New Thinking on Fractionation in Radiotherapy Alan E. Nahum Visiting Professor, Physics dept., Liverpool university, UK alan_e_nahum@yahoo.co.uk 1
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Acknowledgements Aswin Hoffmann PhD OncoRay, Dresden Julien Uzan PhD RaySearch AB, Stockholm (formerly Clatterbridge Cancer Centre, Merseyside, UK) 3
Old thinking on Fractionation up to ~15 years ago: All tumours have α/β ~10 Gy All late normal-tissue complications have α/β ~3 Gy Fraction sizes of 2 Gy ensure optimal therapeutic ratio Hypofractionation (~ 4-6 Gy) reserved for palliative cases New SBRT regimens with 15 20 Gy fraction sizes for small lung tumours considered by many to be dangerous Advances in external-beam radiotherapy heavily focussed on intensity modulation, possibly also protons i.e. on ever more conformal dose distributions. 4
The LINEAR-QUADRATIC model: Surviving fraction SF = exp (-αd - βmaxd 2 ) -ln(sf)/d = α + β MAX D Strong experimental support for the LQ model 5
The classic Withers LQ-based Iso-Effect Formula : 6
Isoeffectivity: Normal Tissues (late effects) 10 0 α/β = 3 Gy Surviving fraction 10-1 10-2 10-3 10-4 3 8.9 Gy Normal-tissue isoeffectivity: 3 x 8.9 Gy 20 2.75 Gy Tumour isoeffectivity: 3 x 11.1 Gy Reference regimen 10-5 0 5 10 15 20 25 30 35 40 45 50 55 Total (tumor) dose (Gy) 7
Breast tumours (thanks to Dr. Navita Somaiah, Royal Marsden) Breast cancer clonogens as sensitive to fraction size as the doselimiting normal tissues α/β 3 from trials done in the UK (J. Yarnold et al) and elsewhere. 40Gy/15F is gentler than 50Gy/25F & non-inferior in terms of tumour control; 5-fraction schedule under test Prostate tumours (thanks to Dr. Isabel Syndikus, Clatterbridge) Clinical/biological modelling results: Total hypo# α/β Ratio 95% CI Mirabel 5969 3559 1.4 Gy 0.9-2.2 Proust-Lima 5093 1949 1.55 Gy 0.46-4.52 Fowler IJROBP 2001;50:1024; Brenner IJROBP 2002;52:6; Mirabel IROBP 2011; Proust-Lima IJROBP 2011;79:195-201 8
We will now use the BioSuite software to refresh our knowledge of the radiobiology of fractionation: TCP of a prostate tumour (α/β =10 Gy) for serial organ-at-risk (rectal bleeding) isoeffect using α/β = 3 Gy, for different numbers of fractions: T C P % 100 50 15 Slow increase in TCP with number of fractions for NT isoeffect (NTCP=3.4%) : Classic Radiobiology 10 30 Number of Fractions 50 9
This time the α/β for the tumour is low : Prostate tumour (α/β = 3 Gy) TCP for serial organ-at-risk (e.g. rectal bleeding) isoeffect using α/β = 3 Gy, for different numbers of fractions: T C P % 100 50 15 TCP constant as number of fractions changes (for NT isoeffect - NTCP=3.4% ) Also Classic Radiobiology as α/β for normal tissue and tumour are equal. 10 Number of Fractions 30 50 10
Now we introduce tumour clonogen proliferation, starting 3 weeks into the treatment: Prostate tumour (α/β = 3 Gy) TCP for serial organ-at-risk (e.g. rectal bleeding) isoeffect using α/β = 3 Gy, for different numbers of fractions: T C P % 100 50 15 15 Number of Fractions 40 50 TCP constant out to fraction number 15 (3 weeks from start) then decreases due to clonogen proliferation; the effect of the weekend breaks can be seen.
P01 PTV = 51.2 cm 3 Non-small-cell Lung Tumours: 3 cases NTCP RP = 12% in each case Why such different behaviour from case to case? T C P % 15 P16 PTV = 106.6 cm 3 Number of Fractions 50 Because the dose distributions in the paired lungs surrounding the tumour are so variable, and NTCP is a function of mean lung dose. P20 PTV = 78.0 cm 3 Significant Potential to individualize the number of fractions i.e. not just SABR vs standard fractionation. Computed using BioSuite 12
Back to the Withers Iso-Effect Formula (WIF) : WIF is valid if: EITHER NT receives the same uniform dose as the tumour. OR the NT response is solely determined by its maximum dose (100% serial organ) tumour dose Early (animal) experiments which formed the basis for the low (α/β) NT and high (α/β) T hypothesis fulfilled the first of the above conditions For all other situations, WIF as presently applied to NTs is simply wrong e.g. Lung NTCP follows mean dose 13
The Hoffmann-Nahum (α/β) eff concept WIF for Normal Tissue Withers Isoeffect Formula (WIF) Left-hand expression should use the dose distribution in the normal tissue instead of the tumour dose Practical Solution: replace (α/β) NT with an effective value which yields exact NT iso-effect whilst retaining the tumour dose in the WIF : Normal tissue with parallel architecture (n = 1): aasss (α/β) eff is frequently much higher than 3 Gy and can approach 10 Gy 14
RE-OXYGENATION another reason to fractionate Alite F. et al, Local control dependendence on consecutive vs. Nonconsecutive fractionation in lung stereotactic body radiation therapy, Radioth. Oncol. 121 9-14 2016. Five-fraction SBRT delivered over non-consecutive days imparts superior Local Control and similar toxicity compared to consecutive fractionation. 15
Take-home messages: The old 2-Gy fraction size only applies to tumours with high α/β and with serial organ(s)-at-risk : i.e. head&neck. Small numbers of large fractions indicated for breast and prostate tumours due to their relatively low α/β Safe SBRT/SABR regimens with 15 20 Gy fraction sizes for early-stage NSC lung tumours are proof of the influence of the volume effect on fractionation sensitivity (N.B. lung tumour α/β not low) The individualization of fraction size/number (TCP as f n of number of fractions under isontcp) e.g. with BioSuite is potentially advantageous for any tumour where the principal organ-at-risk is quasi-parallel e.g. lung tumours surrounded by normal lung Further advances in conformality - i,e. reduced normal-tissue coverage per tumour dose - from RapidARC, proton therapy etc. will favour further hypofractionation: explore with BioSuite!
References: Fowler, J. F., Tome, W. A., Fenwick, J. D., and Mehta, M. P., A challenge to traditional radiation oncology, Int.J. Radiat. Oncol. Biol. Phys. 60 1241 1256 2004. Uzan J and Nahum AE, Radiobiologically guided optimisation of the prescription dose and fractionation scheme in radiotherapy using BioSuite, British Journal of Radiology 85 1279-86 2012. Hoffmann A L and Nahum A E, Fractionation in normal tissues: the (α/β) eff concept can account for dose heterogeneity and volume effects, Physics in MedicineandBiology 58 6897-914 2013. Chapman J.D. and Nahum A.E. Radiotherapy Treatment Planning Linear- Quadratic Radiobiology 2015 (CRC Press: Taylor & Francis Group). ISBN: 978-1- 4398-6259-9. Alan E Nahum. The Radiobiology of Hypofractionation. Clinical Oncology 27 260-269 2015. BioSuite is available from alan_e_nahum@yahoo.co.uk 17
Thank you for your attention 18