Insights into the Dose–Response Relationship of Radioembolization with Resin 90Y-Microspheres: A Prospective Cohort Study in Patients with Colorectal Cancer Liver Metastases

Randomized controlled trials are investigating the benefit of hepatic radioembolization added to systemic therapy in the first- and second-line treatment of patients with colorectal liver metastases (CRLM). Remarkably, administered activity may still be suboptimal, because a dose–response relationship has not been defined. The purpose of this study was to characterize the relationship between tumor-absorbed dose and response after 90Y radioembolization treatment for CRLM. Methods: Thirty patients with unresectable chemorefractory CRLM were treated with resin 90Y-microspheres in a prospective phase II clinical trial. Tumor-absorbed dose was quantified on 90Y PET. Metabolic tumor activity, defined as tumor lesion glycolysis (TLG*) on 18F-FDG PET, was measured at baseline and 1 mo after treatment. The relationship between tumor-absorbed dose and posttreatment metabolic activity was assessed per metastasis with a linear mixed-effects regression model. Results: Treated metastases (n = 133) were identified. The mean tumor-absorbed dose was 51 ± 28 Gy (range, 7–174 Gy). A 50% reduction in TLG* was achieved in 46% of metastases and in 11 of 30 (37%) patients for the sum of metastases. The latter was associated with a prolonged median overall survival (11.6 vs. 6.6 mo, P = 0.02). A strong and statistically significant dose–response relationship was found (P < 0.001). The dose effect depended on baseline TLG* (P < 0.01). The effective tumor-absorbed dose was conservatively estimated at a minimum of 40–60 Gy. Conclusion: A strong dose–response relationship exists for the treatment of CRLM with resin microsphere 90Y radioembolization. Treatment efficacy is, however, still limited, because the currently used pretreatment activity calculation methods curb potentially achievable tumor-absorbed dose values. A more personalized approach to radioembolization is required before concluding on its clinical potential.

[1]  M. Girabent-Farrés,et al.  Methodological Quality and Reporting of Generalized Linear Mixed Models in Clinical Medicine (2000–2012): A Systematic Review , 2014, PloS one.

[2]  Gary D Hutchins,et al.  Microsphere localization and dose quantification using positron emission tomography/CT following hepatic intraarterial radioembolization with yttrium-90 in patients with advanced hepatocellular carcinoma. , 2014, Journal of vascular and interventional radiology : JVIR.

[3]  D. Sze,et al.  Fusion dual-tracer SPECT-based hepatic dosimetry predicts outcome after radioembolization for a wide range of tumour cell types , 2015, European Journal of Nuclear Medicine and Molecular Imaging.

[4]  L. V. Elmbt,et al.  Feasibility of 90Y TOF PET-based dosimetry in liver metastasis therapy using SIR-Spheres , 2010, European Journal of Nuclear Medicine and Molecular Imaging.

[5]  Kathy Willowson,et al.  Quantitative and Qualitative Assessment of Yttrium-90 PET/CT Imaging , 2014, PloS one.

[6]  Paul C. Johnson.  Extension of Nakagawa & Schielzeth's R2GLMM to random slopes models , 2014, Methods in ecology and evolution.

[7]  B. Fisher,et al.  Determination and comparison of radiotherapy dose responses for hepatocellular carcinoma and metastatic colorectal liver tumours. , 2013, The British journal of radiology.

[8]  M. D’Arienzo,et al.  Absorbed dose to lesion and clinical outcome after liver radioembolization with 90Y microspheres: a case report of PET-based dosimetry , 2013, Annals of Nuclear Medicine.

[9]  D. Townsend,et al.  Post-radioembolization yttrium-90 PET/CT - part 2: dose-response and tumor predictive dosimetry for resin microspheres , 2013, EJNMMI Research.

[10]  P. Flamen,et al.  Multimodality imaging can predict the metabolic response of unresectable colorectal liver metastases to radioembolization therapy with Yttrium-90 labeled resin microspheres , 2008, Physics in medicine and biology.

[11]  F Hofheinz,et al.  An automatic method for accurate volume delineation of heterogeneous tumors in PET. , 2012, Medical physics.

[12]  F. Orsi,et al.  Radioembolization of Hepatic Lesions from a Radiobiology and Dosimetric Perspective , 2014, Front. Oncol..

[13]  M Ljungberg,et al.  Evaluation of quantitative 90Y SPECT based on experimental phantom studies , 2008, Physics in medicine and biology.

[14]  F. Forrer,et al.  EANM procedure guideline for the treatment of liver cancer and liver metastases with intra-arterial radioactive compounds , 2011, European Journal of Nuclear Medicine and Molecular Imaging.

[15]  R. Wahl,et al.  From RECIST to PERCIST: Evolving Considerations for PET Response Criteria in Solid Tumors , 2009, Journal of Nuclear Medicine.

[16]  F Hofheinz,et al.  Automatic volume delineation in oncological PET , 2011, Nuklearmedizin.

[17]  Tobias F. Jakobs,et al.  Standards of Practice in Transarterial Radioembolization , 2013, CardioVascular and Interventional Radiology.

[18]  M. D’Arienzo.  Emission of β+ Particles Via Internal Pair Production in the 0+ – 0+ Transition of 90Zr: Historical Background and Current Applications in Nuclear Medicine Imaging , 2013 .

[19]  Marnix G E H Lam,et al.  Safety of a Scout Dose Preceding Hepatic Radioembolization with 166Ho Microspheres , 2015, The Journal of Nuclear Medicine.

[20]  M. A. van den Bosch,et al.  90Y Hepatic Radioembolization: An Update on Current Practice and Recent Developments , 2015, The Journal of Nuclear Medicine.

[21]  R. Salem,et al.  Internal Pair Production of 90Y Permits Hepatic Localization of Microspheres Using Routine PET: Proof of Concept , 2011, The Journal of Nuclear Medicine.

[22]  A. Pasciak,et al.  The impact of an antireflux catheter on target volume particulate distribution in liver-directed embolotherapy: a pilot study. , 2015, Journal of vascular and interventional radiology : JVIR.

[23]  A. Pasciak,et al.  Treatment modification of yttrium-90 radioembolization based on quantitative positron emission tomography/CT imaging. , 2013, Journal of vascular and interventional radiology : JVIR.

[24]  A. Agrawal,et al.  90Y microsphere therapy: does 90Y PET/CT imaging obviate the need for 90Y Bremsstrahlung SPECT/CT imaging? , 2013, Nuclear medicine communications.

[25]  S. Pocock,et al.  The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. , 2007, Preventive medicine.

[26]  B. Tan,et al.  Image-Guided Personalized Predictive Dosimetry by Artery-Specific SPECT/CT Partition Modeling for Safe and Effective 90Y Radioembolization , 2012, The Journal of Nuclear Medicine.

[27]  M. A. van den Bosch,et al.  The Effect of Intra-Arterial Angiotensin II on the Hepatic Tumor to Non-Tumor Blood Flow Ratio for Radioembolization: A Systematic Review , 2014, PloS one.

[28]  J. Martí-Climent,et al.  PET optimization for improved assessment and accurate quantification of 90Y-microsphere biodistribution after radioembolization. , 2014, Medical physics.

[29]  Abass Alavi,et al.  Feasibility and performance of novel software to quantify metabolically active volumes and 3D partial volume corrected SUV and metabolic volumetric products of spinal bone marrow metastases on 18F-FDG-PET/CT. , 2011, Hellenic journal of nuclear medicine.

[30]  S. Minoshima,et al.  Comparison of positron emission tomography and bremsstrahlung imaging to detect particle distribution in patients undergoing yttrium-90 radioembolization for large hepatocellular carcinomas or associated portal vein thrombosis. , 2013, Journal of vascular and interventional radiology : JVIR.

[31]  C. Bodet-Milin,et al.  Assessment of acquisition protocols for routine imaging of Y-90 using PET/CT , 2013, EJNMMI Research.

[32]  Liane Oehme,et al.  A method for model-free partial volume correction in oncological PET , 2012, EJNMMI Research.

[33]  M. A. van den Bosch,et al.  Radioembolization for Treatment of Salvage Patients with Colorectal Cancer Liver Metastases: A Systematic Review , 2013, The Journal of Nuclear Medicine.

[34]  A. Pasciak,et al.  A Comparison of Techniques for 90Y PET/CT Image-Based Dosimetry Following Radioembolization with Resin Microspheres , 2014, Front. Oncol..

[35]  Michael Tapner,et al.  A multicentre comparison of quantitative 90Y PET/CT for dosimetric purposes after radioembolization with resin microspheres , 2015, European Journal of Nuclear Medicine and Molecular Imaging.

[36]  M. A. Bosch,et al.  Added value of FDG-PET imaging in the diagnostic workup for yttrium-90 radioembolisation in patients with colorectal cancer liver metastases , 2012, European Radiology.

[37]  Michael Ljungberg,et al.  Development and evaluation of an improved quantitative (90)Y bremsstrahlung SPECT method. , 2012, Medical physics.

[38]  Marnix G E H Lam,et al.  Prognostic Utility of 90Y Radioembolization Dosimetry Based on Fusion 99mTc-Macroaggregated Albumin–99mTc-Sulfur Colloid SPECT , 2013, The Journal of Nuclear Medicine.

[39]  M. Erkılıç,et al.  Evaluation of factors affecting tumor response and survival in patients with primary and metastatic liver cancer treated with microspheres , 2015, Nuclear medicine communications.

[40]  M. Elschot,et al.  Reply: A Clinical Dosimetric Perspective Uncovers New Evidence and Offers New Insight in Favor of 99mTc-Macroaggregated Albumin for Predictive Dosimetry in 90Y Resin Microsphere Radioembolization , 2013, The Journal of Nuclear Medicine.

[41]  A. Kennedy.  Radioembolization of hepatic tumors. , 2014, Journal of gastrointestinal oncology.

[42]  Ricky A. Sharma,et al.  FOXFIRE protocol: an open-label, randomised, phase III trial of 5-fluorouracil, oxaliplatin and folinic acid (OxMdG) with or without interventional Selective Internal Radiation Therapy (SIRT) as first-line treatment for patients with unresectable liver-only or liver-dominant metastatic colorectal ca , 2014, BMC Cancer.

[43]  M. A. Bosch,et al.  Identifying Aberrant Hepatic Arteries Prior to Intra-arterial Radioembolization , 2014, CardioVascular and Interventional Radiology.