferentially to malignancies, whereas healthy liver parenchyma is mainly perfused by blood from the portal vein. Microspheres injected into the hepatic artery will therefore selectively target tumorous tissue, whereas the healthy liver tissue is spared. Recent research has focused on quantitative imaging for dosimetry to ensure optimum deposition of radioactive microspheres in the tumorous tissue. 3,4 Holmium-166 poly(L-lactic acid) (¹⁶⁶Ho-PLLA) microspheres that can be seen on imaging with multiple modalities have been developed at University Medical Center Utrecht (Utrecht, Netherlands) for quantitative in-vivo imaging. In addition to emitting beta-radiation for tumour destruction, ¹⁶⁶Ho-micro- spheres emit gamma radiation and are paramagnetic, which makes them visible on both single-photon- emission CT (SPECT) and MRI, enabling use of