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Clinical studies and evidence

Ho-166 SIRT: an innovative and proven technology

"An advantage of 166Ho-microspheres over the commonly used 99mTc-MAA is that the absorbed dose to the lungs can be more accurately predicted with a scout dose"
Prince et al.THE JOURNAL OF NUCLEAR MEDICINE • Vol. 59 • No. 4 • April 2018
"In summary, radioembolization with 166Ho seems to be a feasible and safe treatment option which is easy to perform for attending physicians who are familiar with 90Y-RE."
Radosa et al.CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY • Vol. 42 • No. 3 • January 2019
166Ho-radioembolisation is feasible and safe for the treatment of patients with unresectable and chemorefractory liver metastases and enables image-guided treatment.
Smits et al.LANCET ONCOLOGY • Vol. 13 • No. 10 • 2012
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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)

  • Patients with gastroenteropancreatic neuroendocrine tumours (GEP-NET) who have intrahepatic metastases have a poorer prognosis. Liver metastases are the most common type of metastases in patients with GEP-NET.
  • HEPAR Plus is an efficacy study of 166holmium-SIRT in patients with hepatic metastases from GEP-NET who underwent 177lutetium-dotatate treatment (PRRT) (N=30)
  • The pivotal study for PRRT registration in NET (NETTER-1) reported overall response rates of 18%. HEPAR Plus hypothesized that an additional adjuvant liver local boost with 166holmium-SIRT for selected patients, even in the absence of imaging evidence of progression, could increase overall response rates, and possibly benefit overall patient outcomes such as progression free survival and overall survival.

Results

  • Efficacy in terms of response at 3 months of adjuvant 166holmium-SIRT after 177lutetium-dotatate was evaluated in 30 patients
  • Per protocol analysis demonstrated objective response in the treated volume in 13 patients (43%)
  • The adverse event profile was similar to previous studies, with grade 3-4 CTCAE adverse events including abdominal pain (10%), increased gamma glutamyl transpeptidase (54%), lymphocytopenia (23%).
  • One patient developed radioembolization-induced liver disease. In hindsight, the relative hypovascularity of disease and concomitant liver toxic medication should have been reason to exclude the patient from receiving 166holmium-SIRT.
  • Quality of life and symptom scales were not significantly affected with the exception of role functioning, but showed a temporary decrease at 3 weeks, in line with postembolization syndrome.

Conclusion

  • The combination of PRRT and 166holmium-SIRT is safe, and demonstrated substantial tumor reduction with acceptable side effects in patients with hypervascular liver metastases of GEP-NET.

Clinicaltrials.gov Identifier NCT02067988 (External link)

Study completed. View publication by Braat et al. in the Lancet Oncology

  • 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)

Evidence

The highlights on QuiremSpheres®

  • 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)

  • Patients with gastroenteropancreatic neuroendocrine tumours (GEP-NET) who have intrahepatic metastases have a poorer prognosis. Liver metastases are the most common type of metastases in patients with GEP-NET.
  • HEPAR Plus is an efficacy study of 166holmium-SIRT in patients with hepatic metastases from GEP-NET who underwent 177lutetium-dotatate treatment (PRRT) (N=30)
  • The pivotal study for PRRT registration in NET (NETTER-1) reported overall response rates of 18%. HEPAR Plus hypothesized that an additional adjuvant liver local boost with 166holmium-SIRT for selected patients, even in the absence of imaging evidence of progression, could increase overall response rates, and possibly benefit overall patient outcomes such as progression free survival and overall survival.

Results

  • Efficacy in terms of response at 3 months of adjuvant 166holmium-SIRT after 177lutetium-dotatate was evaluated in 30 patients
  • Per protocol analysis demonstrated objective response in the treated volume in 13 patients (43%)
  • The adverse event profile was similar to previous studies, with grade 3-4 CTCAE adverse events including abdominal pain (10%), increased gamma glutamyl transpeptidase (54%), lymphocytopenia (23%).
  • One patient developed radioembolization-induced liver disease. In hindsight, the relative hypovascularity of disease and concomitant liver toxic medication should have been reason to exclude the patient from receiving 166holmium-SIRT.
  • Quality of life and symptom scales were not significantly affected with the exception of role functioning, but showed a temporary decrease at 3 weeks, in line with postembolization syndrome.

Conclusion

  • The combination of PRRT and 166holmium-SIRT is safe, and demonstrated substantial tumor reduction with acceptable side effects in patients with hypervascular liver metastases of GEP-NET.

Clinicaltrials.gov Identifier NCT02067988 (External link)

Study completed. View publication by Braat et al. in the Lancet Oncology

  • 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)

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

HEPAR PLuS

Additional Holmium-166 SIRT after Lutetium-166 dotatate in patients with neuroendocrine tumor liver metastases

Single center, single-arm, open label phase 2 study

  • Patients: n=30 with different origin grade 1-2 NET who underwent 4 cycles of peptide receptor radionuclide therapy (PRRT)
  • Primary endpoint: objective liver tumor response in the treated volume (defined as complete response or partial response) according to RECIST 1.1 at 3 months.

Results

  • Objective liver tumor response at 3 months was  43%, and at 6 months 47%
  • Patient based response at 3 months was 40% and at 6 months 33%
Conclusion
  • Holmium-166 SIRT as a ‘boost’ after PRRT in patients with neuroendocrine liver metastases, is safe and efficacious
  • Patient selection is important and should focus on patients with a higher liver load and hypervascular disease.

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 intrahepatic distribution of 166Ho-scout has a better agreement with the 166Ho-therapeutic dose distribution in comparison with 99mTc-MAA.

  • Patients: 23 procedures (71 lesion and 22 patients) were included for analysis.
  • 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 lesions and normal liver on FDG-PET/CT. These volumes of interest were co-registered to the SPECT/CT images. The predicted absorbed doses based on 99mTc-MAA and 166Ho-scout were compared to the actual absorbed dose on post-treatment SPECT.

Conclusion

Based on the combined results of the quantitative and qualitative analyses, 166Ho-scout was shown to have a superior predictive value for intrahepatic distribution in comparison with 99mTc-MAA.

This editorial concerns the publications on 166Ho scout and comparisons of 166Ho scout with 99mTc-MAA.

The authors highlight the differences between MAA prediction and the actual microsphere distribution of 90Yttrium microspheres. There can be many reasons for discrepancy between the two, but differences in number and size of MAA and microspheres are an important factor. With respect to lung shunt prediction, it is well known that MAA can break up in small pieces that physiologically shunt to the lungs, thereby overestimating the potential lungshunt.

The authors further comment on the recurring finding that prediction of normal liver dose is more reliable than prediction of tumor dose and is likely impacted by image co-registration and delineation of volumes. Furthermore, the impact of catheter placement, type of catheter or vasospasm are still limitations.

Regardless, the authors clearly conclude that 166Ho scout is the ‘best particle’ for individual treatment planning, both in liver and lungs.

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. 

Click below to read more about this case.

Download full case (PDF)
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. 

Click below to read more about this case.

Download full case (PDF)

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. 

Click below to read more about this case.

Download full case (PDF)

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