Skip to main content
SpringerLink
Log in

SIRT of liver metastases: physiological and pathophysiological considerations

  • Review Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Available literature on the differences in circulation and microcirculation of normal liver and liver metastases as well as in rheology of the different radiolabelled microspheres [99mTc-labelled macroaggregates of albumin (MAA), 90Y-TheraSpheres and 90Y-SIR-spheres] used in selective internal radiation therapy (SIRT) are reviewed and implications thereof on the practice of SIRT discussed. As a result of axial accumulation and skimming, large microspheres are preferentially deposited in regions of high flow, whereas smaller microspheres are preferentially diverted to regions of low flow. As flow to normal liver tissue is considerably variable between segments and also within one segment, microspheres will be delivered heterogeneously within the microvasculature of normal liver tissue. This non-uniformity in microsphere distribution in normal liver tissue has a significant “liver-sparing” effect on the dose distribution of 90Y-labelled microspheres. Arterial flow to liver metastases is most pronounced in the hypervascular rim of metastases, followed by the smaller metastases and finally by the central hypoperfused region of the larger metastases. Because of the wide variability in size of labelled MAAs and because of the skimming effect, existing differences in flow between metastatic lesions of variable size are likely exaggerated on 99mTc-MAA scintigraphy when compared to 90Y-TheraSpheres and 90Y-SIR-spheres (smaller variability in size and probably also in specific activity). Ideally, labelled MAAs would contain a size range similar to that of 90Y-SIR-spheres or 90Y-TheraSpheres. Furthermore, the optimal number of MAA particles to inject for the pretreatment planning scintigraphy warrants further exploration as it was shown that concentrated suspensions of microspheres produce more optimal tumour to normal liver distribution ratios. Finally, available data suggest that the flow-based heterogeneous distribution of microspheres to metastatic lesions of variable size might be optimized, that is rendered more homogeneous, through the combined use of angiotensin II and degradable starch microspheres.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kasper HU, Drebber U, Dries V, Dienes HP. Liver metastases: incidence and histogenesis. Z Gastroenterol 2005;43(10):1149–57.

    Article  PubMed  Google Scholar 

  2. Wellner UF, Keck T, Brabletz T. Liver metastases: pathogenesis and oncogenesis. Chirurg 2010;81:551–6.

    Article  PubMed  CAS  Google Scholar 

  3. Kuvshinoff B, Fong Y. Surgical therapy of liver metastases. Semin Oncol 2007;34:177–85.

    Article  PubMed  Google Scholar 

  4. Hoffmann RT, Paprottka P, Jakobs TF, Trumm CG, Reiser MF. Arterial therapies of non-colorectal cancer metastases to the liver (from chemoembolization to radioembolization). Abdom Imaging 2011;36:671–6.

    Article  PubMed  Google Scholar 

  5. Malik U, Mohiuddin M. External-beam radiotherapy in the management of liver metastases. Semin Oncol 2002;29:196–201.

    Article  PubMed  Google Scholar 

  6. Van de Wiele C, Defreyne L, Peeters M, Lambert B. Yttrium-90 labelled resin microspheres for treatment of primary and secondary malignant liver tumors. Q J Nucl Med Mol Imaging 2009;53:317–24.

    Google Scholar 

  7. Memon K, Lewandowski RJ, Kulik L, Riaz A, Mulcahy MF, Salem R. Radioembolization for primary and metastatic liver cancer. Semin Radiat Oncol 2011;21:294–302.

    Article  PubMed  Google Scholar 

  8. Welsh JS, Kennedy AS, Thomadsen B. Selective internal radiation therapy (SIRT) for liver metastases secondary to colorectal adenocarcinoma. Int J Radiat Oncol Biol Phys 2006;66:S62–73.

    Article  PubMed  CAS  Google Scholar 

  9. Wong CY, Savin M, Sherpa KM, Qing F, Campbell J, Gates VL, et al. Regional yttrium-90 microsphere treatment of surgically unresectable and chemotherapy-refractory metastatic liver carcinoma. Cancer Biother Radiopharm 2006;21:305–13.

    Article  PubMed  CAS  Google Scholar 

  10. Salem R, Lewandowski RJ, Sato KT, Atassi B, Ryu RK, Ibrahim S, et al. Technical aspects of radioembolization with 90Y microspheres. Tech Vasc Interv Radiol 2007;10:12–29.

    Article  PubMed  Google Scholar 

  11. Lewandowski RJ, Sato KT, Atassi B, Ryu RK, Nemcek Jr AA, Kulik L, et al. Radioembolization with 90Y microspheres: angiographic and technical considerations. Cardiovasc Intervent Radiol 2007;30:571–92.

    Article  PubMed  Google Scholar 

  12. 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;55:168–97.

    PubMed  CAS  Google Scholar 

  13. Kao YH, Hock Tan AE, Burgmans MC, Irani FG, Khoo LS, Gong Lo RH, et al. Image-guided personalized predictive dosimetry by artery-specific SPECT/CT partition modeling for safe and effective 90Y radioembolization. J Nucl Med 2012;53:559–66.

    Article  PubMed  CAS  Google Scholar 

  14. 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;53:255–63.

    Article  PubMed  CAS  Google Scholar 

  15. Lautt WW. Role and control of the hepatic artery. In: Lautt WW, editor. Hepatic circulation in health and disease. New York: Raven; 1981. p. 203–26.

    Google Scholar 

  16. Vollmar B, Menger MD. The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev 2009;89:1269–339.

    Article  PubMed  CAS  Google Scholar 

  17. Rappaport AM. Hepatic blood flow: morphologic aspects and physiologic regulation. Int Rev Physiol 1980;21:1–63.

    PubMed  CAS  Google Scholar 

  18. Greenway CV, Stark RD. Hepatic vascular bed. Physiol Rev 1971;51:23–65.

    PubMed  CAS  Google Scholar 

  19. Eipel C, Abshagen K, Vollmar B. Regulation of hepatic blood flow: the hepatic arterial buffer response revisited. World J Gastroenterol 2010;16:6046–57.

    Article  PubMed  Google Scholar 

  20. Taniguchi H, Oguro A, Takeuchi K, Miyata K, Takahashi T, Inaba T, et al. Difference in regional hepatic blood flow in liver segments—non-invasive measurement of regional hepatic arterial and portal blood flow in human by positron emission tomography with H2(15)O. Ann Nucl Med 1993;7:141–5.

    Article  PubMed  CAS  Google Scholar 

  21. Oda M, Yokomori H, Han JY. Regulatory mechanisms of hepatic microcirculatory hemodynamics: hepatic arterial system. Clin Hemorheol Microcirc 2006;34:11–26.

    PubMed  Google Scholar 

  22. Pannen BH. New insights into the regulation of hepatic blood flow after ischemia and reperfusion. Anesth Analg 2002;94:1448–57.

    PubMed  CAS  Google Scholar 

  23. Ueno T, Bioulac-Sage P, Balabaud C, Rosenbaum J. Innervation of the sinusoidal wall: regulation of the sinusoidal diameter. Anat Rec A Discov Mol Cell Evol Biol 2004;280:868–73.

    Article  PubMed  Google Scholar 

  24. Ezzat WR, Lautt WW. Hepatic arterial pressure-flow autoregulation is adenosine mediated. Am J Physiol 1987;252:H836–45.

    PubMed  CAS  Google Scholar 

  25. Lautt WW. The 1995 Ciba-Geigy Award Lecture. Intrinsic regulation of hepatic blood flow. Can J Physiol Pharmacol 1996;74:223–33.

    Article  PubMed  CAS  Google Scholar 

  26. Lautt WW. Hepatic vasculature: a conceptual review. Gastroenterology 1977;73:1163–9.

    PubMed  CAS  Google Scholar 

  27. Krylova NV. Characteristics of microcirculation in experimental tumours. Bibl Anat 1969;10:301–3.

    PubMed  CAS  Google Scholar 

  28. Mattsson J, Appelgren L, Hamberger B, Peterson HI. Adrenergic innervation of tumour blood vessels. Cancer Lett 1977;3:347–51.

    Article  Google Scholar 

  29. Hafström L, Nobin A, Persson B, Sundqvist K. Effects of catecholamines on cardiovascular response and blood flow distribution to normal tissue and liver tumors in rats. Cancer Res 1980;40:481–5.

    PubMed  Google Scholar 

  30. Wickersham JK, Barrett WP, Furukawa SB, Puffer HW, Warner NE. An evaluation of the response of the microvasculature in tumors in C3H mice to vasoactive drugs. Bibl Anat 1977;(15 Pt 1):291–3.

  31. Cuenod C, Leconte I, Siauve N, Resten A, Dromain C, Poulet B, et al. Early changes in liver perfusion caused by occult metastases in rats: detection with quantitative CT. Radiology 2001;218:556–61.

    PubMed  CAS  Google Scholar 

  32. Hemingway DM, Cooke TG, Grime SJ, Nott DM, Jenkins SA. Changes in hepatic haemodynamics and hepatic perfusion index during the growth and development of hypovascular HSN sarcoma in rats. Br J Surg 1991;78:326–30.

    Article  PubMed  CAS  Google Scholar 

  33. Fukumura D, Yuan F, Monsky WL, Chen Y, Jain RK. Effect of host microenvironment on the microcirculation of human colon adenocarcinoma. Am J Pathol 1997;151:679–88.

    PubMed  CAS  Google Scholar 

  34. Kruskal JB, Thomas P, Kane RA, Goldberg SN. Hepatic perfusion changes in mice livers with developing colorectal cancer metastases. Radiology 2004;231:482–90.

    Article  PubMed  Google Scholar 

  35. Carter R, Anderson JH, Cooke TG, Baxter JN, Angerson WJ. Splanchnic blood flow changes in the presence of hepatic tumour: evidence of a humoral mediator. Br J Cancer 1994;69:1025–6.

    Article  PubMed  CAS  Google Scholar 

  36. Sjövall S, Ahrén B, Bengmark S. Intermittent hepatic arterial or portal occlusion reduces liver tumor growth. J Surg Res 1991;50:146–9.

    Article  PubMed  Google Scholar 

  37. Kan Z, Ivancev K, Lunderquist A, McCuskey PA, Wright KC, Wallace S, et al. In vivo microscopy of hepatic tumors in animal models: a dynamic investigation of blood supply to hepatic metastases. Radiology 1993;187:621–62.

    PubMed  CAS  Google Scholar 

  38. Archer SG, Gray BN. Vascularization of small liver metastases. Br J Surg 1989;76:545–8.

    Article  PubMed  CAS  Google Scholar 

  39. Haugeberg G, Strohmeyer T, Lierse W, Böcker W. The vascularization of liver metastases. Histological investigation of gelatine-injected liver specimens with special regard to the vascularization of micrometastases. J Cancer Res Clin Oncol 1988;114:415–9.

    Article  PubMed  CAS  Google Scholar 

  40. Lin G, Lunderquist A, Hägerstrand I, Boijsen E. Postmortem examination of the blood supply and vascular pattern of small liver metastases in man. Surgery 1984;96:517–26.

    PubMed  CAS  Google Scholar 

  41. Taylor I, Bennett R, Sherriff S. The blood supply of colorectal liver metastases. Br J Cancer 1978;38:749–56.

    Article  PubMed  CAS  Google Scholar 

  42. Paris AL, Meissner WA, McDermott Jr WV. Histologic changes seen in the hepatic parenchyma and in metastatic nodules following hepatic dearterialization. J Surg Oncol 1982;19:114–8.

    Article  PubMed  CAS  Google Scholar 

  43. Oktar SO, Yücel C, Demirogullari T, Uner A, Benekli M, Erbas G, et al. Doppler sonographic evaluation of hemodynamic changes in colorectal liver metastases relative to liver size. J Ultrasound Med 2006;25:575–82.

    PubMed  Google Scholar 

  44. Shuman WP. Liver metastases from colorectal carcinoma: detection with Doppler US-guided measurements of liver blood flow—past, present, future. Radiology 1995;195:9–10.

    PubMed  CAS  Google Scholar 

  45. Miles KA, Leggett DA, Kelley BB, Hayball MP, Sinnatamby R, Bunce I. In vivo assessment of neovascularization of liver metastases using perfusion CT. Br J Radiol 1998;71:276–81.

    PubMed  CAS  Google Scholar 

  46. Flowerdew ADS, McLaren MI, Fleming JS, Britten AJ, Ackery DM, Birch SJ, et al. Liver tumour blood flow and responses to arterial embolization measured by dynamic hepatic scintigraphy. Br J Cancer 1987;55:269–73.

    Article  PubMed  CAS  Google Scholar 

  47. Ueda H, Lio M, Kaihara S. Determination of regional pulmonary blood flow in various cardiopulmonary disorders. Study and application of macroaggregated albumin (MAA) labelled with I-131 (I). Jpn Heart J 1964;190:431–44.

    Article  PubMed  CAS  Google Scholar 

  48. Taplin GV, Johnson DE, Dore EK, Kaplan HS. Suspensions of radioalbumin aggregates for photoscanning the liver, spleen, lung and other organs. J Nucl Med 1964;5:259–75.

    PubMed  CAS  Google Scholar 

  49. Chandra R, Shamoun J, Braunstein P, DuHov OL. Clinical evaluation of an instant kit for preparation of 99mTc-MAA for lung scanning. J Nucl Med 1973;14:702–5.

    PubMed  CAS  Google Scholar 

  50. Zamora PO, Rhodes BA. Imidazoles as well as thiolates in proteins bind technetium-99m. Bioconjug Chem 1992;3:493–8.

    Article  PubMed  CAS  Google Scholar 

  51. Rudolph AM, Heymann MA. The circulation of the fetus in utero. Methods for studying distribution of blood flow, cardiac output and organ blood flow. Circ Res 1967;21:163–84.

    Article  PubMed  CAS  Google Scholar 

  52. McDevitt DG, Nies AS. Simultaneous measurement of cardiac output and its distribution with microspheres in the rat. Cardiovasc Res 1976;10:494–8.

    Article  PubMed  CAS  Google Scholar 

  53. Fähraeus R. Die Strömungsverhältnisse und die Verteilung der Blutzellen im Gefäßsystem. Klin Wochenschr 1928;7:100–6.

    Article  Google Scholar 

  54. Segré G, Silberberg A. Radial particle displacements in Poiseuille flow of suspensions. Nature 1961;189:209–10.

    Article  Google Scholar 

  55. Segré G, Silberberg A. Behaviour of macroscopic rigid spheres in Poiseuille flow. Parts 1 and 2. J Fluid Mech 1962;14:115–57.

    Article  Google Scholar 

  56. Fung Y. Stochastic flow in capillary blood vessels. Microvasc Res 1973;5:34–48.

    Article  PubMed  CAS  Google Scholar 

  57. Bayliss LE. The axial drift of the red cells when blood flows in a narrow tube. J Physiol 1959;149:593–613.

    PubMed  CAS  Google Scholar 

  58. Ofjord ES, Clausen G, Aukland K. Skimming of microspheres in vitro: implications for measurement of intrarenal blood flow. Am J Physiol 1981;241:H342–7.

    PubMed  CAS  Google Scholar 

  59. Yipintsoi T, Dobbs Jr WA, Scanlon PD, Knopp TJ, Bassingthwaighte JB. Regional distribution of diffusible tracers and carbonized microspheres in the left ventricle of isolated dog hearts. Circ Res 1973;33:573–87.

    Article  PubMed  CAS  Google Scholar 

  60. Domenech RJ, Hoffman JI, Noble MI, Saunders KB, Henson JR, Subijanto S. Total and regional coronary blood flow measured by radioactive microspheres in conscious and anesthetized dogs. Circ Res 1969;25:581–96.

    Article  PubMed  CAS  Google Scholar 

  61. Katz MA, Blantz RC, Rector FC, Seldin DW. Measurement of intrarenal blood flow. I. Analysis of microsphere method. Am J Physiol 1971;220:1903–13.

    PubMed  CAS  Google Scholar 

  62. Meade VM, Burton MA, Gray BN, Self GW. Distribution of different sized microspheres in experimental hepatic tumours. Eur J Cancer Clin Oncol 1987;23:37–41.

    Article  PubMed  CAS  Google Scholar 

  63. Anderson JH, Angerson WJ, Willmott N, Kerr DJ, McArdle CS, Cooke TG. Regional delivery of microspheres to liver metastases: the effects of particle size and concentration on intrahepatic distribution. Br J Cancer 1991;64:1031–4.

    Article  PubMed  CAS  Google Scholar 

  64. Civalleri D, Rollandi G, Simoni G, Mallarini G, Repetto M, Bonalumi U. Redistribution of arterial blood flow in metastases-bearing livers after infusion of degradable starch microspheres. Acta Chir Scand 1985;151:613–7.

    PubMed  CAS  Google Scholar 

  65. Civalleri D, Scopinaro G, Simoni G, Claudiani F, Repetto M, DeCian F, et al. Starch microsphere-induced arterial flow redistribution after occlusion of replaced hepatic arteries in patients with liver metastases. Cancer 1986;58:2151–5.

    Article  PubMed  CAS  Google Scholar 

  66. Harell GS, Corbet AB, Dickhoner WH, Bradley BR. The intraluminal distribution of 15-micrometer-diameter carbonized microspheres within arterial microvessels as determined by vital microscopy of the golden hamster cheek pouch. Microvasc Res 1979;18:384–402.

    Article  PubMed  CAS  Google Scholar 

  67. da-Luz PL, Leite JJ, Barros LF, Dias-Neto A, Zanarco EL, Pileggi FJ. Experimental myocardial infarction: effect of methylprednisolone on myocardial blood flow after reperfusion. Braz J Med Biol Res 1982;15:355–60.

    PubMed  CAS  Google Scholar 

  68. Reed Jr JH, Wood EH. Effect of body position on vertical distribution of pulmonary blood flow. J Appl Physiol 1970;28:303–11.

    PubMed  Google Scholar 

  69. Burton M, Gray B, Coletti A. Effect of angiotensin II on blood flow in the transplanted sheep squamous cell carcinoma. Eur J Cancer Clin Oncol 1988;24:1373–6.

    Article  PubMed  CAS  Google Scholar 

  70. Sasaki Y, Imaoka S, Hasegawa Y, Nakano S, Ishikawa O, Ohigashi H, et al. Changes in distribution of hepatic blood flow induced by intra-arterial infusion of angiotensin II in human hepatic cancer. Cancer 1985;55:311–6.

    Article  PubMed  CAS  Google Scholar 

  71. Hemingway DM, Angerson WJ, Anderson JH, Goldberg JA, McArdle CS, Cooke TG. Monitoring blood flow to colorectal liver metastases using laser Doppler flowmetry: the effect of angiotensin II. Br J Cancer 1992;66:958–60.

    Article  PubMed  CAS  Google Scholar 

  72. Goldberg JA, Bradnam MS, Kerr DJ, Haughton DM, McKillop JH, Bessent RG, et al. Arteriovenous shunting of microspheres in patients with colorectal liver metastases: errors in assessment due to free pertechnetate, and the effect of angiotensin II. Nucl Med Commun 1987;8:1033–46.

    Article  PubMed  CAS  Google Scholar 

  73. Ho S, Lau WY, Leung WT, Chan M, Chan KW, Johnson PJ, et al. Arteriovenous shunts in patients with hepatic tumors. J Nucl Med 1997;38:1201–5.

    PubMed  CAS  Google Scholar 

  74. Chang D, Jenkins SA, Grime SJ, Nott DM, Cooke T. Increasing hepatic arterial flow to hypovascular hepatic tumors using degradable starch microspheres. Br J Cancer 1996;73:961–5.

    Article  PubMed  CAS  Google Scholar 

  75. Ziessman HA, Thrall JH, Gyves W, Ensminger WD, Niederhuber JE, Tuscan M, et al. Quantitative hepatic arterial perfusion scintigraphy and starch microspheres in cancer chemotherapy. J Nucl Med 1983;24:871–5.

    PubMed  CAS  Google Scholar 

  76. Bester L, Salem R. Reduction of arteriohepatovenous shunting by temporary balloon occlusion in patients undergoing radioembolization. J Vasc Interv Radiol 2007;18:1310–4.

    Article  PubMed  Google Scholar 

  77. Roberson PL, Ten Haken RK, McShan DL, McKeever PE, Ensminger WD. Three-dimensional tumor dosimetry for hepatic yttrium-90-microsphere therapy. J Nucl Med 1992;33:735–8.

    PubMed  CAS  Google Scholar 

  78. Campbell AM, Bailey IH, Burton MA. Tumour dosimetry in human liver following hepatic yttrium-90 microsphere therapy. Phys Med Biol 2001;46:487–98.

    Article  PubMed  CAS  Google Scholar 

  79. Vaupel P. Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. Oncologist 2008;13:21–6.

    Article  PubMed  CAS  Google Scholar 

  80. Kunz M, Ibrahim S. Molecular responses to hypoxia in tumor cells. Mol Cancer 2003;2:23.

    Article  PubMed  Google Scholar 

Download references

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine (P7), University Hospital Ghent, De Pintelaan 185B, 9000, Ghent, Belgium

    Christophe Van de Wiele, Yves D’Asseler & Gilles Mees

  2. Department of Nuclear Medicine, AZ Groeninge, Kortrijk, Belgium

    Alex Maes

  3. Department of Morphology and Medical Imaging, University Hospital Leuven, Leuven, Belgium

    Alex Maes

  4. Department of Radiology, AZ Groeninge, Kortrijk, Belgium

    Eddy Brugman

  5. Department of Analytical Chemistry, University Ghent, Ghent, Belgium

    Bart De Spiegeleer

  6. Department of Radiotherapy and Medical Oncology, AZ Groeninge, Kortrijk, Belgium

    Karin Stellamans

Authors
  1. Christophe Van de Wiele
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alex Maes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eddy Brugman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yves D’Asseler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bart De Spiegeleer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gilles Mees
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Karin Stellamans
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christophe Van de Wiele.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Van de Wiele, C., Maes, A., Brugman, E. et al. SIRT of liver metastases: physiological and pathophysiological considerations. Eur J Nucl Med Mol Imaging 39, 1646–1655 (2012). https://doi.org/10.1007/s00259-012-2189-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-012-2189-6

Keywords

Search

Navigation