Radiobiology for particle therapy Marco Durante CNAO-NIRS meeting, Pavia 21.03.2010 INFN Workshop, Napoli, 4.4.2014
2 The radiobiological adavantages of particle therapy Jakob et al., PNAS 2009 PIDE database http://www.gsi.de/bio-pide Friedrich et al., J. Radiat. Res. 2013
3 March 2014: 44 proton/7 heavy ion centers Under construction: 25 proton/ 3 heavy ion centers Only in USA, 27 new centers expected by 2017 NuPECC report Nuclear Physics in Medicine, 2014
CLINICAL INDICATIONS Established clinical indications - Skull base tumors - Spine tumors - Eye tumors (p) Solid literature results - Pediatric tumors (p) - Head and Neck tumors - Prostate tumors Courtesy of Marco Krengli, Novara UK overseas clinical indications for protontherapy, courtesy of Simon Jolly, UCL UK list of typical indications <2% patients
ITALIAN NETWORK FOR HADRONTHERAPY (p+,ions, 3 rooms with fixed beams) CNAO Pavia ATreP Trento (p+, 2 gantries) from 2014 EXISTING CENTRES FINANCED CENTRES Operating INTEREST FOR PROTONS Working Group of AIRO, 2003, 2008, 2009 (120 000 new cases/year with conventional RT): protontherapy - elective: 1 885 pts/year protontherapy clinical trials: 14 490 pts/year therapy with 12 C-ions cl. trials 6 860 pts/year Conclusions of AIRO: 1 centre for ions 4-5 centres for protons Catana (p+,only eye) (p+)
Treatment plans with protons: prostate Courtesy of Reinhold Schulte, LLUMC
SPINE TUMORS PROTON THERAPY (Weber et al., IJROBP 2004)
Protontherapy in paediatric oncology Courtesy of Jeffrey Dihn MD Anderson, Houston, TX
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. Newhauser & Durante, Nature Rev. Cancer 2011 Risk of SMN Mortality
AAPM poll, August 2012 What is the main obstacle to proton therapy replacing X-rays? 22% 38% 40% Cost/benefit ratio Range uncertainties Protons will never replace X-rays
New cancers where charged particles may potentially lead to a breakthrough - Lung - Pancreas - Local recurrence of rectal cancer - Breast - Hepatocellular carcinoma - Glioblastoma - Combined treatments to improve survival Siegel et al., CA Cancer J Clin 2013
Lung cancer: 2 nd in incidence and 1 st in mortality for both sexes in US HDSF by CIRT 40 GyE, 1 fraction, 3 fields, gating Tsujii et al. Carbon Ion Radiotherapy, Springer-Verlag, 2014
Intrafractional movements and hypofractionation in NSCLC courtesy of Chritoph Bert, University of Erlangen & GSI Courtesy of M. Söhn, LMU
Radiosurgery (SBRT): the new frontier in stereotactic imageguided radiotherapy Stage I (T1N0M0) NSCLC Oligometastases Hepatocellular carcinoma Advanced (T2-T4; >3 cm) NSCLC Localized tumors in kidney, prostate, pancreas, adrenal gland, pravertebal tumors etc. BED a/b = nd [1 + d/(a/b) ] (LQ model) SBRT only possible thanks to IGRT and to the low mean dose to parallel organs Brown et al., Int. J. Radiat. Oncol. Biol. Phys. 2013
15 RBE and hypofractionation: differential decrease in normal and tumor tissue HIMAC TPS Scholz et al., Phys. Med. 2014 Ando et al., Radiat. Prot. Dosim. 2002
Ions vs. X-rays in SBRT for NSCLC TCP vs. BED for Stage I NSCLC by X-rays or charged particles Durante, Br. J. Radiol. 2013 HIMAC vs. LEM: dependence of the RBE on the dose/fraction d Steinsträter et al., Int. J. Radiat. Oncol. Biol. Phys. 2012
Re-oxygenation in radiosurgery Models of oligofractionation predict failure for hypoxic tumors re-oxygenation between fractions is in fact essential for local control for at least some tumors (H&N, cervix, pancreas, prostate). if the number of fractions is severely reduced then this vital process will be rendered less effective heavy ions
A new radiobiology for high-dose, single fraction stereotactic radiosurgery (hypofractionation, SBRT)? 18 Girdhani et al., Radiat. Res. 2012 Kolesnick et al., Science 2008
Pancreas cancer 4th cause of cancer death in USA Median survival time 9 months Even after surgery, survival at 5 years <12% Resectable preooperative treatment Locally advanced + gemcitabine 1,000 mg/m 2 Tsujii et al. Carbon Ion Radiotherapy, Springer-Verlag, 2014
po2 measurements in pancreatic tumors and normal pancreatic tissue Tumor Normal Tissue Patient Med po2 %<2.5mmHg Med po2 %<2.5mmHg 1 3.1 35 47.3 9 2 0 94 46.6 0 3 2.7 43 24.3 0 4 3.4 24 67.4 0 5 0.9 95 51.6 0 6 2 54 69.8 7 7 5.3 68 82.7 0 Tumor (Koong AC, IJROBP 48, 2000)
Oxygen effect in vivo Hirayama et al., Mutat. Res. 2013
OER(pO 2, LET) model for adaptive particle treatment planning Scifoni et al., Phys. Med. Biol. 2013 ; 2β α 2β α β N) (c β N c α (N) D x x 2 x x x 2 T i i T i i i bio Krämer & Scholz, Phys. Med. Biol. 2006 ), ( / ), ( ' ), ( / ), ( ' i i i i i i i i i i i i p L OER p L p L OER p L b b a a
OER along an irradiated volume for different ions C, O, p and soon He available @HIT Joining OER driven and Multiion modality in next TRiP release Krämer et al., J. Phys. Chem. Solids 2013
Radiotherapy for Breast Cancer About 200,000 new cases per year in U.S Most affected at the most productive part of life Most patients survive (> 2 millions survivors) Increased risk of cardiac toxicity and second malignancies Horror stories from side effects of radiation leads many women to choose mastectomy over radiotherapy Darby et al. N Engl J Med. 2013 Mar 14
Andrew Chang, Presentation at the 2013 Proton Breast Cancer Workshop, Phoenix, AZ Should phase 3 randomized be done for this? IMRT --- Proton = Difference
Treatment plans with protons: breast MacDonald et al, Int J Radiat Oncol Biol Phys, 1-7, 2013
27 RBE in protontherapy Grün et al., Med. Phys. 2013
28 Combined treatments: beyond LC High risk prostate cancer patients RT + ADT Bolla et al., Lancet 2012 Wan et al., Nat. Med. 2013
29 IGRT+immunotherapy Melanoma Ipilimumab (anti-ctla4) Postow et al.; Hiniker et al. N.Eng. J. Med. 366; 2012 Oligometastasis Sunitinib (anti-stat3 and VEGF) Tong et al., PLoS One 7; 2012 Chondrosarcoma protons + sunitinib Dallas et al., J. Med. Case Rep. 6; 2012
Treatment plan for the abdominal tumor 6M after Treatment Para-aortic metastasis before treatment
Radioimmunology mechanisms Durante et al., Trends Mol. Med. 2013 31
What do we need? 1. A widespread and effective use of particle therapy can only be possible by expanding the clinical indications 2. Accelerator physics should reduce costs (compact accelerators, innovative approaches...) 3. Medical physics should reduce range uncertainty and treatment time, making possible the treatment of moving targets, oligometastasis, benign lesions... 4. Radiobiology is the only possible line potentially leading to breakthroughs in cancer therapy, especially for highly lethal, incurable diseases 5. Hypofractionation, adaptive TP and combined treatments are among the most promising strategies CNAO-NIRS meeting, Pavia 21.03.2010
M. Durante (Director) G. Kraft (Helmholtz Professor) G. Taucher-Scholz (DNA damage) S. Ritter (Stem cells) C. Fournier (Late effects) C. Hartel (Clinical radiobiology) M. Scholz (Biophysical modelling) M. Krämer (Treatment planning) C. Graeff (Moving targets) C. La Tessa (Dosimetry) http://www.gsi.de/biophysik/