Skip to main content
SpringerLink
Log in

Radioembolization of hepatocarcinoma with 90Y glass microspheres: development of an individualized treatment planning strategy based on dosimetry and radiobiology

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

Abstract

Purpose

The aim of this study was to optimize the dosimetric approach and to review the absorbed doses delivered, taking into account radiobiology, in order to identify the optimal methodology for an individualized treatment planning strategy based on 99mTc-macroaggregated albumin (MAA) single photon emission computed tomography (SPECT) images.

Methods

We performed retrospective dosimetry of the standard TheraSphere® treatment on 52 intermediate (n = 17) and advanced (i.e. portal vein thrombosis, n = 35) hepatocarcinoma patients with tumour burden < 50 % and without obstruction of the main portal vein trunk. Response was monitored with the densitometric radiological criterion (European Association for the Study of the Liver) and treatment-related liver decompensation was defined ad hoc with a time cut-off of 6 months. Adverse events clearly attributable to disease progression or other causes were not attributed to treatment. Voxel dosimetry was performed with the local deposition method on 99mTc-MAA SPECT images. The reconstruction protocol was optimized. Concordance of 99mTc-MAA and 90Y bremsstrahlung microsphere biodistributions was studied in 35 sequential patients. Two segmentation methods were used, based on SPECT alone (home-made code) or on coregistered SPECT/CT images (IMALYTICS™ by Philips). STRATOS™ absorbed dose calculation was validated for 90Y with a single time point. Radiobiology was used introducing other dosimetric variables besides the mean absorbed dose D: equivalent uniform dose (EUD), biologically effective dose averaged over voxel values (BEDave) and equivalent uniform biologically effective dose (EUBED). Two sets of radiobiological parameters, the first derived from microsphere irradiation and the second from external beam radiotherapy (EBRT), were used. A total of 16 possible methodologies were compared. Tumour control probability (TCP) and normal tissue complication probability (NTCP) were derived. The area under the curve (AUC) of the receiver-operating characteristic (ROC) curve was used as a figure of merit to identify the methodology which gave the best separation in terms of dosimetry between responding and non-responding lesions and liver decompensated vs non-decompensated liver treatment.

Results

MAA and 90Y biodistributions were not different (71 % of cases), different in 23 % and uncertain in 6 %. Response correlated with absorbed dose (Spearman’s r from 0.48 to 0.69). Responding vs non-responding lesion absorbed doses were well separated, regardless of the methodology adopted (p = 0.0001, AUC from 0.75 to 0.87). EUBED gave significantly better separation with respect to mean dose (AUC = 0.87 vs 0.80, z = 2.07). Segmentation on SPECT gave better separation than on SPECT/CT. TCP(50 %) was at 250 Gy for small lesion volumes (<10 cc) and higher than 1,000 Gy for large lesions (>10 cc). Apparent radiosensitivity values from TCP were around 0.003/Gy, a factor of 3–5 lower than in EBRT, as found by other authors. The dose-rate effect was negligible: a purely linear model can be applied. Toxicity incidence was significantly larger for Child B7 patients (89 vs 14 %, p < 0.0001), who were therefore excluded from dose-toxicity analysis. Child A toxic vs non-toxic treatments were significantly separated in terms of dose averaged on whole non-tumoural parenchyma (including non-irradiated regions) with AUC from 0.73 to 0.94. TD50 was ≈ 100 Gy. No methodology was superior to parenchyma mean dose, which therefore can be used for planning, with a limit of TD15 ≈ 75 Gy.

Conclusion

A dosimetric treatment planning criterion for Child A patients without complete obstruction of the portal vein was developed.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Salem R, Mazzaferro V, Sangro B. Yttrium 90 radioembolization for the treatment of hepatocellular carcinoma: biological lessons, current challenges, and clinical perspectives. Hepatology 2013;58:2188–97.

    Article  CAS  PubMed  Google Scholar 

  2. Ahmadzadehfar H, Biersack HJ, Ezziddin S. Radioembolization of liver tumors with yttrium-90 microspheres. Semin Nucl Med 2010;40:105–21.

    Article  PubMed  Google Scholar 

  3. Spreafico C, Maccauro M, Mazzaferro V, Chiesa C. The dosimetric importance of the number of 90Y microspheres in liver transarterial radioembolization (TARE). Eur J Nucl Med Mol Imaging 2014;41:634–8.

    Article  PubMed  Google Scholar 

  4. Parker C, Nilsson S, Heinrich D, O’Sullivan JM, Fosså SD, Chodacki A, et al. Alpha emitter radium-223 and survival im metastatic prostate cancer. N Engl J Med 2013;369:213–23.

    Article  CAS  PubMed  Google Scholar 

  5. clinicaltrials.gov keyword NETTER-1.

  6. Cremonesi M, Chiesa C, Strigari L, Ferrari M, Botta F, Guerriero F, et al. Radioembolization of hepatic lesions from a radiobiology and dosimetric perspective. Front Oncol 2014;4:210. doi:10.3389/fonc.2014.00210.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Strigari 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;51:1377–85.

    Article  CAS  PubMed  Google Scholar 

  8. Chiesa C, Maccauro M, Romito C, 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.

    CAS  PubMed  Google Scholar 

  9. Walrand S, Hesse M, Chiesa C, Lhommel R, Jamar F. The low hepatic toxicity per gray of 90Y glass microspheres is linked to their transport in the arterial tree favoring a nonuniform trapping as observed in posttherapy PET imaging. J Nucl Med 2014;55:135–40.

    Article  CAS  PubMed  Google Scholar 

  10. Dawson LA, Ten Haken RK, Lawrence TS. Partial irradiation of the liver. Semin Radiat Oncol 2001;11:240–6.

    Article  CAS  PubMed  Google Scholar 

  11. Dawson LA, Ten Haken RK. Partial volume tolerance of the liver to radiation. Semin Radiat Oncol 2005;15:279–83.

    Article  PubMed  Google Scholar 

  12. Mazzaferro V, Sposito C, Bhoori S, Romito R, Chiesa C, Morosi C, et al. Yttrium-90 radioembolization for intermediate-advanced hepatocarcinoma: a phase 2 study. Hepatology 2013;57:1826–37.

    Article  CAS  PubMed  Google Scholar 

  13. Lau WY, Leung WT, Ho S, Leung NWY, 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;70:994–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Ho S, Lau WY, Leung TWT, Chan M, Ngar YK, Johnson PJ, et al. Partition model for estimating radiation doses from yttrium-90 microspheres in treating hepatic tumours. Eur J Nucl Med 1996;23:947–52.

    Article  CAS  PubMed  Google Scholar 

  15. Flamen P, Vanderlinde B, Delatte P, Ghanem G, Ameye L, Van Den Eynde M, et al. Corrigendum: Multimodality imaging can predict the metabolic response of unresectable colorectal liver metastases to radioembolization therapy with yttrium-90 labeled resin microspheres. Phys Med Biol 2008:53;6591–603 (Erratum in Phys Med Biol 2014:59;2549–51). doi:10.1088/0031-9155/59/10/2549.

  16. 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  CAS  PubMed  Google Scholar 

  17. Walrand S, Lhommel R, Goffette P, Van den Eynde M, Pauwels S, Jamar F. Hemoglobin level significantly impacts the tumor cell survival fraction in humans after internal radiotherapy. EJNMMI Res 2012;2:20. http://www.ejnmmires.com/content/2/1/20.

  18. Garin E, Lenoir L, Edeline J, Laffont S, Mesbah H, Porée P, et al. Boosted selective internal radiation therapy with 90Y-loaded glass microspheres (B-SIRT) for hepatocellular carcinoma patients: a new personalized promising concept. Eur J Nucl Med Mol Imaging 2013;40:1057–68. doi:10.1007/s00259-013-2395-x.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Chiesa C, Mira M, Maccauro M, Romito R, Spreafico C, Sposito C, et al. A dosimetric treatment planning strategy in radioembolization of hepatocarcinoma with 90Y glass microspheres. Q J Nucl Med Mol Imaging 2012;56:503–8.

    CAS  PubMed  Google Scholar 

  20. Lassmann M, Chiesa C, Flux G, Bardiès M, EANM Dosimetry Committee. EANM Dosimetry Committee guidance document: good practice of clinical dosimetry reporting. Eur J Nucl Med Mol Imaging 2011;38:192–200.

    Article  CAS  PubMed  Google Scholar 

  21. Dezarn WA, Cessa JT, DeWerd LA, Feng W, Gates VL, Kennedy AS, et al. Recommendations of the American Association of Physicists in Medicine on dosimetry, imaging, and quality assurance procedures for 90Y microsphere brachytherapy in the treatment of hepatic malignancies. Med Phys 2011;38:4824–45.

    Article  PubMed  Google Scholar 

  22. Dale RG. Dose-rate effects in targeted radiotherapy. Phys Med Biol 1996;41:1871–84.

  23. Barone R, Borson-Chazot F, Valkema R, Walrand S, Chauvin F, Gogou L, et al. Patient-specific dosimetry in predicting renal toxicity with (90)Y-DOTATOC: relevance of kidney volume and dose rate in finding a dose–effect relationship. J Nucl Med 2005;46:99S–106.

  24. O’Donoghue J. Implications of nonuniform tumor doses for radioimmunotherapy. J Nucl Med 1999;40:1337–41.

    PubMed  Google Scholar 

  25. Jones LC, Hoban PW. Treatment plan comparison using equivalent uniform biologically effective dose (EUBED). Phys Med Biol 2000;45:159–70.

    Article  CAS  PubMed  Google Scholar 

  26. Krishnan S, Lin EH, Gunn GB, Chandra A, Beddar AS, Briere TM, et al. Conformal radiotherapy of the dominant liver metastasis: a viable strategy for treatment of unresectable chemotherapy refractory colorectal cancer liver metastases. Am J Clin Oncol 2006;29:562–7.

    Article  PubMed  Google Scholar 

  27. Cremonesi M, Ferrari M, Bartolomei M, Orsi F, Bonomo G, Aricò D, et al. Radioembolization with 90Y-microspheres: dosimetric and radiobiological investigation for multi-cycle treatment. Eur J Nucl Med Mol Imaging 2008;35(11):2088–96.

    Article  CAS  PubMed  Google Scholar 

  28. Jackson A, Ten Haken RK, Robertson JM, Kessler ML, Kutcher GJ, Lawrence TS. Analysis of clinical complication data for radiation hepatitis using a parallel architecture model. Int J Radiat Oncol Biol Phys 1995;31(4):883–91.

    Article  CAS  PubMed  Google Scholar 

  29. Tai A, Erickson B, Khater KA, Li XA. Estimate of radiobiologic parameters from clinical data for biologically based treatment planning for liver irradiation. Int J Radiat Oncol Biol Phys 2008;70:900–7.

    Article  PubMed  Google Scholar 

  30. Agresti A, Coull BA. Approximate is better than “exact” for interval estimation of binomial proportions. Am Stat 1998;52(2):119–26.

  31. Lyman JT. Complication probability as assessed from dose-volume histograms. Radiat Res Suppl 1985;8:S13–9.

    Article  CAS  PubMed  Google Scholar 

  32. Moiseenko V, Song WY, Mell LK, Bhandare NA. Comparison of dose-response characteristics of four NTCP models using outcomes of radiation-induced optic neuropathy and retinopathy. Radiat Oncol 2011;6:61.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Walrand S, Hesse M, Jamar F, Lhommel RA. A hepatic dose-toxicity model opening the way toward individualized radioembolization planning. J Nucl Med 2014;55(8):1317–22.

    Article  PubMed  Google Scholar 

  34. Hanley JA, McNeil BJ. A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology 1983;148:839–43.

    Article  CAS  PubMed  Google Scholar 

  35. Dewaraja YK, Frey EC, Sgouros G, Brill AB, Roberson P, Zanzonico PB, et al. MIRD pamphlet No. 23: quantitative SPECT for patient-specific 3-dimensional dosimetry in internal radionuclide therapy. J Nucl Med 2012;53:1310–25.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Kao YH, Steinberg JD, Tay YS, Lim GKY, Yan J, Townsend DW, et al. Post-radioembolization yttrium-90 PET/CT - part 2: dose-response and tumor predictive dosimetry for resin microspheres. EJNMMI Res 2013;3:57.

  37. Pasciak AS, Bourgeois AC, Bradley YC. A comparison of techniques for (90)Y PET/CT image-based dosimetry following radioembolization with resin microspheres. Front Oncol 2014;4:121. doi: 10.3389/fonc.2014.00121 http://journal.frontiersin.org/Journal/10.3389/fonc.2014.00121/abstract.

  38. Pacilio M, Amato E, Lanconelli N, Basile C, Torres LA, Botta F, et al. Differences in 3D dose distributions due to calculation method of voxel S-values and the influence of image blurring in SPECT. Phys Med Biol 2015;60:1945–64.

    Article  PubMed  Google Scholar 

  39. Fertil B, Malaise EP. Intrinsic radiosensitivity of human cell lines is correlated with radioresponsiveness of human tumors: analysis of 101 published survival curves. Int J Radiat Oncol Biol Phys 1985;11:1699–707.

    Article  CAS  PubMed  Google Scholar 

  40. Stokkel MP, Handkiewicz Junak D, Lassmann M, Dietlein M, Luster M. EANM procedure guidelines for therapy of benign thyroid disease. Eur J Nucl Med Mol Imaging 2010;37:2218–28.

    Article  PubMed  Google Scholar 

  41. Maxon HR, Thomas SR, Hertzberg VS, Kereiakes JG, Chen IW, Sperling MI, et al. Relation between effective radiation dose and outcome of radioiodine therapy for thyroid cancer. N Engl J Med 1983;309(16):937–41.

    Article  CAS  PubMed  Google Scholar 

  42. Maxon HR. Quantitative radioiodine therapy in the treatment of differentiated thyroid cancer. Q J Nucl Med 1999;43:313–23.

    CAS  PubMed  Google Scholar 

  43. Sgouros G, Hobbs RF. Patient-specific dosimetry, radiobiology, and the previously-treated patient. In: Medical radiology. Radiation oncology. New York: Springer; 2012.

  44. Ulrich G, Dudeck O, Furth C, Ruf J, Grosser OS, Adolf D, et al. Predictive value of intratumoral 99mTc-macroaggregated albumin uptake in patients with colorectal liver metastases scheduled for radioembolization with 90Y-microspheres. J Nucl Med 2013;54:516–22.

    Article  CAS  PubMed  Google Scholar 

  45. Chiesa C, Lambert B, Maccauro M, Ezziddin S, Ahmadzadehfar H, Dieudonné A, et al. The predictive power of 99mTc-MAA SPECT/CT on lesion response cannot be invalidated for all kind of lesions and all kind of 90Y microspheres by a barely visual evaluation of the uptake and a RECIST response evaluation of colorectal metastases treated with resin microspheres. J Nucl Med 2014;55(7):1215–6.

    Article  PubMed  Google Scholar 

  46. Wondergem M, Smits MLJ, Elschot M, de Jong HWAM, Verkooijen HM, van den Bosch MAAJ, et al. 99mTc-macroaggregated albumin poorly predicts the intrahepatic distribution of 90Y resin microspheres in hepatic radioembolization. J Nucl Med 2013;54:1294–301.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors acknowledge Timo Paulus of Philips for the implementation of LDM in STRATOS, Luigi Mariani, for his suggestion of AUC comparison and Stephan Walrand, Marta Cremonesi, Francesca Botta, Amalia Di Dia and Massimiliano Pacilio for useful discussions.

Compliance with ethical standards

ᅟ

Conflict of interest

The following authors received honorarium from BTG Biocompatibles Ltd for one lecture per year held during the TheraSphere® training course in Foundation IRCCS Istituto Nazionale Tumori of Milan, Italy: C. Chiesa, M. Maccauro, C. Spreafico, R. Romito, C. Morosi, C. Sposito, S. Bhoori, A. Marchianò, F. Crippa and V. Mazzaferro. C. Chiesa C was paid by BTG Biocompatibles Ltd for two consultancy days in the last 2 years.

Research involving human participants and/or animals

For this retrospective study on human subjects, formal consent is not required.

Author information

Authors and Affiliations

  1. Nuclear Medicine Division, Foundation IRCCS Istituto Nazionale Tumori, Via Giacomo Venezian 1, 20133, Milan, Italy

    C. Chiesa, M. Maccauro, G. Aliberti, B. Padovano, M. Migliorisi, E. Seregni & F. Crippa

  2. Postgraduate Health Physics School, University of Milan, Milan, Italy

    M. Mira & A. Negri

  3. Radiology 2, Foundation IRCCS Istituto Nazionale Tumori, Milan, Italy

    C. Spreafico, C. Morosi, E. Civelli, R. Lanocita & A. Marchianò

  4. Surgery 1, Foundation IRCCS Istituto Nazionale Tumori, Milan, Italy

    R. Romito, C. Sposito, S. Bhoori, A. Facciorusso & V. Mazzaferro

  5. Scientific Direction, Foundation IRCCS Istituto Nazionale Tumori, Milan, Italy

    T. Camerini

  6. Health Physics, Foundation IRCCS Istituto Nazionale Tumori, Milan, Italy

    M. Carrara

  7. Engineering Faculty, University La Sapienza, Rome, Italy

    S. Pellizzari

  8. Clinical Engineering, Foundation IRCCS Istituto Nazionale Tumori, Milan, Italy

    M. Migliorisi

  9. Physics Faculty, University of Pavia, Pavia, Lombardy, Italy

    M. C. De Nile

Authors
  1. C. Chiesa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Mira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Maccauro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Spreafico
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. Romito
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C. Morosi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T. Camerini
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M. Carrara
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S. Pellizzari
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A. Negri
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. G. Aliberti
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. C. Sposito
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. S. Bhoori
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. A. Facciorusso
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. E. Civelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. R. Lanocita
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. B. Padovano
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. M. Migliorisi
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. M. C. De Nile
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. E. Seregni
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. A. Marchianò
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. F. Crippa
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. V. Mazzaferro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Chiesa.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 410 kb)

ESM 2

(XLS 124 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chiesa, C., Mira, M., Maccauro, M. et al. Radioembolization of hepatocarcinoma with 90Y glass microspheres: development of an individualized treatment planning strategy based on dosimetry and radiobiology. Eur J Nucl Med Mol Imaging 42, 1718–1738 (2015). https://doi.org/10.1007/s00259-015-3068-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-015-3068-8

Keywords

Search

Navigation