Bio-effect model applied to 131I radioimmunotherapy of refractory non-Hodgkin’s lymphoma

  • Peter L. Roberson
  • Hanan Amro
  • Scott J. Wilderman
  • Anca M. Avram
  • Mark S. Kaminski
  • Matthew J. Schipper
  • Yuni K. Dewaraja
Original Article



Improved data collection methods have improved absorbed dose estimation by tracking activity distributions and tumor extent at multiple time points, allowing individualized absorbed dose estimation. Treatment with tositumomab and 131I-tositumomab anti-CD20 radioimmunotherapy (BEXXAR) yields a cold antibody antitumor response (cold protein effect) and a radiation response. Biologically effective contributions, including the cold protein effect, are included in an equivalent biological effect model that was fit to patient data.


Fifty-seven tumors in 19 patients were followed using 6 single proton emission computed tomography (SPECT)/CT studies, 3 each post tracer (5 mCi) and therapy (∼100 mCi) injections with tositumomab and 131I-tositumomab. Both injections used identical antibody mass, a flood dose of 450 mg plus 35 mg of 131I tagged antibody. The SPECT/CT data were used to calculate absorbed dose rate distributions and tumor and whole-body time-activity curves, yielding a space-time dependent absorbed dose rate description for each tumor. Tumor volume outlines on CT were used to derive the time dependence of tumor size for tracer and therapy time points. A combination of an equivalent biological effect model and an inactivated cell clearance model was used to fit absorbed dose sensitivity and cold effect sensitivity parameters to tumor shrinkage data, from which equivalent therapy values were calculated.


Patient responses were categorized into three groups: standard radiation sensitivity with no cold effect (7 patients), standard radiation sensitivity with cold effect (11 patients), and high radiation sensitivity with cold effect (1 patient).


Fit parameters can be used to categorize patient response, implying a potential predictive capability.


Tumor volume Equivalent biological effect Tumor response Radiolabeled antibody therapy Non-Hodgkin’s lymphoma 



This work was supported by grant 2R01 EB001994 awarded by the National Institute of Health, US Department of Health and Human Services. The authors thank Ken Koral, Ph.D. for many useful discussions.

Supplementary material

259_2010_1699_MOESM1_ESM.doc (103 kb)
(DOC 103 kb)


  1. 1.
    Dewaraja YK, Wilderman SJ, Koral KF, Kaminski MS, Avram AM. Use of integrated SPECT/CT imaging for tumor dosimetry in I-131 radioimmunotherapy: a pilot patient study. Cancer Biother Radiopharm 2009;24:417–26.PubMedCrossRefGoogle Scholar
  2. 2.
    Kaminski MS, Zasadny KR, Francis IR, Milik AW, Ross CW, Moon SD, et al. Radioimmunotherapy of B-cell lymphoma with [131]anti-B1 [anti-CD20] antibody. N Engl J Med 1993;329:459–65.PubMedCrossRefGoogle Scholar
  3. 3.
    Kaminski MS, Estes J, Zasadny KR, Francis IR, Ross CW, Tuck M, et al. Radioimmunotherapy with iodine (131)I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience. Blood 2000;96:1259–66.PubMedGoogle Scholar
  4. 4.
    Davis TA, Kaminski MS, Leonard JP, Hsu FJ, Wilkinson M, Zelenetz A, et al. The radioisotope contributes significantly to the activity of radioimmunotherapy. Clin Cancer Res 2004;10:7792–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Fowler JF. The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol 1989;62:679–94.PubMedCrossRefGoogle Scholar
  6. 6.
    Wheldon TE, O’Donoghue JA. The radiobiology of targeted radiotherapy. Int J Radiat Biol 1990;58:1–21.PubMedCrossRefGoogle Scholar
  7. 7.
    Fowler JF. Radiobiological aspects of low dose rates in radioimmunotherapy. Int J Radiat Oncol Biol Phys 1990;18:1261–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Fowler JF. Correction to Kasibhatla et al. How much radiation is the chemotherapy worth in advanced head and neck cancer? (Int J Radiat Oncol Biol Phys 2007;68:1491–1495). Int J Radiat Oncol Biol Phys 2008;71:326–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Plataniotis GA, Dale RG. Use of the concept of equivalent biologically effective dose (BED) to quantify the contribution of hyperthermia to local tumor control in radiohyperthermia cervical cancer trials, and comparison with radiochemotherapy results. Int J Radiat Oncol Biol Phys 2009;73:1538–44.PubMedCrossRefGoogle Scholar
  10. 10.
    Prideaux AR, Song H, Hobbs RF, He B, Frey EC, Ladenson PW, et al. Three-dimensional radiobiologic dosimetry: application of radiobiologic modeling to patient-specific 3-dimensional imaging-based internal dosimetry. J Nucl Med 2007;48:1008–16.PubMedCrossRefGoogle Scholar
  11. 11.
    O’Donoghue JA. Implications of nonuniform tumor doses for radioimmunotherapy. J Nucl Med 1999;40:1337–41.PubMedGoogle Scholar
  12. 12.
    Amro H, Wilderman SJ, Dewaraja YK, Roberson PL. Methodology to incorporate biologically effective dose and equivalent uniform dose in patient-specific 3-dimensional dosimetry for non-Hodgkin lymphoma patients targeted with 131I-tositumomab therapy. J Nucl Med 2010;51:654–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Dewaraja YK, Schipper MJ, Roberson PL, Wilderman SJ, Amro H, Regan DD, et al. 131I-Tositumomab radioimmunotherapy: initial tumor dose-response results using 3-dimensional dosimetry including radiobiologic modeling. J Nucl Med 2010;51:1155–62.PubMedCrossRefGoogle Scholar
  14. 14.
    Kaminski MS, Zasadny KR, Francis IR, Fenner MC, Ross CW, Milik AW, et al. Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma. J Clin Oncol 1996;14:1974–81.PubMedGoogle Scholar
  15. 15.
    Wilderman SJ, Dewaraja YK. Method for fast CT/SPECT-based 3D Monte Carlo absorbed dose computations in internal emitter therapy. IEEE Trans Nucl Sci 2007;54:146–51.PubMedCrossRefGoogle Scholar
  16. 16.
    Pinheiro JC, Bates DM. Approximations to the log-likelihood function in the nonlinear mixed-effects model. J Comput Graph Stat 1995;4:12–35.CrossRefGoogle Scholar
  17. 17.
    Dale RG. The application of the linear-quadratic dose-effect equation to fractionated and protracted radiotherapy. Br J Radiol 1985;58:515–28.PubMedCrossRefGoogle Scholar
  18. 18.
    Macklis RM, Beresford BA, Humm JL. Radiobiologic studies of low-dose-rate 90Y-lymphoma therapy. Cancer 1994;73(3 Suppl):966–73.PubMedCrossRefGoogle Scholar
  19. 19.
    Hernandez MC, Knox SJ. Radiobiology of radioimmunotherapy: targeting CD20 B-cell antigen in non-Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 2004;59:1274–87.PubMedCrossRefGoogle Scholar
  20. 20.
    Marples B, Lambin P, Skov KA, Joiner MC. Low dose hyper-radiosensitivity and increased radioresistance in mammalian cells. Int J Radiat Biol 1997;71:721–35.PubMedCrossRefGoogle Scholar
  21. 21.
    Koster A, Tromp HA, Raemaekers JM, Borm GF, Hebeda K, Mackenzie MA, et al. The prognostic significance of the intra-follicular tumor cell proliferative rate in follicular lymphoma. Haematologica 2007;92:184–90.PubMedCrossRefGoogle Scholar
  22. 22.
    Tang B, Malysz J, Douglas-Nikitin V, Zekman R, Wong RH, Jaiyesimi I, et al. Correlating metabolic activity with cellular proliferation in follicular lymphomas. Mol Imaging Biol 2009;11:296–302.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Peter L. Roberson
    • 1
  • Hanan Amro
    • 1
  • Scott J. Wilderman
    • 2
  • Anca M. Avram
    • 2
  • Mark S. Kaminski
    • 3
  • Matthew J. Schipper
    • 1
  • Yuni K. Dewaraja
    • 2
  1. 1.Department of Radiation OncologyUniversity of MichiganAnn ArborUSA
  2. 2.Department of RadiologyUniversity of Michigan Medical CenterAnn ArborUSA
  3. 3.Division of Hematology and Oncology, Department of Internal MedicineUniversity of Michigan Medical CenterAnn ArborUSA

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