FLASH Radiotherapy: Current Knowledge and Future Insights Using Proton-Beam Therapy.

FLASH radiotherapy is the delivery of ultra-high dose rate radiation several orders of magnitude higher than what is currently used in conventional clinical radiotherapy, and has the potential to revolutionize the future of cancer treatment. FLASH radiotherapy induces a phenomenon known as the FLASH effect, whereby the ultra-high dose rate radiation reduces the normal tissue toxicities commonly associated with conventional radiotherapy, while still maintaining local tumor control. The underlying mechanism(s) responsible for the FLASH effect are yet to be fully elucidated, but a prominent role for oxygen tension and reactive oxygen species production is the most current valid hypothesis. The FLASH effect has been confirmed in many studies in recent years, both in vitro and in vivo, with even the first patient with T-cell cutaneous lymphoma being treated using FLASH radiotherapy. However, most of the studies into FLASH radiotherapy have used electron beams that have low tissue penetration, which presents a limitation for translation into clinical practice. A promising alternate FLASH delivery method is via proton beam therapy, as the dose can be deposited deeper within the tissue. However, studies into FLASH protons are currently sparse. This review will summarize FLASH radiotherapy research conducted to date and the current theories explaining the FLASH effect, with an emphasis on the future potential for FLASH proton beam therapy.

How rapid advances in imaging are defining the future of precision radiation oncology.

Imaging has an essential role in the planning and delivery of radiotherapy. Recent advances in imaging have led to the development of advanced radiotherapy techniques-including image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic body radiotherapy and proton beam therapy. The optimal use of imaging might enable higher doses of radiation to be delivered to the tumour, while sparing normal surrounding tissues. In this article, we review how the integration of existing and novel forms of computed tomography, magnetic resonance imaging and positron emission tomography have transformed tumour delineation in the radiotherapy planning process, and how these advances have the potential to allow a more individualised approach to the cancer therapy. Recent data suggest that imaging biomarkers that assess underlying tumour heterogeneity can identify areas within a tumour that are at higher risk of radio-resistance, and therefore potentially allow for biologically focussed dose escalation. The rapidly evolving concept of adaptive radiotherapy, including artificial intelligence, requires imaging during treatment to be used to modify radiotherapy on a daily basis. These advances have the potential to improve clinical outcomes and reduce radiation-related long-term toxicities. We outline how recent technological advances in both imaging and radiotherapy delivery can be combined to shape the future of precision radiation oncology.

Incidence of tolerance in children undergoing repeated administration of propofol for proton radiation therapy: a retrospective study.

BACKGROUND: Propofol is an excellent hypnotic drug for use in repeated radiation procedures in young children. To date, tolerance to propofol generally does not develop in pediatric patients undergoing radiation therapy. However, several studies have suggested that there may be potential for development of tolerance to propofol. The aim of this study was to evaluate the development of a tolerance to propofol used for repeated deep sedation in children undergoing proton radiation therapy (PRT). METHODS: All children undergoing PRT at our institution between December 2015 and January 2018 were eligible for inclusion in this study. Sedation was induced by a bolus dose of propofol (2.0 mg.kg- 1) followed by a continuous infusion of 250 µg.kg- 1.min- 1 via an infusion pump to achieve deep sedation. Sedation was maintained with the propofol infusion of 200 µg.kg- 1.min- 1, which was adjusted in 25 µg.kg- 1.min- 1 increments up or down as necessary to ensure deep sedation. The primary outcome was mean doses of propofol over time. RESULTS: Fifty-eight children were analyzed. The mean (SD) age was 4.5 (2.1) years. The mean (SD) number of treatment sessions was 19 (7). Fifteen patients (26%) developed tolerance to propofol. However, there were no significant differences between the children who developed tolerance and the children who did not develop tolerance in mean propofol dose and awakening time over time (p = 0.887 and P = 0.652, respectively). Age, the number of PRT, and attending anesthesiologists was not significantly associated with the incidence of tolerance to propofol. CONCLUSION: Repeated prolonged deep sedation for PRT elicited multiple times over several weeks in young children using propofol did not develop tolerance in 74% of patients. Although the incidence of 26% tolerance to propofol may still be present, the increase in propofol dose was minimal. Therefore, the use of repeated propofol for children was safe.

Current Standard and Future Perspectives in Non-Surgical Therapy for Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive liver tumor with a poor 5-year survival rate. Many HCCs are not amenable to surgical resection, because of tumor size, location, or because of the patient's poor liver function, a common obstacle to HCC therapy, because HCCs almost always develop in chronically inflamed livers. SUMMARY: In recent years, many efforts have been made to improve patient survival by conducting clinical trials investigating local and systemic treatment options for patients with unresectable tumors. These treatment options include radiofrequency ablation (RFA), transarterial chemoembolization (TACE), selective internal radiotherapy with yttrium-90 (SIRT), stereotactic body radiation therapy (SBRT), proton beam therapy, molecular targeted therapy, and checkpoint inhibition. In this "to-the-point" article, we review the current standard and summarize the most recent findings in unresectable HCC treatment. KEY POINTS: (1) RFA is currently the preferred treatment for patients with tumor burden restricted to the liver and not eligible for surgical resection; (2) TACE is utilized in patients who are not eligible for RFA because of tumor location and/or number of tumor lesions; (3) SIRT might improve treatment responses achieved by TACE and is feasible in patients with portal vein thrombosis; (4) new radiation therapy treatment modalities such as SBRT and proton beam therapy show promising results for local tumor control; and (5) sorafenib remains the first-line systemic treatment option after several large clinical trials have failed to show superiority of other molecular targeted therapies in HCC patients.

[New opportunities for proton therapy in Russia].

On November 23, 2015 in Protvino of the Moscow Region there was begun proton therapy using Russia's first medical therapeutic complex "Prometheus" produced by JSC "PRO- TOM" and certified to treat patients with head and neck tumors. The complex allows irradiating patients with active scanning beam. Energy of beam is 30-250MeV and maximum field size is 10 cm vertically and 40 cm horizontally. The manufacturer declared parameters were confirmed during preclinical stud- ies. By April 8, 2016 the successful proton therapy received 20 patients with complex "targets" mostly located, from the point of view of radiation tolerance, near the critical structures.

[Economic and logistical problems of radiation oncology].

An analysis of economic and logistical problems of radiation oncology is presented based on domestic and foreign literature. Despite the high efficacy of radiotherapy this branch of oncology is not financed enough in most countries. As a consequence, it is ubiquitously marked radiotherapy capacity deficit that does not allow to fully realize its therapeutic potential. Medical electron accelerators and related equipment have become increasingly complex and expensive and radiotherapy techniques more consuming. Even in developed countries growing waiting times for radiotherapy, not using the most modern and efficient radiotherapy technologies (image guiding, etc.) has become a daily reality. Based on these data, we assessed the prospects and possibilities of upgrading the technical base of radiation oncology in Russia including the development of hadron therapy.

[Advanced radiation therapy project for cancer treatment--from Hokkaido to the world, the world access to Hokkaido].

Cancer is the most major cause of death in Japan recently. In this symposium, we explained advanced treatment technology for cancer treatment, now used and that will be used in near future at the Hokkaido University Hospital. Intensity Moderated Radiation Therapy (IMRT) and Proton Beam Therapy (PBT) are considered to be the most promising and advanced technologies for cancer treatment. Various kinds of radiation treatment equipment and methods have been developed and constructed at the Hokkaido University. One of the most worlds wide famous one is the real time tumor tracking radiotherapy system. The FIRST (Funding for World-Leading Innovative R&D on Science and Technology) Program has been supporting us to produce cutting-edge technology. We hope that this symposium would help the audience to understand the latest technology for cancer treatment especially in the field of radiation therapy and also we wish the audience would recognize the importance of the research aspect that have been performed at Hokkaido University and its Hospital.

Evolving Role of Proton Radiation Therapy in Clinical Practice.

With the expansion of proton radiation therapy centers across the United States and a gradually expanding body of academic evidence supporting its use, more patients are receiving-and asking about-proton therapy than ever before. Here, we outline, for nonradiation oncologists, the theoretical benefits of proton therapy, the clinical evidence to date, the controversies affecting utilization, and the numerous randomized trials currently in progress. We also discuss the challenges of researching and delivering proton therapy, including the cost of constructing and maintaining centers, barriers with insurance approval, clinical situations in which proton therapy may be approached with caution, and the issue of equitable access for all patients. The purpose of this review is to assist practicing oncologists in understanding the evolving role of proton therapy and to help nonradiation oncologists guide patients regarding this technology.

Future technological developments in proton therapy - A predicted technological breakthrough.

In the current spectrum of cancer treatments, despite high costs, a lack of robust evidence based on clinical outcomes or technical and radiobiological uncertainties, particle therapy and in particular proton therapy (PT) is rapidly growing. Despite proton therapy being more than fifty years old (first proposed by Wilson in 1946) and more than 220,000 patients having been treated with in 2020, many technological challenges remain and numerous new technical developments that must be integrated into existing systems. This article presents an overview of on-going technical developments and innovations that we felt were most important today, as well as those that have the potential to significantly shape the future of proton therapy. Indeed, efforts have been done continuously to improve the efficiency of a PT system, in terms of cost, technology and delivery technics, and a number of different developments pursued in the accelerator field will first be presented. Significant developments are also underway in terms of transport and spatial resolution achievable with pencil beam scanning, or conformation of the dose to the target: we will therefore discuss beam focusing and collimation issues which are important parameters for the development of these techniques, as well as proton arc therapy. State of the art and alternative approaches to adaptive PT and the future of adaptive PT will finally be reviewed. Through these overviews, we will finally see how advances in these different areas will allow the potential for robust dose shaping in proton therapy to be maximised, probably foreshadowing a future era of maturity for the PT technique.

Late effects of craniospinal irradiation for medulloblastomas in paediatric patients.

Along with surgery, radiation therapy (RT) remains an essential option to cure patients suffering from medulloblastoma. However, its long-term adverse effects, particularly due to craniospinal irradiation (CSI), which is necessary to eradicate microscopic spread, are a limiting factor. The most frequent sequelae involve neurocognitive and endocrine impairment, which occurs in nearly all patients. Recent progress achieved through genetic and molecular biology offers the possibility to better stratify patients according to risk factors such as age, post-resection tumour residue and metastasis. Thus, new therapeutic studies assess the possibility to reduce radiation dose and/or radiation field size for patients with the most favourable prognosis. New radiotherapy techniques are also used such as Intensity-Modulated Radiotherapy (IMRT), tomotherapy and proton therapy, which aim at reducing the dose delivered to normal tissue. Conventional photon-based therapy has a relatively high exit dose in contrast with proton therapy which causes less damage to surrounding healthy tissue. It is noteworthy that each technique requires a long follow-up in order to prove that late effects could be reduced without compromising survival rates. Dosimetric comparison theoretically suggests that proton therapy may be the superior method for CSI in terms of late effects, but further research is needed to firmly establish this. Whatever the technique used, the great complexity of CSI requires discipline and expertise along with an external quality control online before the first RT session.

Proton therapy and the European Particle Therapy Network: The past, present and future.

Proton therapy is delivered to selected cancer patients presenting with rare tumours, for which a dose escalation paradigm and/or a reduced dose-bath to the organs at risk is pursued. It is a costly treatment with an additional cost factor of 2-3 when compared to photon radiotherapy. Notwithstanding the 180'000 patients treated with protons, scars robust clinical evidence is available to justify the administration of this treatment modality. The European Particle Therapy Network (EPTN) was created in 2015 to answer the critical European needs for cooperation among protons and carbon ions centres in the framework of clinical research networks. EPTN with other European groups will launch a number of prospective clinical trials that could be practice changing if positive. Alternative way to generate clinical data could be provided by alternative methodologies, such as the Dutch model-based approach, or could be provided by European infrastructure projects.

Treatment planning for proton therapy: what is needed in the next 10 years?

Treatment planning is the process where the prescription of the radiation oncologist is translated into a deliverable treatment. With the complexity of contemporary radiotherapy, treatment planning cannot be performed without a computerized treatment planning system. Proton therapy (PT) enables highly conformal treatment plans with a minimum of dose to tissues outside the target volume, but to obtain the most optimal plan for the treatment, there are a multitude of parameters that need to be addressed. In this review areas of ongoing improvements and research in the field of PT treatment planning are identified and discussed. The main focus is on issues of immediate clinical and practical relevance to the PT community highlighting the needs for the near future but also in a longer perspective. We anticipate that the manual tasks performed by treatment planners in the future will involve a high degree of computational thinking, as many issues can be solved much better by e.g. scripting. More accurate and faster dose calculation algorithms are needed, automation for contouring and planning is required and practical tools to handle the variable biological efficiency in PT is urgently demanded just to mention a few of the expected improvements over the coming 10 years.

Proton therapy delivery: what is needed in the next ten years?

Proton radiation therapy has been used clinically since 1952, and major advancements in the last 10 years have helped establish protons as a major clinical modality in the cancer-fighting arsenal. Technologies will always evolve, but enough major breakthroughs have been accomplished over the past 10 years to allow for a major revolution in proton therapy. This paper summarizes the major technology advancements with respect to beam delivery that are now ready for mass implementation in the proton therapy space and encourages vendors to bring these to market to benefit the cancer population worldwide. We state why these technologies are essential and ready for implementation, and we discuss how future systems should be designed to accommodate their required features.

Past, present and future of proton therapy for head and neck cancer.

Proton therapy has recently gained substantial momentum worldwide due to improved accessibility to the technology and sustained interests in its advantage of better tissue sparing compared to traditional photon radiation. Proton therapy in head and neck cancer has a unique advantage given the complex anatomy and proximity of targets to vital organs. As head and neck cancer patients are living longer due to epidemiological shifts and advances in treatment options, long-term toxicity from radiation treatment has become a major concern that may be better mitigated by proton therapy. With increased utilization of proton therapy, new proton centers breaking ground, and as excitement about the technology continue to increase, we aim to comprehensively review the evidence of proton therapy in major subsites within the head and neck, hoping to facilitate a greater understanding of the full risks and benefits of proton therapy for head and neck cancer.

A population-based assessment of proton beam therapy utilization in California.

OBJECTIVES: Proton beam therapy (PBT) is a type of radiation therapy (RT) used for certain cancer types because it minimizes collateral tissue damage. The high cost and limited availability of PBT have constrained its utilization. This study examined patterns and determinants of PBT use in California. STUDY DESIGN: Persons with diagnoses of all cancer types from 2003 to 2016 inclusive who had any type of RT were identified in the California Cancer Registry in this retrospective analysis. METHODS: Cross-tabulations were performed to summarize the demographic characteristics of the study population, both for individuals who received PBT and for those who received other RT modalities. PBT use patterns over time were assessed. Multivariate logistic regression models assessed the effects of demographics and health insurance type on receipt of PBT. RESULTS: Of the 2,499,510 people with a cancer diagnosis during the study period, 578,632 (23%) received some type of RT, and of these, 8609 received PBT (1.5%). PBT was most often used to treat cancers of the prostate (41.3%), breast (14.0%), eye (11.7%), lung (6.1%), and brain (6.0%). PBT use was highest in 2003-2004 and then declined over time. PBT use was significantly associated with being white or male, younger age, higher socioeconomic status, Medicare or dual Medicare-Medicaid insurance, uninsured/self-pay status, and proximity to treatment. CONCLUSIONS: Significant differences exist in PBT use by demographics and health insurance type. The identified racial and socioeconomic disparities merit further investigation. More granular studies on both use patterns and effectiveness of PBT for specific cancers are needed to draw stronger conclusions about its cost-benefit ratio.

History and current perspectives on the biological effects of high-dose spatial fractionation and high dose-rate approaches: GRID, Microbeam & FLASH radiotherapy.

The effects of various forms of ionising radiation are known to be mediated by interactions with cellular and molecular targets in irradiated and in some cases non-targeted tissue volumes. Despite major advances in advanced conformal delivery techniques, the probability of normal tissue complication (NTCP) remains the major dose-limiting factor in escalating total dose delivered during treatment. Potential strategies that have shown promise as novel delivery methods in achieving effective tumour control whilst sparing organs at risk involve the modulation of critical dose delivery parameters. This has led to the development of techniques using high dose spatial fractionation (GRID) and ultra-high dose rate (FLASH) which have translated to the clinic. The current review discusses the historical development and biological basis of GRID, microbeam and FLASH radiotherapy as advanced delivery modalities that have major potential for widespread implementation in the clinic in future years.

Latest developments in in-vivo imaging for proton therapy.

Owing to the favorable physical and biological properties of swift ions in matter, their application to radiation therapy for highly selective cancer treatment is rapidly spreading worldwide. To date, over 90 ion therapy facilities are operational, predominantly with proton beams, and about the same amount is under construction or planning.Over the last decades, considerable developments have been achieved in accelerator technology, beam delivery and medical physics to enhance conformation of the dose delivery to complex shaped tumor volumes, with excellent sparing of surrounding normal tissue and critical organs. Nevertheless, full clinical exploitation of the ion beam advantages is still challenged, especially by uncertainties in the knowledge of the beam range in the actual patient anatomy during the fractionated course of treatment, thus calling for continued multidisciplinary research in this rapidly emerging field.This contribution will review latest developments aiming to image the patient with the same beam quality as for therapy prior to treatment, and to visualize in-vivo the treatment delivery by exploiting irradiation-induced physical emissions, with different level of maturity from proof-of-concept studies in phantoms and first in-silico studies up to clinical testing and initial clinical evaluation.