8th Warren K. Sinclair Keynote Address 47th Annual NCRP Meeting Bethesda, MD, March 7, 2011 Heavy ions in therapy and space: benefits and risks

Transcription

1 8th Warren K. Sinclair Keynote Address 47th Annual NCRP Meeting Bethesda, MD, March 7, 2011 Heavy ions in therapy and space: benefits and risks Marco Durante

2 What are heavy ions? 50 um

3 What are heavy ions? X-rays 2 kev/μm 2 Gy 177 MeV/u Fe-ions 335 kev/μm 2 Gy, 3.7*10 6 /cm MeV/u Cr-ions 3160 kev/μm 20.3 Gy, 4*10 6 /cm 2 same dose same fluence Courtesy of M. Scholz

4 The most unkindest cut of all (W. Shakespeare, Julius Caesar, Act 3) h n h h n n n h h n h h h h hh n h h Courtesy of NASA Courtesy of D.T. Goodhead

5 Tracks in cells γ-rays silicon iron Cucinotta and Durante, Lancet Oncol. 2006

6 Live cell imaging of heavy ion traversals High energy Fe-ions Low energy Ni-ions ions,, human cells, GFP-APTX GFP-NSBS1 Jakob et al., Proc. Natl. Acad. Sci. USA 2009 GFP-XRCC1

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 β- excision repair pathways) Courtesy of B. Jakob

8 Co-localization of DNA double-strand breaks (green; lebeled by TUNEL) and immunostained XRCC1 (red) 5 min after exposure to U-ions and kinetics of GFP-XRCC1 recruitment and release from euchromatic and heterochromatic compartments of mouse embryo cell nuclei Courtesy of G. Taucher-Scholz

9 From DNA to chromosomes: heavy-ion induced rearrangements

10 to cell killing.. W. Kraft-Weyrather et al., Int. J. Radiat. Biol. 1999

11 and to cancer Acute myeloid leukemia and hepatocellular carcinoma induced in CBA/CaJ mice by γ-rays ( ) or 1 GeV/n Fe-ions ( ) M. M. Weil et al., Radiat. Res. 2009

12 Why are we interested in energetic heavy ions?

13 ROUGH GUIDES Health in Deep Space 1. Protection from space radiation THE ROUGH GUIDE to The Moon & Mars 2. Psychosocial and behavioural problems 3. Physiological changes caused by microgravity Courtesy of Mike Lockwood

14 GCR Charge Contributions 100 Free Space 10 % Contribution Fluence Dose Dose Eq Charge Number

15 Radiation doses in different missions Dose (msv) Apollo Skylab Past STS/Mir Shuttle 1 Population per year Gemini Year ISS Future Mars Moon Callisto Astronauts career RadWork per year

16 Carbon-ion therapy

17 Treatment plans for a base of the skull tumor Heavy Ions (2 Fields) C-ions, 2 fields IMRT, 9 fields Courtesy of O. Jäkel

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

19 Exposure scenarios Particles Max energy (MeV/n) Dose Dose rate Exposure 1 H to 58 Ni ~10,000 Low ( msv in LEO, up to 1 Sv for Mars) 1 H, 12 C ~400 High (60-80 Gyeq. to the tumor) Low (about 1 msv/day) High - fractionated (about 2 Gyeq./day) Wholebody Partialbody

20 Common research topics Individual radiosensitivity Mixed radiation fields Shielding Radioprotectors Biomarkers of sensitivity and risk CNS damage Bystander/abscopal effects Adaptive response Late effects of heavy ions (cancer and noncancer)

21 Risk of heavy-ion carcinogenesis The principal stochastic risk associated with low dose rate galactic cosmic rays is the increased risk of cancer. Estimates of this risk depend on two factors (a) estimates of cancer risk for low-let radiation and (b) values of the appropriate radiation weighting factors, WR, for the high-let radiations of galactic cosmic rays. Both factors are subject to considerable uncertainty. Additional laboratory studies could reduce the uncertainties in WR and thus produce a more confident estimate of the overall risk of galactic cosmic rays. SINCLAIR,W. K., 1994, Adv. Space Res. 14, Durante & Cucinotta, 2008, Nat. Rev. Cancer 8,

22 The Gold Standard: A-bomb Survivors 5-10% Cancer Risk Low Dose Extrapolation Bystander effect High Doses Courtesy of Eric J. Hall Dose (Sv)

23 Durante & Cucinotta, Nature Rev. Cancer (2008)

24 Secondary Malignant Neoplasms (SMN) in particle therapy Radiation Absorbed Dose Risk of SMN Incidence 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. Risk of SMN Mortality Courtesy of W.D. Newhauser

25 Organ doses in therapy and space: MATROSHKA Standard RANDO phantom of property of DLR (German Aerospace center) 850 mm high divided into 34 slices Holders for detectors in several slices Currently used for space radiation dosimetry inside the ISS In collaboration with G. Reitz, T. Berger et al. (DLR)

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27 Secondary neutrons Courtesy of C. La Tessa

28 Early biomarker of late effects: chromosomal aberrations in blood lymphocytes damage in exposed cells damage in survivors cell killing late effects

29 Biodosimetry in astronauts Dicentrics per 1000 lymphocytes Taxi-flights Long-term flights ** Pre-flight Post-flight Pre-flight Post-flight Data for 23 cosmonauts involved in Mir missions. From: Durante et al., Cytogenet. Genome Res. 103 (2003) 40. Biodosimetry can be used to test current models of radiation risk in space (high uncertainties). A significant increase in aberrations has been reported after long-term LEO missions (large NASA JSC study) Taken together, the results indicate a reasonable agreement between chromosome aberration dosimetry and physical dosimetry, assuming a Q = 2.4 in LEO

30 Time-course of dicentrics in cosmonauts involved in multiple missions on Mir/ISS Durante et al., Cytogenet. Genome Res Dicentrics in 1000 lymphocytes Dicentrics in 1000 lymphocytes Dicentrics in 1000 lymphocytes Cosmonaut Cosmonaut Cosmonaut Time after the first blood draw (days) 3000 Time after the first blood draw (days)

31 In vivo: cancer patients X-rays C-ions FISH analysis (chromosomes 2 and 4) of PBL from patients treated for uterus cancer by 10 MV X-rays or 290 MeV/n C-ions at NIRS (Japan) Durante et al., Int. J. Radiat. Oncol. Biol. Phys. 2000

32 Prostate cancer patients treated with C ion boost (mfish( mfish) 20 patients, adenocarcinoma, intermediate risk, mean age 66 years, Carbon ion boost (6 x 3 GyE) followed by 30 x 2 Gy IMRT ( Carbon + IMRT ) or IMRT 38 x 2 Gy ( IMRT ) IMRT, larger planning target volume PTV (including pelvic lymph nodes) 38 x 2 Gy ( IMRT* ) (C.Hartel et al., Radiother. Oncol. 2010)

33 Courtesy of A. Nikoghosyan and J. Debus, University of Heidelberg

34 What is the fate of human cells after a single heavy-ion traversal? If a single α-particle from a radioactive isotope, such as 226 Ra or 239 Pu, has a high probability to kill a cell, then it is difficult to understand how cells whose nuclei have been traversed by α-particles can survive to become malignant SINCLAIR,W. K., 1974, Physical Mechanisms in Radiation Biology, Conf p Survival of V79 hamster cells as a funtion of the number of nuclear α-particle tarversals counted by LR-115 solid state nuclear track deetctors (Pugliese et al., Int. J. Radiat. Biol. 1997)

35 Single heavy ion microbeam Courtesy of B. Fisher

36 Microbeam - Irradiation of single cells Target positions Biological response visualized by immuno-staining C 5x5 M. Heiß et al. Radiat. Res. (2006) 10 μm C 5x5 ions γh2ax

37 Courtesy of G. Taucher-Scholz Sub-cellular targeting with the heavy- ion microbeam

38 Courtesy of C. Fournier & S. Ritter Chromosomal rearrangements in normal human fibroblasts exposed to a single 12 C-ion traversal

39 Courtesy of C. Fournier & S. Ritter Clonal survivors LET=290 kev/μm No evidence of genomic instability (pre-senescence) Persistence of transmissible radiationinduced aberrations No significant changes in expression of cell-cycle regulating proteins (p53, p21 )

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41 Brookhaven National Laboratory Aerial View NASA Space Radiation Lab (NSRL) $33.9 M facility to simulate space radiation NSRL F.A. Cucinotta 39

42 High-energy accelerator facilities where heavy-ion radiobiology studies are currently under way 10 5 Energy, MeV/n LLU JINR-Dubna LNS NSRL (BNL) FAIR HIMAC GANIL GSI 10 HIRFL Atomic number, Z

43 From GSI to FAIR Future Beams: Intensity: primary HI HI 100-fold secondary RIB RIB fold Species: Z = (anti-protons to to uranium) Energies: ions ions up up to to GeV/u antiprotons GeV/c Precision: full full beam cooling

44 Cancer risk Noncancer risk Acute effects Countermeasures Risk estimates Shielding design Genetic screening Countermeasures Risk assessment for exploration Effective countermeasures Basic research Knowledge Applied research Ground and flight experiments Spinoff Hadrontherapy ESA-NASA collaboration

45 Conclusions Heavy ions are different in many facets from X-rays and other genotoxic agents Their special radiobiological properties make them very effective in radiotherapy, but potentially dangerous for late effects, and therefore a major hazard in human space exploration The RBE depends on many different factors, and can drastically change for different endpoints. Notwithstanding many years of research in the field, the uncertainty is still high Accelerator-based research in radiobiology is essential for improving radiotherapy and ensure protection in space: it should be increased, and can serve both medical and space research communities

46 Thank you very much