Radiobiological modelling applied to Unsealed Source (radio) Therapy

Transcription

1 Radiobiological modelling applied to Unsealed Source (radio) Therapy Alan E. Nahum Physics Department Clatterbridge Cancer Centre NHS Foundation Trust Bebington, Wirral CH63 4JY UK Nuclear Medicine Metrology (NM 3 ), National Physical Laboratory, 21 November 2014

2 Acknowledgements Per Nilsson Katarina Sjögreen Gleisner Mark Konijnenberg Glenn Flux Ralph McCready Emiliano Spezi & Nick Patterson (Velindre) Julian Uzan, Colin Baker, Anthony Carver (Clatterbridge) Don Chapman (British Columbia)

3 Contents Radiobiology refresher: LQ model; doserate Brief overview of TCP & NTCP models in external-beam therapy Special radiobiological features of MRT Is the Radiobiological Quality of MRT sources the same as that of megavoltage EBRT beams? TCP applied to MRT I-131/thyroid: case study Summary & Future perspectives

4 Radiobiology a brief refresher The Linear-Quadratic model of cell-killing - two very different mechanisms : Single-hit killing: non repairable - ad Sublethal lesions: singly repairable but can combine to yield bd 2 killing a-killing is unrepairable so makes no difference how it is delivered spaitally or temporally - cannot be influenced by dose rate, fractionation, intensity modulation etc. b-killing is TWO hit, therefore time-dependent : prolonged overall irradiation time will reduce killing due to repair of first lesion before second one arrives 4

5 The effect of delivery time i.e. dose rate Dose-rate effect for a human melanoma cell-line (Steel,1986) Dose repair effects between 1 Gy/min and 0.1 Gy/min (e.g. slow IMRT) may be significant. Also for SBRT with 3 x Gy: overall time is min. Low dose rate means b = 0 ; all cell killing is by the a mechanism 5

6 Are all (therapy) radiations equally effective, per unit dose? Radiobiological effect of different radiations is often expressed in terms of RBE: RBE = Relative Biological Effectiveness = Ratio of doses D ref /D X to produce a given biological effect ref is generally taken as 60 Co gamma rays.

7 40 kv x-rays was the quality under investigation

8 The RBE of other Radiation Qualities Reference radiation: Cobalt 60 g MeV Ultra-soft x-rays - around 3.4 for C X-rays (V79 hamster cells) where secondary electrons all below 1 kev! e.g. Goodhead and Nikjoo, Int. J. Rad. Biol (1989) Megavoltage x-rays, electrons indistinguishable from Cobalt-60, less effective than 250 kv x-rays e.g. Amols, Laguex and Cagna Radiation Research (1986)

9 kv Electron Fluence Per unit Dose Megavoltage 1 kev

10 What about the radionuclides used in MRT?

11 Monte-Carlo (GEANT4) work by Nick Patterson and Emiliano Spezi (Velindre cancer centre,cardiff) X-rays Kilovolt. Megavolt. Ra-223 a-emitter?? Lu-177 and I-131 are predicted to be more radiobiologically effective than P-31 and Y-90 which are equivalent to megavoltage photons 1 kev

12 These graphs explain why all megavoltage qualities have essentially identical radiobiological effectiveness this simplifies treatment planning: doses can simply be added, irrespective of beam direction and depth The marked increase in electron fluence per unit dose at low energies for all kilovoltage qualities over that for megavoltage is consistent with the increased RBE of kilovoltage x-rays The b-emitters we have looked at (I-131, Y-90 etc.) have a value of (1 kev)/d very close to that of megavoltage x-rays (EBRT). e- E

13 TCP and NTCP models in external-beam therapy

14 Modelling the probability of tumour control (TCP) TCP e -N s Where N s is the average number of surviving cells following irrradiation

15 SURVIVING FRACTION N s from the Linear Quadratic (LQ) model 2-Gy fractions CELL KILL IN 2-GY FRACTIONS E E E E E E E E E E E E DOSE(Gy) Clonogenic cells remaining after n fractions: - d d 2 d d 2 d d 2 N N e a b - e a b - e a b Single dose 2-Gy f ractions s 0 N after 1 st fraction N after 2 nd fraction... n times With the exception of fraction sizes above 10 Gy where the LQ model may no longer be valid and at doses less than 0.6 Gy (low dose hypersensitivity)

16 After n fractions of dose, d (Gy): b Ns ( VCTV c) exp -and 1 d ln(2) a T -T T d k Initial clonogen number Total Dose D LQ model Tumour repopulation c a,b T k T d clonogen density (estimated or fitted) radiosensitivities of the tumour clonogens (fitted via LQ model), delay before repopulation (days) clonogen doubling time (days)

17 Fit TCP parameters to clinical data population individual

18 Extension to inhomogeneous dose distributions DVHs summarise the dose distributions in a convenient way Volume Differential DVH Assume cells in each single dose bin j receive uniform total dose D j v j N 0, j c v j Total no. surviving cells, D j Dose N ( a ) N N e i i, j 0, j j j Clonogen density bi -ai Dj 1 d j ln( 2) ai T-T T d k

19 Effect of dose non-uniformity on TCP Tumour dose distribution (differential DVH) normally distributed with varying width but constant mean dose = 60 Gy. Inter-patient radiosensitivity s a varied from 0 to 0.05 to 0.10 to 0.15 s a 19

20

21 Iodine-131 therapy for thyroid cancer (half-life 8.02 days) The facts very high administered activity (AA) required for long-term remission ca. 100 mci or 3.7 GBq Assuming 10% uptake in the thyroid gland, and a mass of 10 g, this AA corresponds to an (equilibrium) absorbed dose of 1000 Gy Should we need such sky-high doses to achieve a high (say 99%) tumour control? Let s see what the TCP model says...

22 TCP TCP analysis ( Marsden model) using BioSuite Parameters a = 0.2 Gy -1 s a = 0.05 Gy -1 b = 0 (a/b v. high) N o = 10 7 clonogens Dose (Gy) Result: 99% TCP obtained with 142 Gy

23 99% TCP obtained with 142 Gy (for the most conservative assumptions on radiosensitivity, clonogen number etc.) But 1000 Gy found to be necessary in clinical practice! Why?

24 BioSuite: TCP (and NTCP) optimization software Freeware, Calculates (from DVHs e.g. from Eclipse or Pinnacle format): TCP (Marsden model) - the user has full control over the parameters NTCP (LKB, RS models) as a function of (total) dose and number of fractions; Iso-NTCP customised prescription doses; TCP at iso-ntcp for variable number of fractions Available from: alan.nahum@clatterbridgecc.nhs.uk

25

26 Take home messages I The low doserates in MRT mean that b 0 in the LQ expression for cell-killing The cell-killing per unit dose of most MRT sources will be very similar to that of megavoltage x-rays. Electron fluence (at 1 kev) per unit dose is a promising surrogate metric for the dependence of a (and b) on radiation quality Radiobiological models for TCP (mechanistic) and NTCP (quasi-mechanistic) for external-beam RT are well established (published around )

27 Take home messages II TCP modelling applied to e.g. I-131 for ca. Thyroid (assuming quasi-uniform uptake) predicts 100% cure rate for much lower activities than those clinically required probable explanation is HETEREGENEOUS uptake (cf. Sgouros et al 2008) Full Dose-Volume Histograms (of reasonable accuracy) will be required for reliable predictions of tumour control probability BioSuite freeware (Uzan and Nahum Br. J. Radiol. 2012) available on request

28 Thank you for your attention