Proton Cancer Therapy: Synchrotron-Based Clinical Experiences 2020 Update

Proton therapy is an efficient high-precision radiotherapy technique. The number of installed proton units and the available medical evidence has grown exponentially over the last 10 years. As a technology driven cancer treatment modality, specific subanalysis based on proton beam characteristics and proton beam generators is feasible and of academic interest. International synchrotron technology-based institutions have been particularly active in evidence generating actions including the design of prospective trials, data registration projects and retrospective analysis of early clinical results. Reported evidence after 2010 of proton therapy from synchrotron based clinical results are reviewed. Physics, molecular, cellular, animal investigation and other non-clinical topics were excluded from the present analysis. The actual literature search (up to January 2020) found 192 publications, including description of results in over 29.000 patients (10 cancer sites and histological subtypes), together with some editorials, reviews or expert updated recommendations. Institutions with synchrotronbased proton therapy technology have shown consistent and reproducible results along the past decade. Bibliometrics of reported clinical experiences from 2008 to early 2020 includes 58% of publications in first quartile (1q) scientific journals classification and 13% in 2q (7% 3q, 5% 4q and 17% not specified). The distribution of reports by cancer sites and histological subtypes shown as dominant areas of clinical research and publication: lung cancer (23%), pediatric (18%), head and neck (17%), central nervous system (7%), gastrointestinal (9%), prostate (8%) and a miscellanea of neplasms including hepatocarcinoma, sarcomas and breast cancer. Over 50% of lung, pediatric, head and neck and gastrointestinal publications were 1q.


Introduction 1.1 Cancer medicine: precision, interdisciplinary and personalization
Proton beam therapy (PBT) is developing in the context of a substantial increase in the incidence of cancer, the enormous advances made in our understanding of the biological basis and clinical implications of the disease, and the need to improve the therapeutic index: tumor control promotion and minimal clinically relevant toxicity.PBT is an accessible precision high-energy particle radiation technology, adapted to the therapeutic demands tendencies in health care and health budget of modern clinical practice [1].Other radiotherapy (RT) solutions using hadron beams (hadron therapy) are too costly in the medium term in most clinical settings [2].
PBT is now firmly established the era of precision medicine [3].In oncology, the principles of medicine must be well defined: Interdisciplinarity and molecular individuation.Technological excellence will only be achieved when it encompasses the different medical specialties involved in treating each individual patient.Multidisciplinary Tumor Boards (MTD) are an essential part of an efficient approach to cancer management [4].Personalized cancer treatment is characterized by a detailed analysis of the molecular configuration and evolution of each patient's tumor (gene expression profile and nanobiology) [5].The latest evidence suggests that tumors are probably unique to each patient, and that each tumor within the same patient (metastasis, primary site or recurrence) has its own biological pattern of progression and host adaptation pathway [6].

Vectors in radiation oncology: individualized, functional, accurate and precise therapy
RT currently helps to achieve cure over half of all patients that require this treatment; it relieves symptoms in 2 out of every 3 patients, and in general terms is a crucial therapeutic component in 3 out of every 4 cancer patients [7].Furthermore, RT preserves organs and tissue structures (in contrast to the status resulting from radical extended surgery) and can be used in the context of radical treatment for oligometastatic and oligo-recurrent disease [8,9].Forecasts in healthcare systems in countries like the US suggest that by 2020, indications for RT in all types of cancer will have increased by 25%, and by 35% in the case of gastrointestinal malignancies [10].
The foregoing estimations are based on the enormous technological advances made in RT in the last 30 years.If medical advances in clinical oncology have ushered in the era of precision medicine, interdisciplinary approach in recent decades in oncological RT (which specifically uses ionizing radiation to treat cancer) have ushered in the era of accurate precise RT.
Precision RT is very efficient in promoting the local control (LC) of macroscopically identifiable cancer lesions (targeted by image-guided RT), and has an excellent therapeutic index, in other words, minimal, toxicity in normal radiationsensitive tissue [11].Because accurate precise RT has minimum effect on the function of the organs, systems (blood, liver, lungs, etc.) and tissues where the tumor is located, it has allowed clinicians to explore the radiobiological effects of hypofractionation, heterogeneous dose distribution within target volumes (adjusted for bioheterogeneity), and of immunomodulatory, radiation-enhancing, radiationsensitive and radiation-protective drug interactions [12].Finally, one of the most promising aspects of accurate precise RT is the potencial of radiation-induced immunogenicity induced by hypofractionated (>8 Gy) RT [13].Checkpoint inhibitors and other inmunomodulators allow clinicians to explore the potential of combining systemic immunotherapy effects with precision local and atoxic RT [14].

Developing proton beam therapy clinical evidence
In the next decade, technological advances in PBT will bring further technological developments in precision RT into mainstream clinical practice.The dosimetric precision of PBT compares favorably with photon therapy and, guided by beam homogeneity in the delivery and imaging systems for precision control (4D and quasi-real-time control), its results in clinical practice will be equivalent and reproducible (Figure 1).
The value of a treatment is defined as the outcomes obtained divided by the cost, measured over the entire cycle of care [15].The clinical potential of proton cancer therapy requires sophisticated and realistic assessment of integral cost of care estimations including "costicity" (the cost of toxicity and general health-related supportive care).A collaborative effort between clinicians, patients, and policy makers is needed to design clinical trials with meaningful patient engagement.In particular, patients may help to identify and refine approaches that will lead to improved enrollment and retention in clinical trials as evidence generators sources.One crucial element in arriving at meaningful conclusions from such analyses is the need to account for the costs of managing not only acute RT toxicity but also long-term morbidities that can occur years to decades after RT is completed.
In 2016, Mishra et al. reviewed the context of developing evidence in cancer proton therapy [16].PBT clinical trials identified from clinicaltrials.govand the

Evolutive and consolidated clinical outcomes
Clinical results based on novel treatments need both time to mature, and a method of comparison that can define the best indications in the context of currently available accurate precise RT.Mature results from some studies recommend PBT for extreme indications in radioresistant, indolent yet highly infiltrative and extensive cancer lesions, and in patients requiring re-irradiation due to symptomatic oligo-recurrence.
The following is a summary of the clinical results of a selective review of the latest, most influential, clinical studies analyzing synchrotron-based PBT institutional outcomes.The data available generally relates to established and developmental indications, together with some comparative analysis with other RT technologies.The information was obtained from a specific literature search and systematic reviews spanning 2010-2020.

Pediatric tumors
In 2020 PBT is the radiation therapy technology of election for pediatric oncology patients.The evolution towards this practice status has been fast.A survey conducted between July 2017 and June 2018 in all proton centers treating pediatric patients in 2016 worldwide identified a total of 54 centers operating in 11 countries (Particle Therapy Co-Operative Group, PTCOG website).Among the 40 participating centers (74%), a total of 1860 patients were treated in 2016 (North America: 1205, Europe: 432, Asia: 223.
More than 30 pediatric tumor types were identified, mainly treated with curative intent.About half of the patients were treated with pencil beam scanning [18].
Pediatric cancer patients referred to proton therapy centers do benefit from expert dedicated highly specialized care both in terms of normal tissue protection to radiation exposure during treatment delivery and from early access to medical integral care and radiotherapy process (5 weeks median starting time) [19].
A critical milestone to facilitate long-term clinical outcomes research in the modern era has been achieved.The Pediatric Proton Consortium Registry (PPCR) has reported a total of 1854 patients enrolled from October 2012 until September 2017.The cohort is 55% male, 70% Caucasian, and comprised of 79% United States residents.Central nervous system (CNS) tumors were the most frequent group of diseases (61%).The most common non-CNS tumors diagnoses were: rhabdomyosarcoma (n = 191), Ewing sarcoma (n = 105), Hodgkin lymphoma (n = 66), and neuroblastoma (n = 55) (Table 1) [20].

Central nervous system
Radiotherapy confers survival advantages to patients with glioblastoma, medulloblastoma, germ cell, ependymoma and other intracranial neoplasms.This costeffective and accessible treatment modality has proven efficacy in the adjuvant and definitive setting, as a first-line treatment or after prior lines of therapy.Neuroradiation oncology has witnessed a burgeoning of new techniques, technologies and strategies that will better optimize the therapeutic ratio.Proton beam therapy (PBT) offers the potential to minimize late-onset toxicities while preserving disease-related outcomes.Multidisciplinary efforts explore synergies between the effects of radiotherapy and novel systemic therapies to tailor the delivery by molecular profile (Table 2) [41].

Head and neck cancer
PBT has emerged as a novel means to reduce toxicity and potentially further improve tumor control in head and neck cancer patients.The unique physical properties of charged particles allow a steep dose gradient with a reduced integral dose delivered to the patient in a proportion that can meaningfully reduce doserelated toxicity.
For the National Comprehensive Cancer Network guidelines, proton therapy is a standard of care for base of skull tumors and is an optimized option for periorbital tumors.The use of proton therapy is expanding for other cancer sites.Novel forms of proton therapy such as IMPT, and technical improvements in dose modeling, patient setup, image guidance and radiobiology, will help further enhance the benefits of proton therapy.The present cost of delivering PBT is approximately 2-3 times higher than for delivering IMRT photons in the head and neck (H&N) cancer model of health care.However, the cost difference is reduced when costs are considered over the entire cycle of care.Predictive models using comorbidity scales could defined a subpopulation of patients for whom proton therapy is likely to reduce side effects and subsequent use of health care resources (Table 3) [52].

Lung cancer
The call for designing and conducting "smart" proton therapy trials for lung cancer patients requires establishing clinical evidence and patient selection criteria to make proton therapy a truly personalized form of treatment.Comparative trials could focus on endpoints such as cardiac toxicity, low-dose radiation bath, and lymphopenia.The enhancement of dosimetric and biological advantages of PBT to improve clinical outcomes requires further developments in image-guided Merchant, [25] 2008 40 Optic pathway glioma (10), craniopharyngioma (10), infratentorial ependymoma (10), medulloblastoma (10).hypofractionated intensity modulated proton therapy (IMPT) and combinations of hypofractionated proton therapy with immunotherapy [63].

Not reported
For early-stage non-small cell lung cancer (NSCLC), the optimal clinical context for proton beam therapy (PBT) is challenging due to the increasing evidence demonstrating high rates of local control and good tolerance of stereotactic ablative body radiation (SABR).The potential advantage may be significant in treating larger tumors, multiple tumors, or central tumors.Most of the published studies are based on passive scattering PBT.Dosimetric benefits are likely to increase whith pencil beam scanning/intensity-modulated proton therapy (IMPT) [64].A prospective longitudinal observational study of 82 patients with unresectable primary or recurrent NSCLC treated with 3-dimensional conformal radiation therapy (3DCRT), IMRT, or proton therapy included patient-reported symptom burden, assessed weekly for up to 12 weeks with the validated MD Anderson Symptom Inventory.Despite the fact that the proton group received significantly higher target radiation doses (P < 0.001), patients receiving proton therapy reported significantly less severe symptoms than did patients receiving IMRT or 3DCRT [63].(Table 4).

Esophageal cancer
Radiation therapy (RT) has become an important component in the curative management of esophageal cancer (EC).Since most of the ECs seen in the Western hemisphere (i.e., Europe and the United States) are located in the mid-to distalesophageal locations, heart and lungs invariably receive significant radiation doses.Proton beam therapy (PBT) provides the ability to further reduce normal tissue exposure because of its lack of exit dose, which is expected to provide clinically meaningful benefit for at least some EC patients [90].
Investigators at MD Anderson Cancer Center have reported a phase IIb randomized trial comparing PBT and IMRT for patients with EC (NCT01512589).The primary endpoints are progression-free survival and total toxicity burden, which is a composite endpoint including serious adverse events and postoperative complications.Among the 145 patients randomized, total toxicity burden was 2.3 times higher for photon IMRT and the postoperative complications (50% of patients were operated) was 7.6 times higher in photon IMRT cohort.The 3-year overall survival was similar in both groups (44%) [91].Results from prospective clinical trials will greatly improve our knowledge regarding the role and benefits expected from proton therapy for EC.(Table 5).

Hepatocellular cancer
Proton beam therapy has the unique dosimetric performance, particularly valuable for the treatment of hepatocellular carcinoma (HCC).Clinical data is available in a limited number of patients, especially from Japan.In a systematic review from 1983 to June 2016 to identify clinical studies on charged particle therapy for HCC, a total of 13 cohorts from 11 papers.The reported actuarial local control rates ranged from 71 to 95% at 3 years, and the overall survival rates ranged from 25-42% at 5 years.Late severe radiation morbidities were uncommon, and a total of 18 patients with grade ≥ 3 late adverse events were reported among the 787 patients included in the analysis.
The   Group (JROSG) and other groups are conducting multi-institutional prospective clinical trials in order to obtain approval for national health insurance for HCC and other cancers.The NCCN guidelines recommend that PBT may be appropriate in specific situations.In the Japanese guidelines, can be considered for HCCs that are difficult to treat with other local therapies, such as those with portal vein or inferior vena cava tumor thrombus and large lesions.The Korean Liver Cancer Study Group also mentioned the efficacy of PBT in their guidelines [104].Guidelines from expert hepatologists evaluating the of data available for HCC patients will influence on the pattern of clinical practice considering the option of PBT as upfront therapy in the decision-making process (Table 6) [105].

Lymphoma
In adult lymphoma survivors, radiation treatment with increase excess of radiation dose to organs at risk (OARs) does increase the risk for side effects, especially late toxicities.Minimizing radiation to organs at risk (OARs) in adult patients with Hodgkin and non-Hodgkin lymphomas involving the mediastinum is the decisive factor to select the treatment modality.
Proton therapy reduces the unnecessary radiation to the OARs and reduces toxicities, especially the risks for cardiac morbidity and second cancers.In modern guidelines for adult lymphoma patients, the benefit from proton therapy and the advantages and disadvantages of proton treatment are considered.The dosimetric advantage of reducing the unnecessary dose to lung, breast, heart, spinal cord, vessels, vertebrae, thyroid and other structures in certain lymphoma involvements can be significant and highly desirable for patients that will be extreme long-term survivors at risk for severe chronic conditions and second malignancies [112] (Table 7).

Prostate
PBT for prostate cancer patients has been a continuously growing option due to its promising characteristics of high precision dose distribution in the target and a sharp distal fall-off.Considering the large number of proton beam facilities in Japan, the further increase of patients undergoing this treatment will be related to the policies of the Japanese National Health Insurance (NHI) together with the development of medical equipment and technology.A review conducted review to identify and discuss research studies of proton beam therapy for prostate cancer in Japan (up to June 2018) included 23 articles (14 observational, focused on the adverse effects), and 7 interventional on treatment planning, equipment parts, as well as target positioning.Favorable clinical results of PBT were consistent and future research should focus on longer follow-up clinical data.PBT is a suitable treatment option for localized prostate cancer [116].
At present, as particle beam therapy for prostate cancer is covered by the Japanese national health insurance system (since April 2018), and the number of facilities practicing particle beam therapy has increased recently, the number of prostate cancer patients treated with particle beam therapy in Japan is expected to increase drastically [117].(Table 8).

Miscellaneous neoplasms and oncological clinical conditions
PBT has been explored in a variety of cancer sites, histological subtypes and disease stages, including localized breast cancer, seminoma, pancreatic cancer, oligo-recurrences and other cancer conditions.(Table 9).A special challenge for defining PBT health value are geriatric cancer patients.Aging and chronic comorbidity is a medical reality in the present and future of oncology practice.It is projected that 1 of 5 Americans will be aged ≥65 years in 2050 and that 60% of cancers will occur in this group.As PBT resources are limited, centers have designed decision-making systems for prioritization.Elderly cancer patients are as fragile as pediatric oncology patients in terms of "normal" tissues protection importance, their tissues are not that "normal" at all but link to comorbid and biological senescence.A small pilot survey of international academic radiation oncologists with particular experience in geriatric care recommended a preference for irradiation with PBT, due to the age condition and cancer stage.Although this finding may sound provocative, it shows that, while currently inclined toward pediatrics, many practitioners see strong indications in the elderly population.
The Eurocare showed that the age-standardized death rate for cancer was ≥12 times higher among elderly persons than among younger persons, in part, because treatments most commonly associated with cancer cure are less commonly given to elderly patients.The use of PBT will, through reducing morbidity, make the delivery of curative therapy more possible, merits a serious thought.Older patients are more likely to be admitted for cancer treatment as a result of an emergency or at an advanced stage.These factors may be associated with increased costs.The societal cost of delayed or inadequate treatment will require formal measurement against the cost of these advanced radiation technologies.PT should now be regarded as a relevant method to limit the short-and long-term toxicity of irradiation and reduce the need for costly supportive care.
While research protocols no longer exclude patients based solely on age, many currently do so because of these patients' comorbidities.It is time to consider the inclusion of comprehensively assessed elderly men and women in clinical trials of PBT.It is among these patients that some of the greatest benefits may yet be revealed.Until specific trials report their findings, a proactive guidance for the    intra-hospital process have had a positive test for COVID infection (up to the moment of writing the present manuscript October 2020), but several patients (11%) under treatment were detected to be infected along the treatment period (Table 10).

Conclusions
In principle, PBT offers a substantial clinical advantage over conventional photon therapy.This is because of the unique dose-deposition characteristics of protons, which can be exploited to achieve significant reductions in normal tissue doses proximal and distal to the target volume.These may allow escalation of tumor doses and greater sparing of normal tissues from unnecessary irradiation exposure, thus

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Proton Therapy -Current Status and Future Directions potentially improving local control and survival while at the same time reducing toxicity, carcinogenesis and improving quality of life.Synchrotron technology matches these benefits with proven reproducibility of its dosimetric properties and clinical observations.Despite the high potential of PBT, the clinical evidence supporting the broad use of protons is still under consolidation.The clinical data generated in institutions with synchrotron technology is abundant and of high scientific quality in terms of bibliometric records.An update has been summarized in the present publication.Clinical scientists operating with synchrotron proton beams are remarkably active in generating knowledge on topics such as cost effectiveness, the implementation of randomized trials and the collection of outcomes data in multi-institutional registries.
Some fundamental issues to understand clinical outcomes are unsolved.This includes the equivalence of passive beams versus pencil beam radiation delivery and the relative biological effectiveness (RBE) of protons which is simplistically assumed to have a constant value of 1.1.In reality, the RBE is variable and a complex function of the energy of protons, dose per fraction, tissue and cell type, end point, etc.
From 2012 to 2017, both ASTRO's Emerging Technology Committee report and ASTRO Model Policy document on proton beam therapy consider its recommendation reasonable in instances where sparing the surrounding normal tissue cannot be adequately achieved with photon-based radiotherapy and is of added clinical benefit to the patient.Based on the medical necessity requirements or the generation of clinical evidence in IRB-approved clinical trials or in multi-institutional patient registries adhering to Medicare requirements, PBT is expanding widely in clinical practice [133].
For a practicing oncologist evaluating treatment plans has uncertainties about the radiobiological equivalences (RBE) and other dosimetric elements that are taken into current models, which means that, the dose displayed on a commercial treatment plan is likely to be less accurate.These features are not intuitive for oncologists and allied cancer specialties clinicians and need further refinement in the assessment of dosimetric displays.It means the dose effects may extend past the isodose lines shown on paper, not considering certain uncertainties and this effect beyond the target will always be in non-target normal tissues [134].
Synchrotron technology is a component of the integral health care of a patient requiring radiotherapy and all the elements involved in the medical process need to be optimized to achieve an improved quality and safety standards in proton cancer therapy [135].

Figure 1 .
Figure 1.Clinical practice-based example of dose distribution in a craneospinal irradiation represented in 2D and 3D images.Treatment planning implementation in PBT enhances the perception of clinical benefit expected by protecting normal anatomy from unnecessary irradiation.

Figure 3 .
Figure 3. Distribution of exclusive synchrotron technology for PBT in the world.Institutions with active 360°gantry equipment available.

Table 3 .
Clinical experiences in head and neck cancer treated with synchrotron technology (2014-2019).(mFT: median follow up time).
American Society for Radiation Oncology (ASTRO) issued a Model Policy on PBT in 2014 and PBT for HCC is covered by medical insurance in the United States.The Japanese Clinical Study Group of Particle Therapy (JCPT), the Japanese Society for Radiation Oncology (JASTRO), the Japanese Radiation Oncology Study 16Proton Therapy -Current Status and Future Directions
20Proton Therapy -Current Status and Future Directions

Table 9 .
Clinical experiences in miscellaneous neoplasms and cancer conditions treated with synchrotron technology (2015-2017); LC: Local Control.

Table 10 .
Early clinical demographic data in patients treated in the Clinica Universidad de Navarra synchrotron PBT system: 6 months period (March-October 2020).