The Impact of Cobalt-60 Source Age on Biologically Effective Dose in Gamma Knife Thalamotomy BH Kann, JB Yu, J Bond, C Loiselle, VL Chiang, RS Bindra, JL Gerrard, DJ Carlson Leksell Gamma Knife Society Meeting 2016 May 17 th, 2016 Presented by Benjamin H. Kann, MD Department of Therapeutic Radiology Yale University School of Medicine New Haven, CT, USA S L I D E 0
Disclosures I have no conflicts of interest to disclose S L I D E 1
Background Tremor greatly reduces QoL Parkinsonian Multiple Sclerosis Essential Incidence ~616 per 100,000 people Treatment options Medical management Surgical thalamotomy RF ablation DBS Gamma Knife (GK) radiosurgery J. Benito-León, et al. Incidence of essential tremor in three elderly populations of central Spain Neurology, 64 (2005), pp. 1721 1725 S L I D E 2
GK Thalamotomy Single 4mm shot to the thalamic ventralis intermedius (VIM) nucleus to ~130 Gy* Kooshkabadi, et al. Gamma knife thalamotomy for tremor in the magnetic resonance imaging era. J Neurosurg, 118 (2013), pp. 713 718 Yamada, et al. MR Imaging of Ventral Thalamic Nuclei. AJNR 2010 31: 732-735 S L I D E 3
GK Thalamotomy Promising efficacy >80% tremor improvement in most series Toxicity rare (<10%), but can be severe Hemiparesis, paresthesia, dysarthria, dysphagia, gait disturbance, death due to hemorrhage/necrosis Multifactorial Anecdotal reports: increased toxicity with Cobalt-60 source replacement Campbell, et al. Gamma knife stereotactic radiosurgical thalamotomy for intractable tremor: A systematic review of the literature, Radiotherapy and Oncology. March 2015, R.F. Young, et al. Gamma knife thalamotomy for treatment of tremor: long-term results. J Neurosurg, 93 (2000), pp. 128 135 Lee et al. Higher dose rate Gamma Knife radiosurgery may provide earlier and longer-lasting pain relief for patients with trigeminal neuralgia. Journal of Neurosurgery. Oct 2015, Vol. 123, No. 4, Pages 961-968 S L I D E 4
GK Thalamotomy Source Age / Dose Rate Cobalt-60 lifespan (half-life ~5.25 years) New source Replacement Old source Source Activity Dose Rate Treatment Time toxicity? efficacy? 1) Fowler et al. Loss of biological effect in prolonged fraction delivery. May 2004, Pages 242 249 S L I D E 5
Hypotheses Given high Rx dose of GK thalamotomy, biologically effective dose (BED) of treatment may vary significantly with Cobalt-60 source age This variation may substantial enough to expect effect on clinical outcome A BED model based on the linear-quadratic (LQ) model with correction for intra-fraction DNA repair could estimate BED variation with source age S L I D E 6
Methods - BED: the LQ Model [ λ,t] ln SD ( ) G D BED = D 1 + α α / β G = protraction factor (~intra-fraction repair) T = irradiation time (~Co-60 source age) τ= DNA repair half-time (~0.1 to 10 hr) λ = ln 2 τ Adapted from Carlson et al. S L I D E 7
GK Thalamotomy BED Model Construction Model Parameters: D, T, α/β, τ Dose Treatment time α/β Alpha / Beta τ DNA repair half-time ln 2 λ = τ S L I D E 8
GK Thalamotomy BED Model Construction Model Parameters: Dose = 130 Gy λ = ln 2 τ Treatment time ~ Co-60 Source Age New Source: Dose Rate(t=0) = 2.99 Gy/min * Exponential activity decay (T 1/2 = 5.25 years = 63 months) Dose Rate(t) = Dose Rate(0) x A [ ] A = Ao exp ln(2) / 63 t t = Source Age (mo) Treatment time (T) = Rx Dose / Dose Rate (t) *derived from departmental/vendor data S L I D E 9
GK Thalamotomy BED Model Construction Model Assumptions: α/β - Empirical data suggests α/β ~ 2 for CNS tissue λ = ln 2 τ τ Bi-exponential DNA repair half-times ( fast and slow components) Model range: τ(fast) = 0.1 to 0.7 h; τ(slow) = 2 to 6 h Most plausible scenario: τ(fast) =.38 h; τ(slow) = 4.1 h K.K Ang, Radiotherapy and Oncology, 1992. Pop et al, Radiotherapy and Oncology, 2000. Landuyt et al, Radiotherapy and Oncology, 1997. S L I D E 10
Results 200 180 160 Change in Treatment Time (T) with Co-60 Source Age Tx time (minutes) 140 120 100 80 60 40 20 TxTime Treatment Time Old source: 88 min (1.48 Gy/ min) New source: 43 min (2.99 Gy/min) 0 0 12 24 36 48 60 72 84 96 108 120 132 144 Age of source (months) S L I D E 11
Results BED 0% -5% -10% -15% -20% -25% -30% -35% -40% % Decrease in BED with Cobalt-60 source age for 130 Gy thalamotomy τ f =.7, τ s = 6 τ f =.38, τ s = 4.1 * τ f =.1, τ s = 2 0 12 24 36 48 60 72 84 96 108 120 132 144 Cobalt-60 Source Age (months) With new source replacement:** 15.6% relative increase in BED (range: 11-20%) *Using most plausible Tau assumptions. **with replacement after 63 months S L I D E 12
Conclusions Using biologically most plausible assumptions, Cobalt-60 source replacement causes a relative BED increase of ~16% for GK Thalamotomy, that then declines by ~3% per year over Cobalt- 60 lifespan Magnitude of BED change dependent on DNA-repair kinetics, timing of source replacement, initial source activity Co-60 source age and dose rate should be considered in the study and use of GK thalamotomy and other high-dose GK treatments S L I D E 13
Limitations / Next Steps Clinically correlated data needed Toxicity vs. efficacy Radiographic changes Practice changes? Prescription dose adjustment with Co-60 source age Prolong treatment time with selective collimation S L I D E 14
Thank You Acknowledgements David Carlson, PhD James Yu, MD Department of Therapeutic Radiology, Yale School of Medicine Department of Neurosurgery, Yale School of Medicine S L I D E 15
Appendix Factors affecting toxicity: -Target placement -Patient sensitivity -Lesion size result S L I D E 16
Results 8000 Decrease in BED with increased treatment times 130 Gy thalamotomy BED 7000 6000 5000 4000 3000 τ f =.7, τ s = 6 τ f =.38, τ s = 4.1 * Increase Rx dose Increase %BED change Increase starting dose rate, DECREASE %BED change Increasing Tau DECREASE %BED change 2000 1000 τ f =.1, τ s = 2 0 40 50 60 70 80 90 100 110 120 130 140 Treatment Time (min) *Using most plausible Tau assumptions S L I D E 17
GK Thalamotomy BED Model Construction Model Assumptions: α/β - Empirical data suggests α/β ~ 2 for CNS tissue τ(dna repair half-time) - Empirical evidence suggest bi-exponential DNA repair half-times ( fast and slow components) Rat Spinal Cord Study Fast (hr) Slow (hr) % fast repair a/b (gy) K.K Ang, Radiotherapy and Oncology, 1992 0.7 3.8 38% 2 Pop et al, Radiotherapy and Oncology, 2000 0.19 2.16 51% 2.47 Landuyt et al, Radiotherapy and Oncology, 1997 0.25 6.4 50% 2 Mean 0.38 4.1 Model range: τ(fast) = 0.1 to 0.7 h; τ(slow) = 2 to 6 h λ = ln 2 τ Most plausible scenario: τ(fast) =.38 h; τ(slow) = 4.1 h With assumed equal contribution (50:50) in DNA repair S L I D E 18
Dose rate effects and DNA damage repair 10 0 Cell survival increases with decreasing dose rate Surviving Fraction 10-1 10-2 10-3 45 Gy h -1 0.12 Gy h -1 0.5 Gy h -1 If dose protraction effects included in the model, a unique set of parameters can predict the entire data set: α = 0.04 Gy -1 β = 0.02 Gy -2 τ = 6.4 h 10-4 0 5 10 15 20 25 30 35 Absorbed Dose (Gy) Chinese Hamster Ovary (CHO) Measured data from Stackhouse M.A. and Bedford J.S. Radiat. Res. 136, 250-254 (1993) and Wells R.L. and Bedford J.S. Radiat. Res. 94(1), 105-134 S L I D E 19
Biologically Effective Dose (BED) BED is an LQ based estimate of the effective biological dose that accounts for delivered total dose, the dose fractionation, and the radiosensitivity of tissue Commonly used for isoeffect calculations Recall = + 2 S( D) exp αd βgd γt Take the negative logarithm of S and divide by α : ln S( D) GD γt BED = D 1 α + α / β α Physical dose Relative effectiveness Lost dose due to repopulation effect S L I D E 20
BED in the literature This derived expression is more general than the commonly used BED formalism 1/n 0 GD γ T BED = ln SD ( ) / α = D 1 + α/ β α In the literature, repopulation effects are usually neglected and G is set equal to 1/n (appropriate for daily fractions), where n = number of fractions. d BED = D 1 + α/ β where d = dose per fraction (Gy) and D = total treatment dose (= nd). HR Withers, HD Thames, LJ Peters. A new isoeffect curve for change in dose per fraction. Radiother. Oncol. 1, 187-191 (1983). S L I D E 21
Absolute Decrease in BED with Cobalt-60 source age for 130 Gy thalamotomy 8000 7000 6000 5000 BED 4000 3000 2000 1000 0 0 10 20 30 40 50 60 70 Cobalt-60 Source Age (months) BED2 BED3 BED4 S L I D E 22
Results % Decrease in BED with Cobalt-60 source age for 130 Gy thalamotomy With new source replacement: 0,0% BED -2,0% -4,0% -6,0% -8,0% -10,0% -9.5% 15.6% relative increase in BED -12,0% -14,0% -16,0% -18,0% τ f =.7, τ s = 6-13.2% τ f =.38, τ s = 4.1 * -16.5% τ f =.1, τ s = 2 0 10 20 30 40 50 60 70 Cobalt-60 Source Age (months) *Using most plausible Tau assumptions S L I D E 23