Clinical Evidence

Ho-166 SIRT: an innovative and proven technology

Trials

  • HEPAR I was a first-in-man, phase I dose finding study, focused on safety, feasibility and finding the Maximum Tolerated Radiation Dose (MTRD).
  • 15 patients with liver metastases from various primary origins were treated in cohorts of 3 with escalating aimed whole-liver absorbed doses.
  • The results showed that 166holmium SIRT is considered safe and feasible.
  • Toxicity after treatment was mainly confined to the expected post-embolization syndrome, and the MTRD was identified to be 60 Gy. This study paved the way for the second study (HEPAR II) on 166holmium SIRT.

Study completed. View publication by Smits et al. in Lancet Oncology on Pubmed (External link)

Clinicaltrials.gov Identifier NCT01031784 (External link)

  • HEPAR II was a single-center phase II efficacy trial, and enrolled 38 patients with unresectable, chemo refractory liver metastases of various origin.
  • The main primary malignancies were colorectal carcinoma (61%), breast cancer (11%), cholangiocarcinoma (11%), neuroendocrine tumors (5%) and uveal melanoma (5%). In this study, an aimed whole liver absorbed dose of 60 Gy was administered, the determined MTRD in HEPAR I.
  • The results showed that 166holmium SIRT was efficacious; 73% of the patients the target lesions showed disease control after 3 months.
  • The adverse events profile was similar to that reported in comparable studies, with transient abdominal pain (18%) and nausea (8%) the most frequent grade 3 adverse events.
  • Additionally, it was shown that 166holmium microspheres could be quantified with high accuracy and precision using SPECT.

Study completed. View publication by Prince et al. in Journal of Nuclear Medicine on Pubmed (External link)

Clinicaltrials.gov Identifier NCT01612325 (External link)

  • Observational, Multicenter Study to Further Confirm The Efficacy and Safety of QuiremSpheres® (166Holmium Microspheres) SIRT in Unresectable Liver Cancer Patients
  • The main purpose of this study is to further assess treatment efficacy and safety after using QuiremSpheres® for the treatment of patients with unresectable primary liver cancer or unresectable liver metastases suitable for SIRT and allocated to this treatment by a multidisciplinary tumor board

Main objectives are:

  • Tumor response in the liver, assessed at 3 months as per routine assessment
  • Safety, expressed by the frequency and severity of adverse events

Study Director: Dragica Paunovic, MD, Chief Medical Officer at Terumo Europe​

Clinicaltrials.gov Identifier NCT03563274 (External link)

  • In this multi-center, dose-finding study, patients with early stage hepatocellular carcinoma according to the Barcelona Clinic Liver Cancer (BCLC) staging system will be included to receive percutaneous radiofrequency ablation in combination with RFA with adjuvant segmental 166holmium SIRT
  • Objective is to find the treatment area dose that will result in delivery of a radiation absorbed dose of ≥ 120Gy to the target area in at least 90% of patients.

Principal Investigator: Mark. C. Burgmans, MD, PhD, Leiden UMC

Clinicaltrials.gov Identifier NCT03437382 (External link)

  • This is a study of 166holmium-SIRT in Hepatocellular Carcinoma Patients (N=30)
  • Patients with hepatocellular carcinoma often die from intrahepatic disease since current treatment options are generally limited.
  • Local treatment using 166holmium SIRT could offer an effective treatment and a more personal approach than 90yttrium SIRT as 166holmium has more imaging options.

Objectives:

  • To establish the safety and toxicity profile of holmium radioembolization in patients with hepatocellular carcinoma.
  • To evaluate efficacy of holmium radioembolization in hepatocellular carcinoma without curative treatment options in a non-comparative phase II study.

Principal Investigator: Marnix G. Lam, MD, PhD, UMC Utrecht

Clinicaltrials.gov Identifier NCT03379844 (External link)

  • An efficacy study of 166holmium-SIRT in patients with hepatic metastases from Neuroendocrine tumors who underwent 177lutetium-dotatate treatment (N=30-48)
  • Patients with gastroenteropancreatic neuroendocrine tumours (NET) often die from intrahepatic disease or are excluded from liver-directed treatment because of extrahepatic disease.
  • Adjuvant liver-directed treatment is warranted to control both intra- and extrahepatic disease.
  • The efficacy and toxicity of adjuvant 166holmium-SIRT after systemic 177lutetium-dotatate will be studied in a this non-comparative phase II study.

Objective

  • Evaluate efficacy in terms of response at 3 months of adjuvant 166holmium-SIRT after 177lutetium-dotatate in a non-comparative phase II study

Principal Investigator: Marnix G. Lam, MD, PhD, UMC Utrecht

Clinicaltrials.gov Identifier NCT02067988 (External link)

Evidence

The highlights on QuiremSpheres®

HEPAR I

Single Center Phase I – Dose Escalation Study

  • Patients: N=15  with different tumor liver metastases from various primary tumors  including colorectal carcinoma.
  • Primary endpoint: Determination of Maximum Tolerated Radiation Dose (MTRD)

Results

  • MTRD was found to be 60 Gy
  • Disease control (PR+SD) in target lesions at 12 weeks was reported in 64% patients.
  • In all patients, 99mTechnetium-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.

Conclusion

  • QuiremSpheres® is safe and effective for the treatment of patients with unresectable and chemorefractory liver metastases with average whole liver absorbed dose of 60Gy, and enables image-guided treatment.

HEPAR II

Single Center Phase II – Safety & Efficacy Study

  • Patients: N=37 with different liver tumor metastases in the salvage setting
    • Of those patients, 23 had metastatic colorectal carcinoma
  • Primary Endpoint: Tumor Response at 3 months

Results

  • Time to liver specific progression was 3 months
  • Disease control (PR + SD) in target lesions at 3 months was reported in 73% patients
  • Median overall survival was 14.5 months
  • Median overall survival for mCRC patients was 13.4 months
  • On SPECT, 166Ho could be quantified with high accuracy and precision

Conclusion

  • Radioembolization with QuiremSpheres® induced a tumor response with an acceptable toxicity profile in salvage patients with liver metastases.

Single Center Retrospective Study

  • Patients: N=9 with hepatocellular carcinoma ( BCLC stage B & C)

Results

  • At 6 months:
    • Tumor Response (CR + PR) reported in 60% of patients
    • Disease control (CR + PR + SD) reported in 90% of patients
  • No death occurred within 2 months after treatment
  • The overall toxicity was low with no observed major complications  (CTCAE grade 3-5)

Conclusion

  • SIRT with QuiremSpheres® seems to be a feasible and safe treatment option for the treatment of HCC with no significant hepatotoxicity after the treatment
  • Easy to perform for physicians familiar with Y-90

The highlights on QuiremScout®

A quantitative evaluation in patients treated with 166Ho-microspheres to compare the performance of pretreatment diagnostic 99mTc-MAA imaging and pretreatment diagnostic 166Ho microsphere imaging for lung absorbed dose estimation in 166Ho radioembolization.
  • Patients: N=14 with different tumour types that were treated with 166Ho microspheres.
Results
  • Mean dose of 166Ho Scout dose was 250MBq
  • The median actual lung absorbed dose was 0.02 Gy, based on posttreatment imaging
  • Lung absorbed doses estimated on the basis of pretreatment diagnostic 166Ho microsphere imaging were better predictors of actual lung absorbed dose than 99mTc-MAA based imaging.
  • Lung absorbed doses estimated using SPECT CT were more accurate than estimations based on planar scintigraphy
Conclusion
  • In clinical practice, lung absorbed doses are significantly overestimated by pretreatment diagnostic 99mTc-MAA imaging. Pretreatment diagnostic 166Ho-microsphere SPECT/CT imaging accurately predicts lung absorbed doses after 166Ho radioembolization.
To retrospectively study the safety of Holmium-166 microspheres as scout dose before treatment with QuiremSpheres®
  • Patients: N=82 with different tumour types that were treated with 166Ho microspheres.
  • To assess the safety of the 166Ho scout dose in clinical practice, the general toxicity and safety concerns of an accidental extra-hepatic deposition of a 166Ho scout dose was studied.
Results
  • Mean dose of 166Ho Scout dose was 250MBq
  • 6 patients had extrahepatic deposition of 166Ho Scout dose with median absorbed dose of 3.6 Gy .
  • The maximum absorbed dose to extrahepatic tissues was 13.8 Gy.
  • No relevant clinical toxicity occurred.
  • No adverse events that were possibly, probably or definitely related to the 166Ho scout dose.
Conclusions:
  • This study demonstrates that the use of 166Ho microspheres as a scout dose (250MBq) prior to SIRT is a safe alternative to 99mTc-MAA
The aim of this study was to analyze whether the agreement between 166Ho-scout and 166Ho-therapeutic dose is better than the agreement between 99mTc-MAA and 166Ho-therapeutic dose.
  • Patients: N=24 were enrolled
  • 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 using a 5-point scale.
  • In addition, agreement was measured quantitatively by delineating liver segments on CT and lesions on FDG-PET or MRI.
Conclusion Based on the combined results of the quantitative and qualitative analyses, 166Ho-scout seemed superior to 99mTc-MAA in predicting the intrahepatic distribution

Cases

61-yo male metastatic colorectal cancer-patient

A 61-year old male patient was diagnosed with right colon adenocarcinoma three years ago (G2, pT3N2, KRAS mut) and liver metastasis one year later. He was treated previously with right hepatectomy and percutaneous ablation. SIRT was approved by multidisciplinary tumor board. Post-treatment SPECT-CT showed excellent concentration of the microspheres in the liver lesions. Use the slider to compare the baseline 18FDG-PET and post-therapy SPECT/CT images. 

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Diagnostic FDG PET Therapy
MR image with dose view calculated from T2* images

a 47-yo FEmale metastatic colorectal cancer-patient

A 47-years old female patient diagnosed with left colon adenocarcinoma and synchronous hepatic metastasis three years before, treated with multiple hepatic resections, percutaneous ablation and >3 lines of systemic chemotherapy. Patient presents with mild hepatic progression (ECOG 0, normal liver function). SIRT was approved by multidisciplinary tumor board. Post-treatment T2* MRI showed excellent concentration of the microspheres in the liver lesions. Fourty-five days after SIRT, CT demonstrated reduction in size of the majority of the hepatic lesions, the largest showing peripheral calcifications. 

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a 64-yo male metastatic colorectal cancer-patient

A 64-year old male patient with a history of metastatic colorectal cancer (mCRC) was diagnosed two years before and  treated by resection of liver segments II and III and IVb. Systemic chemotherapy was given until current diagnosis of multiple advanced unresectable liver metastases. SIRT was approved by the multidisciplinary tumor board for further volume reduction of the liver metastases. At 5 months follow-up, excellent tumor response was seen on contrast enhanced CT. Post-treatment MR imaging was not available.

Use the slider to switch between the baseline contrast enhanced MRI and follow-up contrast enhanced CT images. 

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Pre-treatment MRI Post-treatment CT

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