Ignite Creation Date:
2024-05-06 @ 6:23 PM
Last Modification Date:
2024-10-26 @ 2:47 PM
Study NCT ID:
NCT05643391
Status:
COMPLETED
Last Update Posted:
2023-08-08
First Post:
2022-11-07
Brief Title:
Safety and Feasibility of Radioembolization Using Ho-166 in Patients With Unresectable Hepatocellular Carcinoma
Sponsor:
Erasme University Hospital
Organization:
Erasme University Hospital
Study Overview
Official Title:
RadioEmbolizaTion Using hOlmium-166 in Patients With Unresectable Hepatocellular Carcinoma Prospective Open Label Single-center Pilot Study
Status:
COMPLETED
Status Verified Date:
2022-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
RETOUCH
Brief Summary:
Background Hepatocellular carcinoma HCC accounts for 90 of primary liver cancers and represents a growing health problem worldwide Most patients present locally advanced disease and are candidates for palliative transarterial locoregional treatment Transarterial radioembolization TARE using 90Y has been used for more than a decade for patients with advanced disease The use of 166Ho could offer a more personalized approach in terms of imaging and dosimetry Aim to evaluate the feasibility and safety of TARE using 166Ho in a selected population of HCC patients and assess the biological peripheral response to this therapy Materials and methods In this open-label prospective non-randomized singlecenter pilot study 20 patients with unresectable hepatocellular carcinoma will undergo TARE using 166Ho The primary outcome is the feasibility of 166Ho radioembolization as well as the assessment of safety and toxicity profiles CTAE V50 Secondary outcomes include the evaluation of efficacy of 166Ho radioembolization in unresectable hepatocellular carcinoma according to mRECIST and metabolic criteria as well as the impact on the tumor marker alpha-fetoprotein AFP assessment of biodistributiondosimetry using a scout dose and time to progression TTP A substudy will assess the hepatic function using 99mTc-IDA hepato-biliary scintigraphy HBS and the comparison between pre-scout HBS and HBS just after scout dose Finally blood samples will be collected at different time points in order to explore the biological peripheral response to these therapies Perspectives The newly developed 166Ho-microspheres have distinctive advantages over the existing 90Ymicrospheres with improved dosimetry that represents a prerequisite for optimal safety and efficacy
Detailed Description:
Primary liver cancer is a growing health problem worldwide Hepatocellular carcinoma HCC represents more than 90 of primary liver cancers and is considered to be the fifth most common cancer and the second leading cause of cancer-related deaths with the majority being associated to cirrhosis
Choosing the most suitable treatment option depends not only on the tumor stage but also on the severity of the underlying liver disease and performance status Current guidelines consider the Barcelona Clinic Liver Cancer BCLC staging system as the algorithm of choice for tumor staging and therapeutic options taking into account tumor burden Child-Pugh class and performance status ECOG
Surgical approach such as resection and liver transplantation and radiofrequency RFA represent the curative treatment options Despite screening of at-risk populations most patients are diagnosed with locally advanced disease BCLC B - intermediate stage and will not be suitable for curative therapies Moreover only HCC within the Milan criteria one nodule 5 cm or up to three nodules 3 cm in diameter without macroscopic vascular invasion or extrahepatic disease are potential candidates for transplantation Resection can be proposed only in case of compensated cirrhosis in the absence of portal hypertension and RFA is only possible for small lesions 5 cm 3 cm in diameter
Locally advanced HCC is suitable for transarterial locoregional therapies conducted mostly in a palliative setting They take advantage on the double vascularization of the liver with 75 of the parenchymas blood supply coming from the portal vein while tumor nodules blood supply being almost exclusively provided by the hepatic artery When macrovascular involvement or extrahepatic disease are discovered but patients present a good performance status and a compensated liver function BCLC C systemic therapy with the tyrosine kinase inhibitor Sorafenib leads to a limited survival benefit approximately 3 months advantage compared to placebo
Transarterial chemoembolization TACE either conventional cTACE or using drug-eluting embolic DEE agents is recommended for patients with BCLC stage B and as bridging therapy for liver transplantation candidates while on the waiting list Furthermore it has been shown that in selected patients it can be successfully used as a downstaging treatment to transplantation criteria
Technically TACE involves the injection of a chemotherapeutic agent ie doxorubicin mixed with an embolic material administered selectively into the feeding arteries of the tumor resulting in tumoral necrosis induced by ischemia and cytotoxic effect
During the last decade transarterial radioembolization TARE with yttrium-90 microspheres Y90 was introduced in case of TACE failure or for patients who were not suitable for TACE ie large tumors or macrovascular invasion This technic consists of the intra-arterial infusion of smaller beads that are loaded with a radioactive isotope yttrium-90 and it relies on the beta radiation emitted by the isotope to induce tumor necrosis with a minor contribution from microembolization and without risk of ischemia of the remaining liver Its efficacy was reported in several large patient series Two products are commercially available for TARE 90Y-labelled resin microspheres SIR-Spheres Sirtex Medical Sydney and 90Y glass microspheres TheraSphere Boston International
The radioembolization procedure are performed over two different sessions work-up session and treatment session
The work-up evaluation starts with an angiography in order to obtain a precise map of the patients abdominal vascular anatomy and coil embolization might be performed if gastro-intestinal branches arising from the hepatic arteries are found This will prevent radioactive microspheres administered into the hepatic artery from ending up in extrahepatic organs via this route
The second step of the work-up implies the injection of 150 MBq Technetium-99 m-labeled macro aggregated albumin 99mTc-MAA in order to predict the distribution pattern of 90Y-microspheres The uptake of 99mTc-MAA will be visualized by whole body planar imaging and single-photon emission computed tomography SPECT-CT including low dose computer tomography of the abdomen 99mTc-MAA lung shunt fraction will be calculated and lung dosage must not exceed 30 Gy in a single treatment
In case on an unfavorable 99mTc-MAA workup the procedure will be repeated if possible to detect the cause of the extrahepatic deposition for example previously undetected patent extrahepatic vessels arising from the hepatic artery and a solution will be searched for for example more selective placement of the catheter during injection to improve the targeting of the lesion In the unlikely event no solution can be found and 90Y TARE cannot be performed the patient will be treated according to best medical practice
If the work-up will have a favorable outcome the patients will be re-admitted for the treatment within 15 days
Several retrospective studies and non-controlled prospective studies have shown higher rates of objective tumor responses prolonged time to progression and overall survival for TARE with study advocating it more effective than TACE as a downstaging tool to curative treatment Nevertheless its place in the treatment of HCC is still to be defined especially due to the non-compartmental predictive dosimetry usually performed in recent studies
Post-treatment calculation of the radiation absorbed dose in the tumors and the healthy liver tissue cannot be easily performed because quantitative PET imaging of the beta-emitting 90Y-microspheres is challenging New generation microspheres may help to achieve post-treatment dosimetry easily
New Holmium-166 166Ho loaded polyL-lactic acid microspheres have been developed at the Department on Radiology and Nuclear Medicine of the University Medical center UMC Utrecht and are commercialized by Terumo Europe QuiremSpheres Just like 90Y 166Ho relies on the emitted beta radiation to induce tumor necrosis The advantage provided by this isotope is its gamma radiation emission which allows for quantitative SPECT imaging 166Ho T12 of 27 hours gamma-radiation 81 keV beta-radiation 18 MeV and the assessment of the radiation absorbed dose delivered in both the tumors and the remaining part of the liver ie dosimetry Besides holmium is a highly paramagnetic metal and as such may be visualized by MRI This is useful because quantitative analysis of the MRI scans is possible including R2 relaxometry for microsphere concentration and especially useful for medium- and long-term monitoring of the intra-hepatic behavior of the microspheres
TARE using 166Ho -microspheres underwent a first evaluation in a clinical phase I safety study with an administration system specifically designed for 166Ho radioembolization HEPAR I METC 08-450 Fifteen patients with unresectable chemorefractory liver metastases were enrolled using a standard dose escalation protocol They were treated in cohorts of 3 target absorbed dose 20 Gy 40 Gy 60 Gy and 80 Gy The maximum tolerable radiation dose was 60 Gy In the 80 Gy cohort dose-limiting toxicity occurred in two patients grade four thrombocytopenia grade three leukopenia and grade three hypoalbuminaemia in one patient and grade three abdominal pain in another patient The most frequently encountered laboratory toxicities including grade one were lymphocytopenia hypoalbuminaemia raised alkaline phosphatase raised aspartate aminotransferase and raised gamma-glutamyltransferase which were all noted in 12 of 15 patients 80 Stable disease or partial response regarding target lesions was achieved in 14 of 15 patients 93 95 CI 70-99 at 6 weeks and 9 of 14 patients 64 95 CI 39-84 at 3 months after TARE It was concluded that 166Ho radioembolization is feasible and safe for the treatment of patients with unresectable and chemorefractory liver metastases and enables image-guided treatment
This was followed by a non-randomized single-arm phase II study that included 56 patients with unresectable chemorefractory liver metastases HEPAR II METC 11-538 166Ho radioembolization was performed with a mean liver absorbed dose of 60 Gy The primary outcome was tumor response of two target lesions on triphasic liver CT scans 3 months after therapy using modified RECIST criteria as evaluated by three blinded readers After treatment of 38 eligible patients the target lesions showed disease control in 73 after 3 months 95 confidence interval CI 57 to 85 The median overall survival was 153 months 95 CI 91 to months Grade three or four toxic events according to CTCAE version 403 criteria after treatment included abdominal pain in 18 of patients nausea 9 ascites 3 gastric stenosis 3 liver abscesses 3 paroxysmal atrial tachycardia 3 REILD 3 thoracic pain 3 upper gastrointestinal hemorrhage 3 and vomiting 3 Laboratory examination after treatment showed grade three or four toxicities in alkaline phosphatase 70 γGT 78 lymphocytes 11 and ALAT 4 From the results of this study it was concluded that 166Ho radioembolization induced a favorable tumor response with an acceptable toxicity profile in patients with liver metastases
The University Medical center UMC of Utrecht is currently conducting a third study for patients with HCC HEPAR Primary NCT03379844 The primary objective is to evaluate safety and toxicity profile of 166Ho-TARE HCC patients were not included in previous studies because underlying liver disease in HCC patients puts a higher demand on safety issues which should be studied separately
The investigators aim to evaluate the efficacy and safety of TARE using the newly developed 166Ho-microspheres in our HCC population at ERASME Hospital Using 166Ho has distinctive advantages over the existing 90Y-microspheres making quantitative individualized dose planning possible by means of SPECT and MRI Accurate dosimetry in radiation treatment is a prerequisite for optimal safety and efficacy evaluation This is particularly relevant in patients with hepatocellular carcinoma and underlying chronic liver disease which limits the maximum tolerated absorbed dose that can be applied to the liver
Regarding this underlying chronic liver disease assessment of hepatic function with 99mTc-IDA hepatobiliary scintigraphy is routinely performed at Erasme hospital before TARE However in classical 90Y TARE workflow because both MAA and IDA are labeled with 99mTc the predictive dosimetry and the evaluation of the hepatic function with IDA cannot be performed on the same day The management of the patient and the planning of TARE may be greatly optimized if both predictive dosimetry and evaluation of hepatic function can be performed on the same day And it becomes possible with the use of 166Ho
Choosing the most suitable treatment option depends not only on the tumor stage but also on the severity of the underlying liver disease and performance status Current guidelines consider the Barcelona Clinic Liver Cancer BCLC staging system as the algorithm of choice for tumor staging and therapeutic options taking into account tumor burden Child-Pugh class and performance status ECOG
Surgical approach such as resection and liver transplantation and radiofrequency RFA represent the curative treatment options Despite screening of at-risk populations most patients are diagnosed with locally advanced disease BCLC B - intermediate stage and will not be suitable for curative therapies Moreover only HCC within the Milan criteria one nodule 5 cm or up to three nodules 3 cm in diameter without macroscopic vascular invasion or extrahepatic disease are potential candidates for transplantation Resection can be proposed only in case of compensated cirrhosis in the absence of portal hypertension and RFA is only possible for small lesions 5 cm 3 cm in diameter
Locally advanced HCC is suitable for transarterial locoregional therapies conducted mostly in a palliative setting They take advantage on the double vascularization of the liver with 75 of the parenchymas blood supply coming from the portal vein while tumor nodules blood supply being almost exclusively provided by the hepatic artery When macrovascular involvement or extrahepatic disease are discovered but patients present a good performance status and a compensated liver function BCLC C systemic therapy with the tyrosine kinase inhibitor Sorafenib leads to a limited survival benefit approximately 3 months advantage compared to placebo
Transarterial chemoembolization TACE either conventional cTACE or using drug-eluting embolic DEE agents is recommended for patients with BCLC stage B and as bridging therapy for liver transplantation candidates while on the waiting list Furthermore it has been shown that in selected patients it can be successfully used as a downstaging treatment to transplantation criteria
Technically TACE involves the injection of a chemotherapeutic agent ie doxorubicin mixed with an embolic material administered selectively into the feeding arteries of the tumor resulting in tumoral necrosis induced by ischemia and cytotoxic effect
During the last decade transarterial radioembolization TARE with yttrium-90 microspheres Y90 was introduced in case of TACE failure or for patients who were not suitable for TACE ie large tumors or macrovascular invasion This technic consists of the intra-arterial infusion of smaller beads that are loaded with a radioactive isotope yttrium-90 and it relies on the beta radiation emitted by the isotope to induce tumor necrosis with a minor contribution from microembolization and without risk of ischemia of the remaining liver Its efficacy was reported in several large patient series Two products are commercially available for TARE 90Y-labelled resin microspheres SIR-Spheres Sirtex Medical Sydney and 90Y glass microspheres TheraSphere Boston International
The radioembolization procedure are performed over two different sessions work-up session and treatment session
The work-up evaluation starts with an angiography in order to obtain a precise map of the patients abdominal vascular anatomy and coil embolization might be performed if gastro-intestinal branches arising from the hepatic arteries are found This will prevent radioactive microspheres administered into the hepatic artery from ending up in extrahepatic organs via this route
The second step of the work-up implies the injection of 150 MBq Technetium-99 m-labeled macro aggregated albumin 99mTc-MAA in order to predict the distribution pattern of 90Y-microspheres The uptake of 99mTc-MAA will be visualized by whole body planar imaging and single-photon emission computed tomography SPECT-CT including low dose computer tomography of the abdomen 99mTc-MAA lung shunt fraction will be calculated and lung dosage must not exceed 30 Gy in a single treatment
In case on an unfavorable 99mTc-MAA workup the procedure will be repeated if possible to detect the cause of the extrahepatic deposition for example previously undetected patent extrahepatic vessels arising from the hepatic artery and a solution will be searched for for example more selective placement of the catheter during injection to improve the targeting of the lesion In the unlikely event no solution can be found and 90Y TARE cannot be performed the patient will be treated according to best medical practice
If the work-up will have a favorable outcome the patients will be re-admitted for the treatment within 15 days
Several retrospective studies and non-controlled prospective studies have shown higher rates of objective tumor responses prolonged time to progression and overall survival for TARE with study advocating it more effective than TACE as a downstaging tool to curative treatment Nevertheless its place in the treatment of HCC is still to be defined especially due to the non-compartmental predictive dosimetry usually performed in recent studies
Post-treatment calculation of the radiation absorbed dose in the tumors and the healthy liver tissue cannot be easily performed because quantitative PET imaging of the beta-emitting 90Y-microspheres is challenging New generation microspheres may help to achieve post-treatment dosimetry easily
New Holmium-166 166Ho loaded polyL-lactic acid microspheres have been developed at the Department on Radiology and Nuclear Medicine of the University Medical center UMC Utrecht and are commercialized by Terumo Europe QuiremSpheres Just like 90Y 166Ho relies on the emitted beta radiation to induce tumor necrosis The advantage provided by this isotope is its gamma radiation emission which allows for quantitative SPECT imaging 166Ho T12 of 27 hours gamma-radiation 81 keV beta-radiation 18 MeV and the assessment of the radiation absorbed dose delivered in both the tumors and the remaining part of the liver ie dosimetry Besides holmium is a highly paramagnetic metal and as such may be visualized by MRI This is useful because quantitative analysis of the MRI scans is possible including R2 relaxometry for microsphere concentration and especially useful for medium- and long-term monitoring of the intra-hepatic behavior of the microspheres
TARE using 166Ho -microspheres underwent a first evaluation in a clinical phase I safety study with an administration system specifically designed for 166Ho radioembolization HEPAR I METC 08-450 Fifteen patients with unresectable chemorefractory liver metastases were enrolled using a standard dose escalation protocol They were treated in cohorts of 3 target absorbed dose 20 Gy 40 Gy 60 Gy and 80 Gy The maximum tolerable radiation dose was 60 Gy In the 80 Gy cohort dose-limiting toxicity occurred in two patients grade four thrombocytopenia grade three leukopenia and grade three hypoalbuminaemia in one patient and grade three abdominal pain in another patient The most frequently encountered laboratory toxicities including grade one were lymphocytopenia hypoalbuminaemia raised alkaline phosphatase raised aspartate aminotransferase and raised gamma-glutamyltransferase which were all noted in 12 of 15 patients 80 Stable disease or partial response regarding target lesions was achieved in 14 of 15 patients 93 95 CI 70-99 at 6 weeks and 9 of 14 patients 64 95 CI 39-84 at 3 months after TARE It was concluded that 166Ho radioembolization is feasible and safe for the treatment of patients with unresectable and chemorefractory liver metastases and enables image-guided treatment
This was followed by a non-randomized single-arm phase II study that included 56 patients with unresectable chemorefractory liver metastases HEPAR II METC 11-538 166Ho radioembolization was performed with a mean liver absorbed dose of 60 Gy The primary outcome was tumor response of two target lesions on triphasic liver CT scans 3 months after therapy using modified RECIST criteria as evaluated by three blinded readers After treatment of 38 eligible patients the target lesions showed disease control in 73 after 3 months 95 confidence interval CI 57 to 85 The median overall survival was 153 months 95 CI 91 to months Grade three or four toxic events according to CTCAE version 403 criteria after treatment included abdominal pain in 18 of patients nausea 9 ascites 3 gastric stenosis 3 liver abscesses 3 paroxysmal atrial tachycardia 3 REILD 3 thoracic pain 3 upper gastrointestinal hemorrhage 3 and vomiting 3 Laboratory examination after treatment showed grade three or four toxicities in alkaline phosphatase 70 γGT 78 lymphocytes 11 and ALAT 4 From the results of this study it was concluded that 166Ho radioembolization induced a favorable tumor response with an acceptable toxicity profile in patients with liver metastases
The University Medical center UMC of Utrecht is currently conducting a third study for patients with HCC HEPAR Primary NCT03379844 The primary objective is to evaluate safety and toxicity profile of 166Ho-TARE HCC patients were not included in previous studies because underlying liver disease in HCC patients puts a higher demand on safety issues which should be studied separately
The investigators aim to evaluate the efficacy and safety of TARE using the newly developed 166Ho-microspheres in our HCC population at ERASME Hospital Using 166Ho has distinctive advantages over the existing 90Y-microspheres making quantitative individualized dose planning possible by means of SPECT and MRI Accurate dosimetry in radiation treatment is a prerequisite for optimal safety and efficacy evaluation This is particularly relevant in patients with hepatocellular carcinoma and underlying chronic liver disease which limits the maximum tolerated absorbed dose that can be applied to the liver
Regarding this underlying chronic liver disease assessment of hepatic function with 99mTc-IDA hepatobiliary scintigraphy is routinely performed at Erasme hospital before TARE However in classical 90Y TARE workflow because both MAA and IDA are labeled with 99mTc the predictive dosimetry and the evaluation of the hepatic function with IDA cannot be performed on the same day The management of the patient and the planning of TARE may be greatly optimized if both predictive dosimetry and evaluation of hepatic function can be performed on the same day And it becomes possible with the use of 166Ho
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None