Feasibility of using O-18 for PET proton range verification Cho JM1, Gillin M2, Ibbott GS2, Mawlawi O1. Dept. of Imaging Physics Dept. of Radiation Physics MD Anderson Cancer Center Good afternoon. I am going to talk about the feasibility of using O-18 for PET proton range verification. Since my research is a therapy-imaging hybrid, I am going to go over some basics of proton therapy. Followed by the current method of proton range verification using PET. And then, an innovation made in this research will be presented with the results of experiments I performed at Loma Linda University Proton Center and MD Anderson Cancer Center Proton Center.

Proton Therapy Pros Bragg Peak (BP) No distal dose Cons Range accuracy is critical Range uncertainty up to 10% As you can see from the picture, x-ray beam intensity decreases with depth. Let’s say the tumor is located here. Then, x-ray radiotherapy tends to give higher dose to the normal tissue lying on top of tumor. However, proton therapy has a great characteristic called Bragg Peak. This graph is called pristine Bragg Peak which is from a single proton beam. However, when the proton beams are modulated, we can created a nice spread out Bragg Peak as shown in this graph. This covers tumor with high dose while maintaining low surface dose. Another benefit of the proton therapy is there is no distal dose. To take the best advantage of this Bragg Peak, we need to know the range of the proton beam quite accurately. The current CT based proton treatment plan can created up to 10% of range uncertainty in case of tissue heterogeneity. This uncertainty is not acceptable in case there is a critical organ beyond the tumor.

Proton range verification using PET Planned Dose Measured PET I am going to talk about the current method of proton range verification using PET. MC Dose MC PET Antje-Christin Knopf et al

Proton range verification using PET Planned Dose Measured PET MC Dose MC PET Antje-Christin Knopf et al

Proton range verification using PET 2018-11-19 Proton range verification using PET Dose Dose Activity Activity Antje-Christin Knopf et al

Interaction Cross Sections in Tissue Extremely rare isotope in the body Litzenberg et al

O-18 enriched water Biologically H2O18=H2O16 Precursor for FDG 18F half-life 110 min Extremely rare isotope in the body Litzenberg et al

Measurements & Results (LLUMC)

Measurements & Results (MDACC) 4 different depths 160MeV Proton O16 water O18 water Heptane Empty Plastic water Depth (cm) % Dose Empty C12 O18 O16

Measurements & Results (MDACC) 4 different depths 160MeV Proton O16 water O18 water Heptane Empty Plastic water Depth (cm) PDD (%) dose at depth % Empty C12 O18 O16 96-70% 70-30% 30- 6% 15- 3%

Measurements & Results (MDACC) Depth (cm) PDD (%) dose at depth % Empty 12C 18O 16O 99-87% 87-65% 65-20% 39- 8%

Measurements & Results (MDACC) Depth (cm) PDD (%) dose at depth % Empty 12C 18O 16O 96-70% 70-30% 30- 6% 15- 3%

Conclusion O-18 : strong signal at distal end. O-18 : candidate for proton range verification using PET.

How to obtain O-18? From FDG precursor providers? $20 ~ $100 / gram

How to obtain O-18? From plants? 4~10% enrichment Natural enrichment in plant

Future Research Direction Gel dosimetry study Monte Carlo study O-18 transport study Animal study Affordable O-18

Acknowledgement Authors thank Dr. Schulte at Loma Linda University Medical Center and Dr. Gonzalez-Lepera at CABIR, MD Anderson Cancer Center. Author contact: jcho2@mdanderson.org

Nuclear Interactions of Protons with Tissue 4 most abundant elements Total over 99% 6 most common interactions 16O(p,pn)15O (83.5%) 16O(p,3p4n)10C (4.2%) 16O(p,αpn)11C (2.4%) 12C(p,pn)11C (2.3%) 16O(p,p2n)14O (1.9%) 16O(p,α)13N (1.7%) 16O comprises 94 % Muscle Adipose Oxygen 72.9 % 27.8 % Carbon 12.3 % 59.8 % Hydrogen 10.2 % 11.4 % Nitrogen 3.5 % 0.7 % Litzenberg et al

Discussion At COM, 16O water initially gave high signal but after 20 minutes, 18O water signal was stronger. At Distal end, 18O water was strongest over the entire time. After 20 minutes, 16O water was at noise level. 18O water shows stronger PET signals in both COM and distal end. 16O signal was noise at distal end. Even diluted 10% 18O water gave more signal than 16O in both Gamma Camera and PET.

In-vivo dosimetry using PET 2018-11-19 In-vivo dosimetry using PET Proton beam Water in tissue Daughter product p ~> + 16O → 15O + p + n decay 15N (stable) + e+ combine e- → PET 0.511 MeV 0.511 MeV

Proton range verification using PET Planned Dose Measured PET MC Dose MC PET Antje-Christin Knopf et al

Bragg-Peak Review Most protons < 10 MeV with max ~ 30 MeV Proton at few MeV

Overview Proton Therapy Proton Range Verification using PET Purpose 2018-11-19 Overview Proton Therapy Proton Range Verification using PET Purpose Properties of O-18 Method and Materials Results Conclusion Future Direction

O-18 enriched water Biologically O-18 water = O-16 water Precursor for FDG -18O(p,n)18F Cross section threshold 2.6 MeV and maximum 5 MeV 18F half-life 110 min

O-18 enriched water Biologically O-18 water = O-16 water Precursor for FDG -18O(p,n)18F Cross section threshold 2.6 MeV and maximum 5 MeV 18F half-life 110 min Litzenberg et al

Material and Methods

Results – Gamma Camera at COM

Results – Gamma Camera at distal end

Results – PET Axial COM PET axial images Distal end PET axial images Images taken over 60 minutes 98% O18 10% O18 100% O16

Method & Materials (LLUMC)

Results (LLUMC) 98% O18 10% O18 100% O16

Results (MDACC)