Reply to: “Pre-therapeutic dosimetry evaluation and selective internal radiation therapy of hepatocellular carcinoma using yttrium-90-loaded microspheres”
Authors: Bruno Sangro, Mercedes Iñarrairaegui, Jose I. Bilbao
Journal: Journal of Hepatology (2013)

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 AccessPre-therapeutic dosimetry evaluation and selective internal radiation therapy of hepatocellular carcinoma using yttrium-90-loaded microspheresJournal of HepatologyVol. 58Issue 5PreviewWe have read with great interest the recent review article by Sangro et al. published in the Journal of Hepatology [1], 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. Full-Text PDF Open Access We 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]Sangro B. Iñarrairaegui M. Bilbao J.I. Radioembolization for hepatocellular carcinoma.J Hepatol. 2012; 56: 464-473Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar]. 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.We never claimed that no correlation exists between the distribution of radiolabeled macroaggregated albumin (MAA) and therapeutic microspheres. The referred study by Knesaureck et al. shows that when such correlation between MAA and resin microspheres was analyzed, it ranged from high to very poor, and the average correlation was not the ideal one. A more recent study by the same group indicates that differences in catheter tip position are likely to be the main contributor to this mismatch [[2]Jiang M. Fischman A. Nowakowski F.S. Segmental perfusion differences on paired Tc-99m Macroaggregated Albumin (MAA) hepatic perfusion imaging and yttrium-90 (Y-90) Bremsstrahlung imaging studies in SIR-sphere radioembolization: associations with angiography.J Nucl Med Radiat Ther. 2012; 3 (http://dx.doi.org/10.4172/2155-9619.1000122): 122Crossref Google Scholar]. No study has been done with glass microspheres so unless Garin et al. may provide additional data, there is no evidence to suggest that a better correlation exists for glass microspheres. In any case, these sorts of data have to be considered cautiously since the actual distribution of beta radiation cannot be accurately quantified in vivo after RE.Furthermore, we made it clear that the MAA scan could be used to anticipate the average dose of radiation that can be delivered to tumor areas. The statement made by Garin et al. that MAA only predicts response when using glass microspheres is unfounded and it can be misleading for the inexperienced reader. Several retrospective studies have shown that unsurprisingly, the average dose received by tumors was higher for those that showed an objective response after therapy, both for resin [3Strigari L. Sciuto R. Rea S. Carpanese L. Pizzi G. Soriani A. et al.Efficacy and toxicity related to treatment of hepatocellular carcinoma with 90Y-SIR spheres: radiobiologic considerations.J Nucl Med. 2010; 51: 1377-1385Crossref PubMed Scopus (177) Google Scholar, 4Lau W.Y. Leung W.T. Ho S. Leung N.W. Chan M. Lin J. et al.Treatment of inoperable hepatocellular carcinoma with intrahepatic arterial yttrium-90 microspheres: a phase I and II study.Br J Cancer. 1994; 70: 994-999Crossref PubMed Scopus (198) Google Scholar] and for glass microspheres [5Garin E. Lenoir L. Rolland Y. Edeline J. Mesbah H. Laffont S. et al.Dosimetry based on 99mTc-macroaggregated albumin SPECT/CT accurately predicts tumor response and survival in hepatocellular carcinoma patients treated with 90Y-loaded glass microspheres: preliminary results.J Nucl Med. 2012; 53: 255-263Crossref PubMed Scopus (193) Google Scholar, 6Mazzaferro V. Sposito C. Bhoori S. Romito R. Chiesa C. Morosi C. et al.Yttrium 90 radioembolization for intermediate-advanced hepatocarcinoma: a phase II study.Hepatology. 2012; (Aug 22. http://dx.doi.org/10.1002/hep.26014 [Epub ahead of print])Google Scholar]. Nevertheless, a significant overlap was also observed and a consistent cut-off value has not been reported. For glass microspheres, proposed thresholds for aimed tumor absorbed doses range from 205 Gy in the Rennes series [[5]Garin E. Lenoir L. Rolland Y. Edeline J. Mesbah H. Laffont S. et al.Dosimetry based on 99mTc-macroaggregated albumin SPECT/CT accurately predicts tumor response and survival in hepatocellular carcinoma patients treated with 90Y-loaded glass microspheres: preliminary results.J Nucl Med. 2012; 53: 255-263Crossref PubMed Scopus (193) Google Scholar] to 500 Gy in the Milano series [[6]Mazzaferro V. Sposito C. Bhoori S. Romito R. Chiesa C. Morosi C. et al.Yttrium 90 radioembolization for intermediate-advanced hepatocarcinoma: a phase II study.Hepatology. 2012; (Aug 22. http://dx.doi.org/10.1002/hep.26014 [Epub ahead of print])Google Scholar]. According to the manufacturer’s instructions, the prescribed activity of glass microspheres is based on a 2-compartment dosimetry model with the aim of delivering a radiation dose of 120 Gy to the targeted liver (irrespective of the tumor burden). For resin microspheres, users have to choose between an empiric formula based on body surface area and tumor burden, or by a 3-compartment dosimetry model with the aim of delivering a radiation dose of 70–80 Gy to the targeted non-tumoral liver. However, experienced centers have described different attempts to use other dosimetry models to improve the efficacy of RE with both resin [[7]Kao Y.H. Hock Tan A.E. Burgmans M.C. Irani F.G. Khoo L.S. Gong Lo R.H. et al.Image-guided personalized predictive dosimetry by artery-specific SPECT/CT partition modeling for safe and effective 90Y radioembolization.J Nucl Med. 2012; 53: 559-566Crossref PubMed Scopus (126) Google Scholar] and glass microspheres [[8]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 (90)Y microspheres: the experience of the National Tumor Institute of Milan.Q J Nucl Med Mol Imaging. 2011; 55: 168-197PubMed Google Scholar]. The statement that the dosimetry approach developed by Garin et al. resulted in treatment intensification in 25% of patients, along with good tolerance has to be taken with caution since it is based on only 4 patients that received a dose higher than that prescribed by the conventional method of activity calculation for glass microspheres [[5]Garin E. Lenoir L. Rolland Y. Edeline J. Mesbah H. Laffont S. et al.Dosimetry based on 99mTc-macroaggregated albumin SPECT/CT accurately predicts tumor response and survival in hepatocellular carcinoma patients treated with 90Y-loaded glass microspheres: preliminary results.J Nucl Med. 2012; 53: 255-263Crossref PubMed Scopus (193) Google Scholar]. This early experience from their and other groups with these dosimetry models is certainly encouraging but only prospective studies in large series of patients will tell us if this approach proves to preserve safety while they increase efficacy.It is well know that with a comparable size range but a different activity per sphere, the number of particles used in a typical RE treatment is higher for resin than for glass microspheres. Garin et al. invalidly derive from this fact that resin microspheres are associated with a higher embolic effect and a higher chance of intrahepatic reflux without providing any scientific support to these assertions. Furthermore, they sustain that resin microspheres carry an increased risk of gastric ulcer, which again is a misleading statement. Gastric ulcers result from the unnoticed presence of collateral vessels and therefore, they are much dependent on the experience of the interventional radiologist performing the procedure and on the site of injection. The higher number of studies reporting gastric ulcers after RE using resin microspheres is most likely due to the fact that glass microspheres are almost invariably delivered by a selective lobar or sublobar injection while resin microspheres are quite often injected into the proper hepatic artery (particularly for unresectable liver metastases). When glass microspheres were injected into the hepatic artery in an early series of HCC patients, 13.6% of them developed gastric ulcerations [[9]Dancey J.E. Shepherd F.A. Paul K. Sniderman K.W. Houle S. Gabrys J. et al.Treatment of nonresectable hepatocellular carcinoma with intrahepatic 90Y-microspheres.J Nucl Med. 2000; 41: 1673-1681PubMed Google Scholar]. For resin microspheres, in the study referenced by Garin et al., the Mount Sinai group reported an incidence of 2.6% among 270 RE-treated patients [[10]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].Finally, Garin et al. conclusion that “resin and glass microspheres are different products, with differing efficacy and toxicity profiles” is against all available scientific evidence. As shown in Fig. 5 of our review, the overall survival of patients treated with glass or resin microspheres across the different HCC tumor stages is very consistent. The incidence of liver-related adverse events shown in Table 3 is also very similar despite the above-mentioned differences in the proportion of patients treated in a lobar fashion.In summary, we totally agree with Garin et al. that better dosimetry models for therapeutic planning will be welcomed and their development is warranted, but we respectfully disagree that they are crucial, since the currently used methods result in significant clinical activity with an acceptable incidence of liver toxicity. Most importantly, we cannot find any scientific basis to sustain that glass microspheres have substantial benefits over resin microspheres or vice versa. What the available evidence shows is that radioembolization is indeed a very consistent therapeutic procedure irrespective of the device used and the type of tumor treated, and that future efforts should be dedicated to improve their performance and to find the precise role it may play in the evolving treatment paradigm of primary and secondary liver tumors.Conflict of interestBS, MI and JIB have received lecture fees, and BS and JIB have consulted for Sirtex Medical. We 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]Sangro B. Iñarrairaegui M. Bilbao J.I. Radioembolization for hepatocellular carcinoma.J Hepatol. 2012; 56: 464-473Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar]. 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. We never claimed that no correlation exists between the distribution of radiolabeled macroaggregated albumin (MAA) and therapeutic microspheres. The referred study by Knesaureck et al. shows that when such correlation between MAA and resin microspheres was analyzed, it ranged from high to very poor, and the average correlation was not the ideal one. A more recent study by the same group indicates that differences in catheter tip position are likely to be the main contributor to this mismatch [[2]Jiang M. Fischman A. Nowakowski F.S. Segmental perfusion differences on paired Tc-99m Macroaggregated Albumin (MAA) hepatic perfusion imaging and yttrium-90 (Y-90) Bremsstrahlung imaging studies in SIR-sphere radioembolization: associations with angiography.J Nucl Med Radiat Ther. 2012; 3 (http://dx.doi.org/10.4172/2155-9619.1000122): 122Crossref Google Scholar]. No study has been done with glass microspheres so unless Garin et al. may provide additional data, there is no evidence to suggest that a better correlation exists for glass microspheres. In any case, these sorts of data have to be considered cautiously since the actual distribution of beta radiation cannot be accurately quantified in vivo after RE. Furthermore, we made it clear that the MAA scan could be used to anticipate the average dose of radiation that can be delivered to tumor areas. The statement made by Garin et al. that MAA only predicts response when using glass microspheres is unfounded and it can be misleading for the inexperienced reader. Several retrospective studies have shown that unsurprisingly, the average dose received by tumors was higher for those that showed an objective response after therapy, both for resin [3Strigari L. Sciuto R. Rea S. Carpanese L. Pizzi G. Soriani A. et al.Efficacy and toxicity related to treatment of hepatocellular carcinoma with 90Y-SIR spheres: radiobiologic considerations.J Nucl Med. 2010; 51: 1377-1385Crossref PubMed Scopus (177) Google Scholar, 4Lau W.Y. Leung W.T. Ho S. Leung N.W. Chan M. Lin J. et al.Treatment of inoperable hepatocellular carcinoma with intrahepatic arterial yttrium-90 microspheres: a phase I and II study.Br J Cancer. 1994; 70: 994-999Crossref PubMed Scopus (198) Google Scholar] and for glass microspheres [5Garin E. Lenoir L. Rolland Y. Edeline J. Mesbah H. Laffont S. et al.Dosimetry based on 99mTc-macroaggregated albumin SPECT/CT accurately predicts tumor response and survival in hepatocellular carcinoma patients treated with 90Y-loaded glass microspheres: preliminary results.J Nucl Med. 2012; 53: 255-263Crossref PubMed Scopus (193) Google Scholar, 6Mazzaferro V. Sposito C. Bhoori S. Romito R. Chiesa C. Morosi C. et al.Yttrium 90 radioembolization for intermediate-advanced hepatocarcinoma: a phase II study.Hepatology. 2012; (Aug 22. http://dx.doi.org/10.1002/hep.26014 [Epub ahead of print])Google Scholar]. Nevertheless, a significant overlap was also observed and a consistent cut-off value has not been reported. For glass microspheres, proposed thresholds for aimed tumor absorbed doses range from 205 Gy in the Rennes series [[5]Garin E. Lenoir L. Rolland Y. Edeline J. Mesbah H. Laffont S. et al.Dosimetry based on 99mTc-macroaggregated albumin SPECT/CT accurately predicts tumor response and survival in hepatocellular carcinoma patients treated with 90Y-loaded glass microspheres: preliminary results.J Nucl Med. 2012; 53: 255-263Crossref PubMed Scopus (193) Google Scholar] to 500 Gy in the Milano series [[6]Mazzaferro V. Sposito C. Bhoori S. Romito R. Chiesa C. Morosi C. et al.Yttrium 90 radioembolization for intermediate-advanced hepatocarcinoma: a phase II study.Hepatology. 2012; (Aug 22. http://dx.doi.org/10.1002/hep.26014 [Epub ahead of print])Google Scholar]. According to the manufacturer’s instructions, the prescribed activity of glass microspheres is based on a 2-compartment dosimetry model with the aim of delivering a radiation dose of 120 Gy to the targeted liver (irrespective of the tumor burden). For resin microspheres, users have to choose between an empiric formula based on body surface area and tumor burden, or by a 3-compartment dosimetry model with the aim of delivering a radiation dose of 70–80 Gy to the targeted non-tumoral liver. However, experienced centers have described different attempts to use other dosimetry models to improve the efficacy of RE with both resin [[7]Kao Y.H. Hock Tan A.E. Burgmans M.C. Irani F.G. Khoo L.S. Gong Lo R.H. et al.Image-guided personalized predictive dosimetry by artery-specific SPECT/CT partition modeling for safe and effective 90Y radioembolization.J Nucl Med. 2012; 53: 559-566Crossref PubMed Scopus (126) Google Scholar] and glass microspheres [[8]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 (90)Y microspheres: the experience of the National Tumor Institute of Milan.Q J Nucl Med Mol Imaging. 2011; 55: 168-197PubMed Google Scholar]. The statement that the dosimetry approach developed by Garin et al. resulted in treatment intensification in 25% of patients, along with good tolerance has to be taken with caution since it is based on only 4 patients that received a dose higher than that prescribed by the conventional method of activity calculation for glass microspheres [[5]Garin E. Lenoir L. Rolland Y. Edeline J. Mesbah H. Laffont S. et al.Dosimetry based on 99mTc-macroaggregated albumin SPECT/CT accurately predicts tumor response and survival in hepatocellular carcinoma patients treated with 90Y-loaded glass microspheres: preliminary results.J Nucl Med. 2012; 53: 255-263Crossref PubMed Scopus (193) Google Scholar]. This early experience from their and other groups with these dosimetry models is certainly encouraging but only prospective studies in large series of patients will tell us if this approach proves to preserve safety while they increase efficacy. It is well know that with a comparable size range but a different activity per sphere, the number of particles used in a typical RE treatment is higher for resin than for glass microspheres. Garin et al. invalidly derive from this fact that resin microspheres are associated with a higher embolic effect and a higher chance of intrahepatic reflux without providing any scientific support to these assertions. Furthermore, they sustain that resin microspheres carry an increased risk of gastric ulcer, which again is a misleading statement. Gastric ulcers result from the unnoticed presence of collateral vessels and therefore, they are much dependent on the experience of the interventional radiologist performing the procedure and on the site of injection. The higher number of studies reporting gastric ulcers after RE using resin microspheres is most likely due to the fact that glass microspheres are almost invariably delivered by a selective lobar or sublobar injection while resin microspheres are quite often injected into the proper hepatic artery (particularly for unresectable liver metastases). When glass microspheres were injected into the hepatic artery in an early series of HCC patients, 13.6% of them developed gastric ulcerations [[9]Dancey J.E. Shepherd F.A. Paul K. Sniderman K.W. Houle S. Gabrys J. et al.Treatment of nonresectable hepatocellular carcinoma with intrahepatic 90Y-microspheres.J Nucl Med. 2000; 41: 1673-1681PubMed Google Scholar]. For resin microspheres, in the study referenced by Garin et al., the Mount Sinai group reported an incidence of 2.6% among 270 RE-treated patients [[10]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]. Finally, Garin et al. conclusion that “resin and glass microspheres are different products, with differing efficacy and toxicity profiles” is against all available scientific evidence. As shown in Fig. 5 of our review, the overall survival of patients treated with glass or resin microspheres across the different HCC tumor stages is very consistent. The incidence of liver-related adverse events shown in Table 3 is also very similar despite the above-mentioned differences in the proportion of patients treated in a lobar fashion. In summary, we totally agree with Garin et al. that better dosimetry models for therapeutic planning will be welcomed and their development is warranted, but we respectfully disagree that they are crucial, since the currently used methods result in significant clinical activity with an acceptable incidence of liver toxicity. Most importantly, we cannot find any scientific basis to sustain that glass microspheres have substantial benefits over resin microspheres or vice versa. What the available evidence shows is that radioembolization is indeed a very consistent therapeutic procedure irrespective of the device used and the type of tumor treated, and that future efforts should be dedicated to improve their performance and to find the precise role it may play in the evolving treatment paradigm of primary and secondary liver tumors. Conflict of interestBS, MI and JIB have received lecture fees, and BS and JIB have consulted for Sirtex Medical. BS, MI and JIB have received lecture fees, and BS and JIB have consulted for Sirtex Medical.