Pre-therapeutic dosimetry evaluation and selective internal radiation therapy of hepatocellular carcinoma using yttrium-90-loaded microspheres
Authors: Etienne Garin, Yan Rolland, Eveline Boucher
Journal: Journal of Hepatology (2013)

We have read with great interest the recent review article by Sangro et al. published in the Journal of Hepatology [[1]Sangro B. Iñarrairaegui M. Bilbao J.I. Radioembolization for hepatocellular carcinoma.J Hepatol. 2012; 56: 464-473Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar], which demonstrated that selective internal radiation therapy (or radioembolisation) with yttrium-90-loaded microspheres constitutes a promising therapeutic approach for the management of hepatocellular carcinoma. The authors judiciously recollect that the concept of radioembolization is based on the delivery of a tumoricidal dose to the tumor, while sparing healthy liver tissue. This point is of paramount importance, as the chief active principle of radioembolization is associated with ionizing radiation, making it necessary to reach a threshold tumor absorbed dose in order to achieve good efficacy. As reminded by the author, the absorbed dose depends on: (i) injected activity; (ii) tumor vessel density; (iii) arterial flow. These last two features are tumor characteristics that cannot be modified, except, possibly, when combining radioembolization with the administration of antiangiogenic substances. However, the injected activity is modifiable. It is thus crucial to be able to retain reliable dosimetry models for therapeutic planning. Sangro et al. claimed that there is no correlation between the scintigraphic distribution of technetium-99m-labeled macroaggregates of albumin (Tc-99m-MAA) and that of microspheres, and thus there is no reliable dosimetry model. However, this is only the case for resin microspheres (SIR Sphere, SIRTex Medical Limited, Sydney, Australia). The study conducted by Knesaureck et al. [[2]Knesaurek K. Machac J. Muzinic M. DaCosta M. Zhang Z. Heiba S. Quantitative comparison of yttrium-90 (90Y)-microspheres and technetium-99m (99mTc)-macroaggregated albumin SPECT images for planning 90Y therapy of liver cancer.Technol Cancer Res Treat. 2010; 9: 253-262Crossref PubMed Scopus (66) Google Scholar], which is referenced in the Sangro publication, clearly showed that only resin microspheres had no correlation. Data relating to glass microspheres was not provided. The Milan team [[3]Chiesa C. Maccauro M. Romito R. Spreafico C. Pellizzari S. Negri A. et al.Need, feasibility and convenience of dosimetric treatment planning in liver selective internal radiation therapy with 90Y microspheres: the experience of the National Tumor Institute of Milan.Q J Nucl Med Mol Imaging. 2011; 55: 168-197PubMed Google Scholar], revealed a strong correlation between the tumor-absorbed dose, which is based on Tc-99m-MAA hepatic arterial perfusion scintigraphy, and tumor responses for treatments using glass microspheres (TheraSphere, MDS Nordion, Ontario, Canada). Therefore, contrary to Sangro's conclusion, MAA-based dosimetry appears reliable when using glass microspheres. These results have been confirmed by our research team [[4]Garin E. Laurence Lenoir L. Yan Rolland Y. Julien Edeline J. Habiba Mesba H. Sophie Laffont S. et al.99mTc-MAA SPECT/CT based dosimetry accurately predicts tumour response and survival in HCC patients treated with 90Y-loaded glass microspheres: preliminary results.J Nucl Med. 2012; 53: 255-263Crossref PubMed Scopus (188) Google Scholar]. This difference in the prognostic value of Tc-99m-MAA dosimetry using either glass microspheres or resin microspheres prior to performing radioembolisation may be accounted for by fundamental differences between the two products. As highlighted by the authors, the specific activity of glass microspheres is 50 times higher than that of resin microspheres (2500 Bq per sphere vs. 50 Bq per sphere). Consequently, for the same injected activity, the embolic effect is much higher and well-recognized with resin microspheres, requiring slow administration, with repeated angiographic controls for detecting reflow during the procedure. The consequences include an increased risk of gastric ulcer [[5]Naymagon S. Warner R.R.P. Patel K. Harpaz N. Machac J. Weintraub J.L. et al.Gastroduodenal ulceration associated with radioembolization for the treatment of hepatic tumors: an institutional experience and review of the literature.Dig Dis Sci. 2010; 55: 2450-2458Crossref PubMed Scopus (54) Google Scholar], intrahepatic reflux (accidental injection of total liver during selective injection into the liver lobe that was not detected on angiography), and reflux from the treated liver area into the non-tumor liver tissue. Therefore, the injection of small amounts of MAA appears to exhibit a good predictive value of response when using glass microspheres, which have a low embolic effect, and a poor predictive value of response when using resin microspheres, which have a high embolic effect. It is also important to stress that the maximal activity significantly differs between the two products, which is crucial from a radiobiological point of view: 3.2 GBq for resin microspheres vs. 20 GBq for glass microspheres. Previously, we established a mean tumoral threshold dose of 205 Gy in order to achieve a response [[4]Garin E. Laurence Lenoir L. Yan Rolland Y. Julien Edeline J. Habiba Mesba H. Sophie Laffont S. et al.99mTc-MAA SPECT/CT based dosimetry accurately predicts tumour response and survival in HCC patients treated with 90Y-loaded glass microspheres: preliminary results.J Nucl Med. 2012; 53: 255-263Crossref PubMed Scopus (188) Google Scholar]. This threshold dose of 205 Gy enables response prediction with an accuracy of 91%. In this study, overall survival of patients having received a tumor dose ⩾205 was significantly higher compared to that of those having received a tumor dose <205 Gy (18 months [95% CI: 11–∞ months] vs. 9 months [95% CI: 2–31 months], respectively, p = 0.0322) [[4]Garin E. Laurence Lenoir L. Yan Rolland Y. Julien Edeline J. Habiba Mesba H. Sophie Laffont S. et al.99mTc-MAA SPECT/CT based dosimetry accurately predicts tumour response and survival in HCC patients treated with 90Y-loaded glass microspheres: preliminary results.J Nucl Med. 2012; 53: 255-263Crossref PubMed Scopus (188) Google Scholar]. These findings contradict Sangro's observation stating, "a cut-off point has not been yet established". This dose-response concept is of major interest, since the availability of a reliable predictive model makes it possible to model the response. In a preliminary study, this approach resulted in treatment intensification in 25% of patients, along with good tolerance [[4]Garin E. Laurence Lenoir L. Yan Rolland Y. Julien Edeline J. Habiba Mesba H. Sophie Laffont S. et al.99mTc-MAA SPECT/CT based dosimetry accurately predicts tumour response and survival in HCC patients treated with 90Y-loaded glass microspheres: preliminary results.J Nucl Med. 2012; 53: 255-263Crossref PubMed Scopus (188) Google Scholar]. A study to confirm these findings is currently in progress. From a radiobiological point of view and as recently highlighted [[6]Garin E. Radioembolisation of hepatocellular carcinoma patients using yttrium-90 labelled microspheres: towards a diffusion of the technique?.Eur J Nucl Med. 2011; 38: 2114-2116Crossref Scopus (4) Google Scholar], we conclude that resin and glass microspheres are different products, with probably differing efficacy and toxicity profiles. At present, reliable and predictive dosimetry is possible when using glass microspheres but not when using resin microspheres. As a result, in the future, using glass microspheres is likely to be associated with a significant improvement in clinical outcomes, as this tumor dosimetry approach renders the clinical application of treatment intensification possible. E.G. received lectures fees from MDS Nordion. Radioembolization for hepatocellular carcinomaJournal of HepatologyVol. 56Issue 2PreviewRadioembolization is a form of brachytherapy in which intra-arterially injected 90Y-loaded microspheres serve as sources for internal radiation purposes. It produces average disease control rates above 80% and is usually very well tolerated. Main complications do not result from the microembolic effect, even in patients with portal vein occlusion, but rather from an excessive irradiation of non-target tissues including the liver. All the evidence that support the use of radioembolization in HCC is based on retrospective series or non-controlled prospective studies. Full-Text PDF Open AccessReply to: "Pre-therapeutic dosimetry evaluation and selective internal radiation therapy of hepatocellular carcinoma using yttrium-90-loaded microspheres"Journal of HepatologyVol. 58Issue 5PreviewWe have read with interest the comments made by Garin et al. to our recently published review on yttrium-90 radioembolization (RE) for hepatocellular carcinoma (HCC) [1]. Yet, while they raise relevant questions regarding the dosimetric approach to RE using yttrium-90 microspheres, they also convey erroneous messages regarding pretended advantages of glass vs. resin microspheres that should be clarified. Full-Text PDF Open Access