1. Radiobiological concepts for treatment planning of schemes that combines external beam radiotherapy and systemic targeted radiotherapy (CIERT) Carlos Calderón Marín, M.Sc. Nuclear Medicine Dept. Oncology and Radiobiology Institute, Havaba, Cuba cfcalder@infomed.sld.cu Physics and Applications of High Brightness Beams March 28-April 1, 2016 in Havana, Cuba

2. Our previous experiences and conditions Experiences performing 2D and 3D internal dose estimations using NM imaging Experiences performing 2D and 3D internal dose estimations using NM imaging Projects for the development of methods for treatment planning in targeted systemic radiotherapy (  emitters mainly) Projects for the development of methods for treatment planning in targeted systemic radiotherapy (  emitters mainly) Availability of medical imaging systems (SPECT, SPECT/CT and PET/CT) Availability of medical imaging systems (SPECT, SPECT/CT and PET/CT) Availability of therapeutic radiopharmaceuticals and treatment systems for external beam radiotherapy (linacs, brachytherapy, IORT ) Availability of therapeutic radiopharmaceuticals and treatment systems for external beam radiotherapy (linacs, brachytherapy, IORT ) Radiobiology modeling for treatment planning and evaluation of prescriptions. A long way to run yet! Radiobiology modeling for treatment planning and evaluation of prescriptions. A long way to run yet! Calderón CF | ICFA workshop | Habana, 2016

3. Combined Radiotherapy (CIERT) Calderón CF | ICFA workshop | Habana, 2016 Basics! The combination of different therapy modalities for cancer treatment have been often used in order to enhance the outcomes The combination of different therapy modalities for cancer treatment have been often used in order to enhance the outcomes CIERT = Combining Internal (sMRT) and External (eLRT) Radiotherapy CIERT = Combining Internal (sMRT) and External (eLRT) Radiotherapy CIERT could be an alternative: CIERT could be an alternative: – in those patients with multiple lesions, or – when the constrains for OARs will difficult the planning, or – to increase dose in tumor without overlapping toxicity Since the dose rate are different it should be taken into account calculations! Since the dose rate are different it should be taken into account calculations!

4. Combined Radiotherapy (CIERT) Pre-clinical CIERT studies have been conducted for more than 25 years, but published outcomes are difficult to compare: Pre-clinical CIERT studies have been conducted for more than 25 years, but published outcomes are difficult to compare: – Different tumors and target entities, – Different radiopharmaceuticals (carriers + radionuclides – Different treatment schedules – Clarity of endpoints Few clinical researches, but the experiences have confirmed that it is a promising approach! Few clinical researches, but the experiences have confirmed that it is a promising approach! Systemic Radiotherapy branch Both branchs Calderón CF | ICFA workshop | Habana, 2016 Basics!

5. Combined Radiotherapy (CIERT) Calderón CF | ICFA workshop | Habana, 2016 OARs CIERT = OARs eLRT + OARs sMRT OARs CIERT = OARs eLRT + OARs sMRT  eLRT: depends of anatomical region and the treatment plan  sMRT: Highly dependent of the RF type and organs uptake  OARs eLRT ≠ OARs sMRT PTV: PTV:  eLRT: depends of anatomical region  sMRT: heterogeneous dose distribution (spatial and temporal). Highly dependent of the RF type and tumor uptake Basics!

6. Combined Radiotherapy (CIERT) SOME PROBLEMS, BUT NOT THE UNIQUES! The most of studies only reports TCP from 3D dose distribution in tumors The most of studies only reports TCP from 3D dose distribution in tumors The acceptance criteria of treatment prescriptions are based on the maximum tolerable dose in OAR instead NTCP The acceptance criteria of treatment prescriptions are based on the maximum tolerable dose in OAR instead NTCP There are not protocols for patient- specific 3D internal dose estimations of dose distribution in normal tissues There are not protocols for patient- specific 3D internal dose estimations of dose distribution in normal tissues Lack of radiobiological parameters Lack of radiobiological parameters Calderón CF | ICFA workshop | Habana, 2016 Systemic Radiotherapy branch Radiobiology

7. Combined Radiotherapy (CIERT) Calderón CF | ICFA workshop | Habana, 2016 INTERNAL DOSE ESTIMATIONS Needs for improvement of accuracy of internal dose estimation! Needs for improvement of accuracy of internal dose estimation! Activity quantification – the main contributor! Activity quantification – the main contributor! Hybrid technology (SPECT/CT & PET/CT) allows to perform patient-specific corrections for physical (scatter, attenuation) and instrumental (PVE) phenomena improving the accuracy of activity quantification in clinical routine Hybrid technology (SPECT/CT & PET/CT) allows to perform patient-specific corrections for physical (scatter, attenuation) and instrumental (PVE) phenomena improving the accuracy of activity quantification in clinical routine Systemic Radiotherapy branch

8. Combined Radiotherapy (CIERT) Calderón CF | ICFA workshop | Habana, 2016 ACTIVITY QUANTIFICATION – work in progress! GOAL = standardize a clinical protocol for activity quantification from SPECT images to perform internal dose estimations in normal tissues GOAL = standardize a clinical protocol for activity quantification from SPECT images to perform internal dose estimations in normal tissues SIMIND : free code, Lund University, Sweden SIMIND : free code, Lund University, Sweden – Obtain SPECT projections by simulation using Monte Carlo techniques. – Ideal image without physical and instrument influence. It could be used as reference! – Input data: gamma camera technical data (crystal sizes, collimators, etc.) and performance characteristic (energy resolution, spatial resolution, etc.) TASKS: Evaluating different activity quantification protocols (acquisition parameters, reconstruction algorithms and post-processing, physical and instrumental corrections) using simulated and acquired images TASKS: Evaluating different activity quantification protocols (acquisition parameters, reconstruction algorithms and post-processing, physical and instrumental corrections) using simulated and acquired images Systemic Radiotherapy branch

9. Combined Radiotherapy (CIERT) Sequential CIERT (sCIERT) Concurrent CIERT (cCIERT) [n sMRT, A inj PS]! [n eLRT, DPS]! TWO MODALITIES COULD BE EXPLORED IN CLINICAL APPLICATIONS! Calderón CF | ICFA workshop | Habana, 2016

10. Linear-quadratic (LQ) model  There are some clinical experiences in both modalities (increasing!)  Simplicity, few parameters! + Partial effects are additive!  iso-effect = Biological equivalence for different irradiation schemes  Easily adjustable to different tissues (acute or late response). B iologically E ffective D ose = BED where: Calderón CF | ICFA workshop | Habana, 2016

11. Combined Radiotherapy (CIERT) LQ model - SOME RESULTS SEQUENTIAL (sCIERT): CONCURRENT (cCIERT): ALFIM, Costa Rica, 2013 Calderón CF | ICFA workshop | Habana, 2016

12. Combined Radiotherapy (CIERT) LQ model - Influence of BED cross  = 3Gy  = 10Gy sMRT using multiple administrations could be an option for optimization Calderón CF | ICFA workshop | Habana, 2016

13. Combined Radiotherapy (CIERT)  Dose distribution parameters: EUBED, SED 2Gy, etc.  Iso-effect profiles  Inter-subject variability  Irradiated volume effect in OARs Calderón CF | ICFA workshop | Habana, 2016 TCP(D) {D ijk } eLRT {D ijk } sMRT {BED ijk } CIERT LQ model NTCP (D) (BED)VH CIERT Iso-effects relationships In practice…

14. Combined Radiotherapy (CIERT) LQ model – TCP /NTCP Inter-subject variability & Radiosensitivity (  )  =0.35Gy -1  =0.25Gy -1 Calderón CF., et al, ALFIM, 2013

15. Combined Radiotherapy (CIERT) Calderón CF., et al, ALFIM, 2013 LQ model – TCP /NTCP Inter-subject variability & Tissue response (  )  =3Gy  =10Gy

16. Combined Radiotherapy (CIERT) The formulation could be used for biological evaluation of prescriptions and optimization in CIERT The formulation could be used for biological evaluation of prescriptions and optimization in CIERT OARs should carefully controlled in cCIERT as the administered activity is increased – prescription with multiples administration must be evaluated! OARs should carefully controlled in cCIERT as the administered activity is increased – prescription with multiples administration must be evaluated! Treatment planning and optimization are possible to be done in those cases where high conformed dose boost using systemic molecular radiotherapy may be chosen. Treatment planning and optimization are possible to be done in those cases where high conformed dose boost using systemic molecular radiotherapy may be chosen. Calderón CF | ICFA workshop | Habana, 2016 … remarks!

17. Trends for nearest & not to distant future Internal dose estimation: Internal dose estimation: – Clinical protocol for estimation of 3D dose distribution in OARs that could be used for biological treatment planning in sMRT – End to End verifying protocol for validating internal dose estimations Radiobiology: Radiobiology: – Formulation for inverse planning methods – Include functional information for calculating TCP (hypoxia) & NTCP – Evaluation of treatment planning based on goal functions (UTCP, f EUD ) – ior/RB Software - from Excel worksheets to a more friendly interface and integrated facilities. Coming soon! – Clinical trials – end points  radiobiological parameters! Calderón CF | ICFA workshop | Habana, 2016 IPET meeting IAEA, 2011 IDOS meeting IAEA, 2010

18. … Some reports González J., et al. Dose response model for targeted radionuclide therapy. World J Nucl Med 2004; 3:225-228 González J., et al. Dose response model for targeted radionuclide therapy. World J Nucl Med 2004; 3:225-228 González J., et al. Determination of radionuclides S values for any voxel size, based on three-dimensional discrete Fourier transform convolution method. World J Nucl Med 2007; 6:40-44. González J., et al. Determination of radionuclides S values for any voxel size, based on three-dimensional discrete Fourier transform convolution method. World J Nucl Med 2007; 6:40-44. Nápoles M, et al. Pre-clinical commissioning of plans with an aperture based IMRT treatment planning system. ICARO Proceeding of International Symposium, IAEA, Vienna, Austria, 2009 Nápoles M, et al. Pre-clinical commissioning of plans with an aperture based IMRT treatment planning system. ICARO Proceeding of International Symposium, IAEA, Vienna, Austria, 2009 C. Calderón, et al. “Validating activity prescription schemes in radionuclide therapy based on TCP and NTCP indexes calculation”. IDOS Proceeding of International Symposium, IAEA, Vienna, Austria, 2010 C. Calderón, et al. “Validating activity prescription schemes in radionuclide therapy based on TCP and NTCP indexes calculation”. IDOS Proceeding of International Symposium, IAEA, Vienna, Austria, 2010 Calderón Marín CF, et al. Using the hypoxia volume distribution for calculation of Tumor Control Probability (TCP) IPET Proceeding of International Symposium, IAEA, Vienna, Austria, 2011Calderón Marín CF, et al. Basis for the biological evaluation of treatment combining irradiation at high and low dose rate using the linear-quadratic model. World Congress on Medical Physics and Biomedical Engineering, Beijing, China, 2012 Calderón Marín CF, et al. Using the hypoxia volume distribution for calculation of Tumor Control Probability (TCP) IPET Proceeding of International Symposium, IAEA, Vienna, Austria, 2011Calderón Marín CF, et al. Basis for the biological evaluation of treatment combining irradiation at high and low dose rate using the linear-quadratic model. World Congress on Medical Physics and Biomedical Engineering, Beijing, China, 2012 Cancino JL, et al. Construction and dosimetrical evaluation of a beta particles irradiator designed to study the cellular response to irradiation at low dose rate. World Congress on Medical Physics and Biomedical Engineering, Beijing, China, 2012 Cancino JL, et al. Construction and dosimetrical evaluation of a beta particles irradiator designed to study the cellular response to irradiation at low dose rate. World Congress on Medical Physics and Biomedical Engineering, Beijing, China, 2012 Calderón CF | ICFA workshop | Habana, 2016

19. MUCHAS GRACIAS! | THANKS A LOT! MUCHAS GRACIAS! | THANKS A LOT! Physics and Applications of High Brightness Beams March 28-April 1, 2016 in Havana, Cuba