8/3/2016. Clinical Significance of RBE Variations in Proton Therapy. Why RBE (relative biological effectiveness)?

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1 8//06 Clinical Significance of Variations in Proton Therapy H. Paganetti PhD Professor, Harvard Medical School Director of Physics Research, Massachusetts General Hospital, Radiation Oncology Introduction Why (relative biological effectiveness)? Prescriptions are based on dose (physics), not outcome (biology; tumor control probability (TCP) or normal tissue complication probability (NTCP)) The dose in proton therapy is prescribed as Gy(); is a dose modifying factor Proton therapy is using a generic of. Introduction The is defined as the ratio of doses to reach the same level of effect when comparing two modalities for TCP could potentially deduced from tumor control data for NTCP is difficult to assess based on clinical data because photons generally deliver a more uniform dose to critical structures and the probability of radiation damage for a specified dose is sensitive to the volume of normal tissues irradiated The majority of laboratory data are on for cell survival in vitro

8//06 for cell survival Endpoint dependency S(D) = e -(ad+bd ) Cells with higher repair capacity (low α/β)

Scholz, GSI for cell survival Endpoint dependency Uncertainties due to α/β McNamara, Schuemann, Paganetti:

survival Endpoint dependency Inter-patient variability on cell survival can be substantial Links Fanconi

Efstathiou, Lu, Held, Willers: Int J Radiat Oncol Biol Phys 05 9: 08-089 Repair kinetics in HR-deficient

2 8//06 for cell survival Endpoint dependency S(D) = e -(ad+bd ) Cells with higher repair capacity (low α/β) show higher Carbon ions Photons M. Scholz, GSI for cell survival Endpoint dependency Uncertainties due to α/β McNamara, Schuemann, Paganetti: Phys Med Biol 05 60; Carabe, España, Grassberger, Paganetti: Phys Med Biol 0 58: 0-7 for cell survival Endpoint dependency Inter-patient variability on cell survival can be substantial Links Fanconi Anemia/BRCA pathway defects to elevated proton Liu, Ghosh, Magpayo, Testa, Tang, Biggs, Paganetti, Efstathiou, Lu, Held, Willers: Int J Radiat Oncol Biol Phys 05 9: Repair kinetics in HR-deficient cells were significantly delayed after proton irradiation, with elevated amounts of residual ghax foci Grosse, Fontana, Hug, Lomax, Coray, Paganetti, Sartori, Pruschy: Int J Radiat Oncol Biol Phys 0 88: 75-8

3 Cell Survival 8//06 for cell survival Endpoint dependency relevant for NTCP: Effect of interest (organ level): early effects such as erythema late effects such as lung fibrosis, lung function, spinal cord injury, or necrosis Typically measured other than cell survival (cellular level): Double-strand break induction Foci formation Chromosome aberrations Micronuclei formation Cell cycle disruption for cell survival Dose dependency LET d =.5 kev/mm.5.5 (a/b) = Gy (a/b) = Gy x x.. 0. protons g S(D) = e -(ad+bd ). Our Model Carabe et al. Wedenberg et al Dose (Gy) Dose (Gy) (a/b) x = 0 Gy..5 (a/b) = 5 Gy x Dose [Gy] 0.9 L,d H, a b L a b L 0.8 a b L max d H min d H Dose a (Gy) b L d H Dose (Gy) McNamara, Schuemann, Paganetti: Phys Med Biol 05 60; for cell survival Dose dependency Most experiments in vitro look at cell survival Precise measurements of cell survival below Gy are sparse Prescription doses are typically Gy/fraction There are only a few data points regarding dose dependency of in vivo below Gy for protons Aoki-Nakano et al. J Rad Res 0

M. Krämer et al.: Techn. Cancer Res. Treatm., 7-6, 00 Paganetti: Phys. Med.

(Protons) 0 5 0 5 0 LET d (kev/mm) (a/b) x = Gy 0 5 0 5 0 LET (kev/mm) d

Paganetti: Phys Med Biol 05 60; 899-86 Radiation is more effective when energy

Implication of (LET) for (depth) Dose = Fluence [/cm ] LET [kev/cm] / r [g/cm

Healthy tissue Entrance: ~. Center: ~.5 Distal edge: ~.5 Distal fall-off: ~.

4 M. Krämer et al.: Techn. Cancer Res. Treatm., 7-6, 00 Paganetti: Phys. Med. Biol. 998;, //06 for cell survival LET dependency Photons Low-LET (Protons) LET d (kev/mm) (a/b) x = Gy LET (kev/mm) d High-LET ( C) (a/b) x = 0 Gy LET (kev/mm) d McNamara, Schuemann, Paganetti: Phys Med Biol 05 60; Radiation is more effective when energy depositions are more concentrated in space for cell survival LET dependency Implication of (LET) for (depth) Dose = Fluence [/cm ] LET [kev/cm] / r [g/cm ] for cell survival LET dependency. is a conservative estimate! Healthy tissue Entrance: ~. Center: ~.5 Distal edge: ~.5 Distal fall-off: ~.7 (values averaged over all cell lines and SOBPs for in vitro cell survival) Paganetti H: Phys Med Biol 0 59: R9-R7

Giantsoudi, Sethi, Yeap, Eaton, Ebb, Caruso, Rapalino, Chen, Adams, Yock,

06 96; 87-96 Gy() Gy() kev/μm Gy() 06 96; 87-96 8//06 for cell survival

higher close to the target edge (mainly in OAR) Average across a typical

depends on a/b seems to be higher for tissues with a low a/b ratio

decreasing dose Indicates higher for OAR Measurements (in vitro and in

5 5 59. 5. Dose x. LET 5. Dose x Dose(-weighted) Dose (=.

Correlation of toxicity and LET Note: All 9 cases had similar LET

5 Giantsoudi, Sethi, Yeap, Eaton, Ebb, Caruso, Rapalino, Chen, Adams, Yock, Tarbell, Paganetti, MacDonald: Int. J. Radiat. Oncol. Biol. Phys ; Gy() Gy() kev/μm Gy() Giantsoudi, Sethi, Yeap, Eaton, Ebb, Caruso, Rapalino, Chen, Adams, Yock, Tarbell, Paganetti, MacDonald: Int. J. Radiat. Oncol. Biol. Phys ; //06 for cell survival depends on LET Increased effectiveness as a function of depth might be higher close to the target edge (mainly in OAR) Average across a typical SOBP is, on average, about. depends on a/b seems to be higher for tissues with a low a/b ratio (mainly OAR) values for endpoints other than cell survival are less well known. The for normal tissue response is unclear depends on dose increases with decreasing dose Indicates higher for OAR Measurements (in vitro and in vivo) typically do not provide high resolution below Gy Clinical evidence? Dose x. LET 5. Dose x Dose(-weighted) Dose (=.) - Clinical evidence? Correlation of toxicity and LET Note: All 9 cases had similar LET distributions Only with symptomatic treatment change Only symptomatic change correlated with LET increases with LET LET is not the sole indicator 5

considerations in treatment planning Planning technique maximizing target conformality 50. 6 55..5.5 Dose x.

6 Gy( ) kev/μm Gy( ) Gy( ) kev/μm Gy( ) 8//06 Clinical evidence? There is currently no clinical evidence for a correlation between areas of elevated LET () and toxicities Should we consider for NTCP in treatment planning? considerations in treatment planning Planning technique maximizing target conformality Dose x. LET Dose x Giantsoudi, Adams, Kim, MacDonald, Paganetti: Int. J. Radiat. Oncol. Biol. Phys. 06 under review considerations in treatment planning Planning technique minimizing maximum LET in the brainstem Dose x. LET Dose x Giantsoudi, Adams, Kim, MacDonald, Paganetti: Int. J. Radiat. Oncol. Biol. Phys. 06 under review 6

06 in preparation Giantsoudi, Adams, MacDonald,

LET Dose x considerations in treatment planning

7 Gy() Gy() Giantsoudi, Adams, MacDonald, Paganetti: Int. J. Radiat. Oncol. Biol. Phys. 06 in preparation Giantsoudi, Adams, MacDonald, Paganetti: Int. J. Radiat. Oncol. Biol. Phys. 06 in preparation 8//06 considerations in treatment planning!! =. =. var. var. stop through stop through Giantsoudi, Adams, Kim, MacDonald, Paganetti: Int. J. Radiat. Oncol. Biol. Phys. 06 under review considerations in treatment planning Passive Scattering Dose x. LET Pencil beam scanning Dose x.7 Dose x. LET Dose x considerations in treatment planning CTV Chiasm Passive Scattering Beam Scanning 7

OAR dose for Scanning increases the OAR dose for Uncertainties!

PLAN Biological treatment planning using physics information atypical

8 Giantsoudi, Adams, MacDonald, Paganetti: Int. J. Radiat. Oncol. Biol. Phys. 06 in preparation Grassberger, Trofimov, Lomax, Paganetti: Int. J. Radiat. Oncol. Biol. Phys. 0 80: //06 considerations in treatment planning Scanning reduces the OAR dose for Scanning increases the OAR dose for Uncertainties!! Biological treatment planning using physics information PLAN IMPT Dose LETd PLAN Biological treatment planning using physics information atypical meningioma CTV overlaps with optic nerve chiasm brainstem Unkelbach, Botas, Grassberger, Giantsoudi, Paganetti: Int. J. Radiat. Oncol. Biol. Phys. 06 under review 8

8//06 Biological treatment planning using physics information Scaling of LET x dose such

in center of 5cm SOBP 50 Gy 0 Gy 5 Gy physical dose LET x dose Unkelbach, Botas,

06 under review Biological treatment planning using physics information Meningioma reference

physics information Base-of-skull Chordoma TH-CD-09-6 (Thursday, August, 06) 0:00 AM - :00

9 8//06 Biological treatment planning using physics information Scaling of LET x dose such that =. in center of 5cm SOBP 50 Gy 0 Gy 5 Gy physical dose LET x dose Unkelbach, Botas, Grassberger, Giantsoudi, Paganetti: Int. J. Radiat. Oncol. Biol. Phys. 06 under review Biological treatment planning using physics information Meningioma reference plan re-optimized Unkelbach, Botas, Grassberger, Giantsoudi, Paganetti: Int. J. Radiat. Oncol. Biol. Phys. 06 under review Biological treatment planning using physics information Base-of-skull Chordoma TH-CD-09-6 (Thursday, August, 06) 0:00 AM - :00 PM Room: 09 reference plan re-optimized Unkelbach, Botas, Grassberger, Giantsoudi, Paganetti: Int. J. Radiat. Oncol. Biol. Phys. 06 under review 9

10 8//06 SUMMARY Proton therapy uses a generic of. because of substantial uncertainties in as a function of dose, endpoint and LET The is potentially higher towards the distal end of an SOBP and for low α/β. The relevance of endpoints other than cell survival for defining clinical s is unclear. For a given dose and organ, the dependency on LET is monotone (reasonably linear) There is no evidence (yet) for a correlation between LET and toxicity or recurrence /LET optimization may improve treatment outcome Inter-patient variability (biomarkers?) is not well understood MGH Radiation Oncology Monte Carlo and Biophysics Research Team Stephen McMahon Harald Paganetti Jan Unkelbach David Hall Jan Schuemann Clemens Grassberger Aimee McNamara Pablo Botas Tracy Underwood Hakan Oesten Jungwook Shin Maria Marteinsdottir Drosoula Giantsoudi Changran Geng 0

Clinical considerations of RBE in proton therapy

Clinical considerations of RBE in proton therapy H. Paganetti PhD Professor, Harvard Medical School Director of Physics Research, Massachusetts General Hospital, Radiation Oncology Why do we need the RBE