Low-dose vs. high-dose effects New schedule of fractionation and their impact on local control and survival Low-dose vs. high-dose effects Marco Durante Jan. 21, 2012 PARTNER - EU FP 7

Contents Short summary of fractionation High-dose vs. low dose radiobiology Nontargeted effects High- and low doses for heavy ions Fractionation in heavy-ion treatment plans in Japan and Europe Jan. 21, 2012 PARTNER - EU FP 7

1. Recapitulation Jan. 21, 2012 PARTNER - EU FP 7

Fractionation (Recovery) Surviving cells behave like unirradiated cells, if dose is split and time for recovery is given Fractionation (Protraction) reduces the effect of total dose Jan. 21, 2012 PARTNER - EU FP 7

Jan. 21, 2012 PARTNER - EU FP 7

Early- and late-responding tissues a/b~10 1<a/b<7 Jan. 21, 2012 PARTNER - EU FP 7

Isoeffect doses for early and late normal tissue damage Accelerated repopulation in mouse tumors Gordon Steel, 2002 Jan. 21, 2012 PARTNER - EU FP 7

Variation in Radiation Sensitivity Among Adult Human Organs Approximate Tolerance Dose (TD) beyond which there is a high probability of delayed injury, e.g. 5% clinical injury within 5 years after exposure. Jan. 21, 2012 PARTNER - EU FP 7

2. Is high-dose radiobiology different from low-dose radiobiology? Jan. 21, 2012 PARTNER - EU FP 7

Different gene expression after low- and high-doses p53 dominates at high doses, HNF4A at low doses Slide courtesy of Sally Amundson, Columbia University Jan. 21, 2012 PARTNER - EU FP 7

Inflammation response epithelial cells leukocytes endothelial cells macrophages/ dentritic cells fibroblasts [courtesy of Claudia Fournier] Jan. 21, 2012 PARTNER - EU FP 7

Pro-inflammatory response (high-doses) lymphocytes macrophages acute phase reactions: acute phase proteins, fever, tiredness, low appetite endothelial effects: leukocyte adherence, increase of adhesion molecules fibroblast effects: proliferation, proteases, collagenases activation phagocytosis NO-induction IL-1 TNF-α endothelial cells endothelial cells endothelial cells leukocyte blood vessel rolling leukocyte leukocyte increase of adhesion molecules adhesion endothelial cells endothelial cells endothelial cells leukocyte [Rödel et al. 2001, LD-RT: molecular and functional aspects] [Feghali et al. 1997, cytokines in acute and chronic inflammation] migration Jan. 21, 2012 PARTNER - EU FP 7

Anti-inflammatory response (low doses) induction of apoptosis in various cell types inhibition of pro-inflammatory cytokine production endothelial effects: suppression of proliferation fibroblast effects: proliferation, ECM components e.g. collagen lymphocytes macrophages suppression: proliferation, ROS, NO TGF-β endothelial cells endothelial cells endothelial cells leukocyte blood vessel inhibition of adhesion leukocyte leukocyte decrease of adhesion molecules endothelial cells endothelial cells endothelial cells [Rödel et al. 2001, LD-RT: molecular and functional aspects][Rödel et al. 2004, Dose dependent induction...of NF-κB...] Jan. 21, 2012 PARTNER - EU FP 7

pro-inflammatory cytokines Basic idea of anti-inflammatory mechanism low dose IR epithelial cells epithelial cells epithelial cells epithelial cells fibroblasts fibroblasts fibroblasts apoptotic cells cytokines e.g. TGF-β macrophages DC suppression of: proliferation pro-inflammatory cytokines NO production [Rödel et al.2001, LD-RT: molecular and functional aspects"][Flatscher 2006,"efects of alpha radiation on...langerhans cells"] [Herrmann et al. 1997, immunosuppressive effects of apoptotic cells"] Jan. 21, 2012 PARTNER - EU FP 7

Phoenix rising (Huang et al. Nat. Med. 2011) Dead cells get absorbed by “scavenger” cells such as macrophages However, studies that originated more than 40 years ago have indicated that tumors respond to radiotherapy by initiating a process called “accelerated repopulation”. New studies have now clarified that this is caused by caspase 3, a cysteine protease involved in the “execution” phase of cellular apoptosis, Caspase-3 activates the Ca-independent phosholipase A2 (iPA2)  iPA2 activation increases the production of arachidonic acid (AA), whose downstream eicosanoid derivatives (i.e. prostaglandin E2), stimulate tumor growth and stem cell proliferation. What is the dose/fractionation dependence of this mechanism? Jan. 21, 2012 PARTNER - EU FP 7

3. Nontargeted effects in therapy Prise & O’Sullivan, Nat. Rev. Cancer 2009 Jan. 21, 2012 PARTNER - EU FP 7

Medulloblastoma in Ptch-1 radiosensitive mice (Mancuso et al Medulloblastoma in Ptch-1 radiosensitive mice (Mancuso et al., PNAS 2008) Jan. 21, 2012 PARTNER - EU FP 7

Radiation Absorbed Dose Secondary Malignant Neoplasms (SMN) in particle therapy Comparison of relative radiation dose distribution with the corresponding relative risk distribution for radiogenic second cancer incidence and mortality. This 9-year old girl received craniospinal irradiation for medulloblastoma using passively scattered proton beams. The color scale illustrates the difference for absorbed dose, incidence and mortality cancer risk in different organs. Radiation Absorbed Dose Risk of SMN Mortality Newhauser & Durante, Nature Rev. Cancer 2011 Risk of SMN Incidence Jan. 21, 2012 PARTNER - EU FP 7

Newhauser & Durante, Nat. Rev. Cancer 2011 Jan. 21, 2012 PARTNER - EU FP 7

4. Is there a “low dose” of heavy ions? X-rays 2 keV/mm 2 Gy 177 MeV/u Fe-ions 335 keV/mm 2 Gy, 3.7*106 /cm2 4.1 MeV/u Cr-ions 3160 keV/mm 20.3 Gy, 4*106 /cm2 same dose same fluence Jan. 21, 2012 PARTNER - EU FP 7

Beamline live microscopy Jan. 21, 2012 PARTNER - EU FP 7

Live cell imaging of heavy ion traversals High energy Fe-ions Low energy Ni-ions, human cells, GFP-APTX GFP-NSBS1 Jakob et al., Proc. Natl. Acad. Sci. USA 2009 GFP-XRCC1 Jan. 21, 2012 PARTNER - EU FP 7

Recruitment of XRCC1 to heterochromatin and euchromatin after exposure of mouse embryo fibroblasts to heavy ions X-ray repair complementing defective in Chinese hamster cells 1 (SSB and b-excision repair pathways) Jakob et al. Nucl. Acids Res. 2011 Jan. 21, 2012 PARTNER - EU FP 7

From DNA to chromosomes: heavy-ion induced rearrangements Jan. 21, 2012 PARTNER - EU FP 7

Chromosomal rearrangements in normal human fibroblasts exposed to a single 12C-ion traversal gH2AX DAPI Jan. 21, 2012 C. Fournier & S. Ritter PARTNER - EU FP 7

5. Fractionation on heavy-ion TPS Jan. 21, 2012 PARTNER - EU FP 7

Durante & Loeffler, Nature Rev Clin Oncol 2010 Potential advantages . 2 8 6 4 Tumor Normal tissue Relative dose Potential advantages 5 1 2 Depth (mm) Energy LET Dose RBE OER Cell-cycle dependence Fractionation Angiogenesis Cell migration high low low high low high  1 > 1  3 < 3 Increased Decreased High tumor dose, normal tissue sparing Effective for radioresistant tumors Effective against hypoxic tumor cells Increased lethality in the target because cells in radioresistant (S) phase are sensitized Fractionation spares normal tissue more than tumor Reduced angiogenesis and metastatization

Heavy ion therapy HIMAC (Heavy Ion Medical Accelerator) NIRS (National Institute for Radiological Science) Since 1994 over 5,000 patient treated with C-ions LEM (Local Effect Model) / TRiP (TReatment planning for Particles) GSI (Helmholtzzentrum für Schwerionenforschung) and other centers Since 1997 over 440 patient treated with C-ions HIMAC / LEM Very different beam delivery systems Very different specifications of RBE-weighted dose A common basis for mapping between center-related beam parameters and clinical outcome is essential. Jan. 21, 2012 PARTNER - EU FP 7

Beam Delivery System: GSI/HIT/CNAO x y z Active scanning technique 3D shapes of physical depth dose distributions, individually optimized according to clinical requirements Jan. 21, 2012 PARTNER - EU FP 7

Beam Delivery System: HIMAC/Hyogo/Gunma Range Shifter Bolus Ridge Filter Multileaf Collimator Passive beam shaping technique Jan. 21, 2012 PARTNER - EU FP 7

RBE and GyE 6.4 4.8 3 2.8 2.5 GyE=GyxRBE Sv=GyxQ > GyE Jan. 21, 2012 PARTNER - EU FP 7

RBE-Weighted Dose: HIMAC HIMAC: Basis: Long term experience in clinical trials with neutrons at NIRS Wheel of 8 Fixed Ridge Filters Empirical Results for Neutrons: Clinical determined RBE ≈ 3.0 Clinically Prescribed Dose RBE = 3.0 Scaling of the complete physical depth dose profile to ensure: Scaled Physical Depth Dose Profile of Carbon Ions = 3.0 Clinically Prescribed Dose Phys. Dose at Neutron-Equ. Pos. Neutron-Equivalent Position Jan. 21, 2012 PARTNER - EU FP 7

Conversion Method: HIMAC LEM LEM Prescribed RBE-Weighted Dose 1. HIMAC Prescribed RBE-Weighted Dose RBE = 3.0 RBE-Weighted Dose Distribution Estimated by LEM / TRiP Simulated HIMAC Physical Depth Dose Distribution RBE table LEM / TRiP 1. HIMAC prescribed RBE-weighted dose 2. Simulation of the related HIMAC physical depth dose distribution (in TRiP) 3. Estimation of the RBE-weighted dose distribution by LEM / TRiP 4. LEM prescribed RBE-weighted dose (median) Jan. 21, 2012 PARTNER - EU FP 7

Conversion Method: HIMAC LEM LEM Prescribed RBE-Weighted Dose HIMAC Prescribed RBE-Weighted Dose RBE = 3.0 RBE-Weighted Dose Distribution Estimated by LEM / TRiP Simulated HIMAC Physical Depth Dose Distribution RBE 2. table LEM / TRiP 1. HIMAC prescribed RBE-weighted dose 2. Simulation of the related HIMAC physical depth dose distribution (in TRiP) 3. Estimation of the RBE-weighted dose distribution by LEM / TRiP 4. LEM prescribed RBE-weighted dose (median) Jan. 21, 2012 PARTNER - EU FP 7

Conversion Method: HIMAC LEM LEM Prescribed RBE-Weighted Dose HIMAC Prescribed RBE-Weighted Dose RBE = 3.0 RBE-Weighted Dose Distribution Estimated by LEM / TRiP Simulated HIMAC Physical Depth Dose Distribution RBE 3. table LEM / TRiP 1. HIMAC prescribed RBE-weighted dose 2. Simulation of the related HIMAC physical depth dose distribution (in TRiP) 3. Estimation of the RBE-weighted dose distribution by LEM / TRiP 4. LEM prescribed RBE-weighted dose (median) Jan. 21, 2012 PARTNER - EU FP 7

Conversion Method: HIMAC LEM LEM Prescribed RBE-Weighted Dose 4. HIMAC Prescribed RBE-Weighted Dose RBE = 3.0 RBE-Weighted Dose Distribution Estimated by LEM / TRiP Simulated HIMAC Physical Depth Dose Distribution RBE table LEM / TRiP 1. HIMAC prescribed RBE-weighted dose 2. Simulation of the related HIMAC physical depth dose distribution (in TRiP) 3. Estimation of the RBE-weighted dose distribution by LEM / TRiP 4. LEM prescribed RBE-weighted dose (median) Jan. 21, 2012 PARTNER - EU FP 7

Dependence of the conversion factor from the dose and the SOBP position Details: LEM IV LEM IV Proximal End Median Distal End Conversion Factors Jan. 21, 2012 PARTNER - EU FP 7

Conversion factors for different tumor sizes Dependence on SOBP width: LEM IV LEM IV 20 mm SOBP … 120 mm SOBP Conversion Factors Jan. 21, 2012 PARTNER - EU FP 7

Summary Significant differences between HIMAC- and LEM-based RBE-weighted doses: Conversion factors between 0.4 and 2.0 for prescribed doses from 1 Gy (RBE) to 60 Gy (RBE) Conversion factor decreases monotonically with increasing prescribed dose/fraction For interpretation and comparison of clinical trials performed using HIMAC- and LEM-bases RBE-weighted doses, it is of extreme importance to consider these conversion factors. Steinsträter et al. Int. J. Radiat. Oncol. Biol. Phys. 2012 Jan. 21, 2012 PARTNER - EU FP 7

Biophysics Department M. Durante (Director) G. Kraft (Helmholtz Professor) G. Taucher-Scholz (DNA damage) B. Jakob (DNA repair) S. Ritter (Chromosome aberrations) C. Fournier (Late effects) W. Kraft-Weyrather (Clinical radiobiology) M. Scholz (Biophysical modelling) M. Krämer (Treatment planning) C. Bert (Moving targets) C. La Tessa (Dosimetry) Thank you very much! http://www.gsi.de/forschung/bio/ Jan. 21, 2012 PARTNER - EU FP 7