New Thinking on Fractionation in Radiotherapy

Transcription

1 New Thinking on Fractionation in Radiotherapy Alan E. Nahum Visiting Professor, Physics dept., Liverpool university, UK 1

2 An honorarium is provided by Accuray for this presentation The views expressed in this presentation are those of the presenter and do not necessarily reflect the views or policies of Accuray Incorporated or its subsidiaries. No official endorsement by Accuray Incorporated, or any of its subsidiaries, of any vendor, products or services contained in this presentation is intended or should be inferred. 2

3 Acknowledgements Aswin Hoffmann PhD OncoRay, Dresden Julien Uzan PhD RaySearch AB, Stockholm (formerly Clatterbridge Cancer Centre, Merseyside, UK) 3

4 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 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

5 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

6 The classic Withers LQ-based Iso-Effect Formula : 6

7 Isoeffectivity: Normal Tissues (late effects) 10 0 α/β = 3 Gy Surviving fraction Gy Normal-tissue isoeffectivity: 3 x 8.9 Gy Gy Tumour isoeffectivity: 3 x 11.1 Gy Reference regimen Total (tumor) dose (Gy) 7

8 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 Gy Proust-Lima Gy Fowler IJROBP 2001;50:1024; Brenner IJROBP 2002;52:6; Mirabel IROBP 2011; Proust-Lima IJROBP 2011;79:

9 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 % Slow increase in TCP with number of fractions for NT isoeffect (NTCP=3.4%) : Classic Radiobiology Number of Fractions 50 9

10 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 % 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

11 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 % Number of Fractions 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.

12 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 = 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

13 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

14 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

15 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 Five-fraction SBRT delivered over non-consecutive days imparts superior Local Control and similar toxicity compared to consecutive fractionation. 15

16 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 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!

17 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 Uzan J and Nahum AE, Radiobiologically guided optimisation of the prescription dose and fractionation scheme in radiotherapy using BioSuite, British Journal of Radiology 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 Chapman J.D. and Nahum A.E. Radiotherapy Treatment Planning Linear- Quadratic Radiobiology 2015 (CRC Press: Taylor & Francis Group). ISBN: Alan E Nahum. The Radiobiology of Hypofractionation. Clinical Oncology BioSuite is available from alan_e_nahum@yahoo.co.uk 17

18 Thank you for your attention 18