Beltran, Chris

Abstract Proton therapy has a distinct dosimetric advantage over conventional photon therapy due to its Bragg peak profile. This allows greater accuracy in dose delivery and dose conformation to the target, however it requires greater precision in setup, delivery and for quality assurance (QA) procedures. The AAPM TG 224 report recommends daily range and spot position checks with tolerance on the order of a millimetre. Daily QA systems must therefore be efficient for daily use and be capable of sub-millimetre precision however few suitable commercial systems are available. In this work, a compact, real-time daily QA system is optimised and characterised for proton range verification using an ad-hoc Geant4 simulation. The system is comprised of a monolithic silicon diode array detector embedded in a perspex phantom. The detector is orientated at an angular offset to the incident proton beam to allow range in perspex to be determined for flat proton fields. The accuracy of the system for proton range in perspex measurements was experimentally evaluated over the full range of clinical proton energies. The mean R 100 , R 90 and R 80 ranges measured with the system were accurate within ±0.6 mm of simulated ranges in a perspex phantom for all energies assessed. This system allows real-time read-out of individual detector channels also making it appropriate for temporal beam delivery diagnostics and for spot position monitoring along one axis. The system presented provides a suitable, economical and efficient alternative for daily QA in proton therapy.

Abstract Proton Bragg peak irradiation has a higher ionizing density than conventional photon irradiation or the entrance of the proton beam profile. Whether targeting the DNA damage response (DDR) could enhance vulnerability to the distinct pattern of damage induced by proton Bragg peak irradiation is currently unknown. Here, we performed genetic or pharmacologic manipulation of key DDR elements and evaluated DNA damage signaling, DNA repair, and tumor control in cell lines and xenografts treated with the same physical dose across a radiotherapy linear energy transfer spectrum. Radiotherapy consisted of 6 MV photons and the entrance beam or Bragg peak of a 76.8 MeV spot scanning proton beam. More complex DNA double-strand breaks (DSB) induced by Bragg peak proton irradiation preferentially underwent resection and engaged homologous recombination (HR) machinery. Unexpectedly, the ataxia-telangiectasia mutated (ATM) inhibitor, AZD0156, but not an inhibitor of ATM and Rad3-related, rendered cells hypersensitive to more densely ionizing proton Bragg peak irradiation. ATM inhibition blocked resection and shunted more DSBs to processing by toxic ligation through nonhomologous end-joining, whereas loss of DNA ligation via XRCC4 or Lig4 knockdown rescued resection and abolished the enhanced Bragg peak cell killing. Proton Bragg peak monotherapy selectively sensitized cell lines and tumor xenografts with inherent HR defects, and the repair defect induced by ATM inhibitor coadministration showed enhanced efficacy in HR-proficient models. In summary, inherent defects in HR or administration of an ATM inhibitor in HR-proficient tumors selectively enhances the relative biological effectiveness of proton Bragg peak irradiation. Significance: Coadministration of an ATM inhibitor rewires DNA repair machinery to render cancer cells uniquely hypersensitive to DNA damage induced by the proton Bragg peak, which is characterized by higher density ionization. See related commentary by Nickoloff, p. 3156

Stereotactic radiosurgery (SRS) involves the delivery of a highly conformal ablative dose of radiation to both benign and malignant targets. This has traditionally been accomplished in a single fraction; however, fractionated approaches involving five or fewer treatments have been delivered for larger lesions, as well as lesions in close proximity to radiosensitive structures. The clinical utilization of SRS has overwhelmingly involved photon-based sources via dedicated radiosurgery platforms (e.g., Gamma Knife® and Cyberknife®) or specialized linear accelerators. While photon-based methods have been shown to be highly effective, advancements are sought for improved dose precision, treatment duration, and radiobiologic effect, among others, particularly in the setting of repeat irradiation. Particle-based techniques (e.g., protons and carbon ions) may improve many of these shortcomings. Specifically, the presence of a Bragg Peak with particle therapy at target depth allows for marked minimization of distal dose delivery, thus mitigating the risk of toxicity to organs at risk. Carbon ions also exhibit a higher linear energy transfer than photons and protons, allowing for greater relative biological effectiveness. While the data are limited, utilization of proton radiosurgery in the setting of brain metastases has been shown to demonstrate 1-year local control rates >90%, which are comparable to that of photon-based radiosurgery. Prospective studies are needed to further validate the safety and efficacy of this treatment modality. We aim to provide a comprehensive overview of clinical evidence in the use of particle therapy-based radiosurgery.

Abstract The treatment of cancer with proton radiation therapy was first suggested in 1946 followed by the first treatments in the 1950s. As of 2020, almost 200 000 patients have been treated with proton beams worldwide and the number of operating proton therapy (PT) facilities will soon reach one hundred. PT has long moved from research institutions into hospital-based facilities that are increasingly being utilized with workflows similar to conventional radiation therapy. While PT has become mainstream and has established itself as a treatment option for many cancers, it is still an area of active research for various reasons: the advanced dose shaping capabilities of PT cause susceptibility to uncertainties, the high degrees of freedom in dose delivery offer room for further improvements, the limited experience and understanding of optimizing pencil beam scanning, and the biological effect difference compared to photon radiation. In addition to these challenges and opportunities currently being investigated, there is an economic aspect because PT treatments are, on average, still more expensive compared to conventional photon based treatment options. This roadmap highlights the current state and future direction in PT categorized into four different themes, ‘improving efficiency’, ‘improving planning and delivery’, ‘improving imaging’, and ‘improving patient selection’.

Abstract Pancreatic cancer is the fourth most common cause of cancer-related morality worldwide, and the prognosis remains poor despite aggressive therapy. Carbon ion radiotherapy has favorable radiobiological and physical characteristics in the treatment, including a higher linear energy transfer and higher relative biological effectiveness, which increase the cell kill while potentially reducing toxicities to nearby normal tissues. Although small, early clinical studies have shown promise in both the resectable and unresectable settings to improve local control and overall survival while minimizing toxicities. Currently, there are several trials, including 2 sponsored by institutions in the United States, investigating the role of carbon ion radiotherapy for the treatment of locally advanced pancreatic cancer.

PurposeTo provide a proof of principle of a Pareto‐based method to automatically generate optimal intensity‐modulated proton therapy (IMPT) plans for various noncoplanar beam orientations.MethodsA novel multicriteria beam orientation optimization (MCBOO) method was developed to generate Pareto database of optimal plans. The MCBOO method automatically explores the beam orientations and the scalarization parameters of the IMPT plans simultaneously. The MCBOO method is based on multicriteria bilevel optimization (i.e., hierarchical optimization with two nested levels, named the upper and lower level optimization). In MCBOO, the upper level optimization explores the noncoplanar beam orientation space, while the lower level explores the scalarization parameters for a given beam orientation. Differential evolution method was used in both levels, and the Pareto optimal plans were aggregated from the bilevel optimizations to construct the Pareto database. The MCBOO method was implemented on a multinode multi‐GPU cluster, and it was tested on three brain tumor patient cases. The Pareto database of the three patients was generated for a set of DVH‐based objectives. A statistical analysis was performed between a selected set of MCBOO plans and the manual plan (plan with manually selected beam orientation based on the clinical experience and optimized with the same single plan iterative optimizer used in the MCBOO). The selected set of MCBOO plans consisted of plans that matched the performance of the manual plan [i.e., MCBOO plans that have the same target coverage (within 2%) as the manual plan or better and achieved the same dose (within 2%) or lower to all of the organs at risks (OARs) but one OAR]. Additionally, a dosimetric comparison between of one of the selected MCBOO plans vs the manual plan was conducted.ResultsThe multicriteria beam orientation optimization algorithm automatically generated Pareto plans for the three noncoplanar brain tumor cases. The MCBOO plans provided an alternative objective trade‐offs to the manual plan. The selected MCBOO plans showed a reduction in dose to multiple organs at risk vs the manual plan with a maximum value which ranged between 10.8 and 12.9 Gy for the three patients. The trade‐off of the OAR dose reduction resulted in higher dose to no more than one OAR for each of the selected MCBOO plans vs the manual plan. The maximum dose increase in the MCBOO plans over the manual plan ranged from 7.8 to 11.8 Gy.ConclusionsA novel multicriteria beam orientation optimization method was developed and tested on three IMPT patient cases. The method automatically generates Pareto plans database by exploring the noncoplanar beam orientations. The method was able to identify beam orientations with Pareto optimal plans that are comparable to the manually created plans with varying objective trade‐offs.

Treatment planning for protons and heavier ions is adapting technologies originally developed for photon dose optimization, but also has to meet its particular challenges. Since the quality of the applied dose is more sensitive to geometric uncertainties, treatment plan robust optimization has a much more prominent role in particle therapy. This has led to specific planning tools, approaches, and research into new formulations of the robust optimization problems. Tools for solution space navigation and automatic planning are also being adapted to particle therapy. These challenges become even greater when detailed models of relative biological effectiveness ( RBE ) are included into dose optimization, as is required for heavier ions.