Isoeffective Dose Specification of Normal Liver in Yttrium-90 Microsphere Radioembolization*

Transcription

1 Isoeffective Dose Specification of Normal Liver in Yttrium-90 Microsphere Radioembolization* Barry W. Wessels, Ph.D 1 ; Amilia G. Di Dia, PhD 2 ;Yiran Zheng, PhD 1 Marta Cremonesi, PhD 2 1 University Hospitals Case Medical Center, Cleveland, Ohio 2 Unit of Medical Physics, European Institute of Oncology, Milan, Italy *In collaboration with the Task Group on IsoEffective Dose Specification - MIRD Committee, Society of Nuclear Medicine November 10, 2010

2 Biological Effects of Radiation 1. Stochastic effects (cancer induction, genetic) Health Physics application Probability of effect occurrence increases with dose Observed at lower absorbed dose < 1 Gy Application to public/worker exposure Fixed weighting factor used (Sv = w R w T Gy) The Sievert 2. Non-stochastic (deterministic) or Acute effects Radiation Therapy application - Toxicity (NTCP),Tumor Control Probability (TCP) Severity/effect increases with dose Higher absorbed dose range Gy Useful in defining dose-response for cancer therapy Dependent on RBE, Dose rate, volume of irradiation, other biological endpoints (e.g. platelet count, prior therapies). No special unit or named quantity uniformly adopted as yet!

3 An Array of Biologically Equivalent Dose Equivalent Dose (Sv) (rem) Effective dose (Sv) RBE weighted-dose (Gy) Gy equivalent dose (GyE or CGE) NSD Nominal Standard Dose (rets) TDF time dose fractionation (unitless) BED Biological Effective Dose (Gy) EUD Equivalent Uniform dose (Gy) ERD Extrapolated Response Dose (Gy) SED Standard Effective Dose (Gy) SFED Single Fraction Equivalent Dose (Gy) LQED - Linear Quadratic Equivalent Dose (Gy) EQD2 Equivalent dose in 2 Gy fractions (Gy) D IsoE Isoffective Dose (Gy) or Bd

4 Biological Effects in Ion Beam Therapy

5 Isoeffective Dose ( D IsoE )

6 A New Dosimetry Unit barendsen (Bd)

7 barendsen (Bd) Definition 1 Bd = Deterministic Equivalent biologic effect to Co-60 irradiation of 1 Gy given in 2 Gy fractions over a uniform, whole organ volume Similar to: 1. LQED (Yaes 1989 ), EQD2 (Joiner 2002), or SED (Timmerman 2008) used for dose rate effects only. No special unit Gy used. 2. D IsoE (Isoeffective Dose) Adopted by ICRU/IAEA 2006 No special unit Gy used

8 Barendsen Unit gaining some recognition in the literature 1. J. Fowler and R. Dale s Letter to Editor (INT J RADIAT ONCOL BIOL PHYS 2010;76: ) WHEN IS A BED NOT A BED? WHEN IT IS AN EQD2 As the originators and two of the most experienced users of BED (4, 5, 6, 9), it gives us pleasure to support the proposal of the barendsen unit, as distinct from the EQD2. Note Authors advocate Bd to be based on infinitesimally small doses BED definition rather than 2 Gy fractions. 2. C. Ma in his Med. Physics correspondence (Apr 2010) On the definition of biologically equivalent radiation dose quantities advocates the need for a deterministc unit Cites barendsen.

9 Yttrium-90 Microspheres Radioembolization Treatment for Liver Cancer 35μm m diameter Yttrium 90 Beta 0.93MeV Half life 64.1hrs Penetration 2.5mm mean 11mm max

10 Radiation Dose Delivery in 90 Y Radioembolization Non-uniform dose distribution Varying dose rate The prescription dose is Gy delivered uniformly to entire liver!

11 Quantities Relevant to the Deterministic Effects in 90 Y Radioembolization 1. RBE-Weighted Dose Accounts for beam quality 2. Biologically Effective Dose (BED) - sensitive to dose rate and tissue repair time 3. Equivalent Uniform Dose (EUD) Accounts for dose heterogeneity, including DVH sensitivity

12 D IsoE Calculation - 90 Y Radioembolization DIsoE = WBED WEUD WRBE Mean Absorbed dose to the NL Assumption # 1 - Linear multiplication of weighting factors similar to methods to calculate Radiation Protection doses in Sieverts. Assumption # 2 Weighting factors are functionally independent quantities.

13 Relative biological effectiveness (RBE) RBE compares the effects of test radiation with a standard radiation type, which is usually 250 kvp x-rays: Dose from standard radiation RBE = to produce a given biological effect Dose from the test radiation to produce the same biological effect W RBE = nominally 1.0 for 90 Y radioembolization

14 BED Biologically Effective Dose 1. BED is a single quantity which may be used to compare dose given at different dose rates, tissue repair times or fractionation schemes. 2. For fractionated EBRT or HDR, the BED is given by: d BED = Dtotal RE = Nd (1 + ) α / β 3. For LDR or radioembolization, * λ D BED = D(1 + ) ( λ + μ) ( α / β) 4. W BED = Equivalent dose to NL in 2 Gy daily fractions Mean Absorbed dose to the NL *Dale RG. Dose-rate effects in targeted radiotherapy. Phys Med Biol. 1996;41:

15 Equivalent Uniform Dose (EUD) The EUD model converts the spatially varying absorbed dose distribution into an a single equivalent uniform dose value that would yield a similar biologic response based on same survival fraction value. ( D ) = e ( ) { } SF D 1 N = i = N i = 1 ( ) ( ) SF EUD SF D SF D For Radioembolization: (First-order model) i W EUD = EUD for DVH data of absorbed dose Mean Absorbed dose to the NL

16 Typical DVH for 90 Y Radioembolization

17 Sample Results for 5 patient distributions of Y-90 spheres in normal liver Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Mean Absorbed Dose (Gy) Mean BED (Gy) Mean EQD2 (Gy) EUD (Gy) W BED W EUD D IsoE (Gy) O'Donoghue's method (Gy) Difference 17% 16% 13% 28% 19% 1..O'Donoghue JA. Implications of nonuniform tumor doses for radioimmunotherapy. J Nucl Med. 1999;40(8):1337-.

18 Summary and conclusions (1) 1. Current method of prescribing absorbed dose uniformly to normal liver (80 Gy) shows that patients are receiving estimated 1/3 of the DLT (dose limiting toxicity). 2. Alternative prescription: Specify that a minimum 1/3 of liver volume receive < 20 Gy. The equivalent dose should not reach DLT, despite tumor and rest of the normal liver heterogeneously irradiated with dose > 100 Gy.

19 Summary and conclusions (2) 3. Patient Specific Dosimetry can play an active role in determining proper dose escalation for patient undergoing Y-90 microsphere radioembolization. 4. D IsoE method using weighting factors first describe for computing effective doses for particle beam therapy can be applied to similar problems encountered with radionuclide therapy.

20 Future Directions Deterministic Dose specification and biological endpoints 1. Recognize that ICRP, IAEA, NCRP, ICRU and MIRD committees continue to actively examine the biological effects of dose in terms of stochastic or non-stochastic endpoints. 2. Sort out which endpoints are most meaningful to a specific applications (e.g. ion beam therapy, radionuclide therapy, hypofractionated therapy). 3. Arrive at consensus documents which uses J/Kg, Gy, GyE or Bd for deterministic dose specification? 4. Provide a benchmark for IRB-FDA drug and device evaluation for future clinical trial design.