The European Joint Research Project UHDpulse – Metrology for advanced radiotherapy using particle beams with ultra-high pulse dose rates

UHDpulse – Metrology for advanced radiotherapy using particle beams with ultra-high pulse dose rates is a recently started European Joint Research Project with the aim to develop and improve dosimetry standards for FLASH radiotherapy, very high energy electron (VHEE) radiotherapy and laser-driven medical accelerators. This paper gives a short overview about the current state of developments of radiotherapy with FLASH electrons and protons, very high energy electrons as well as laser-driven particles and the related challenges in dosimetry due to the ultra-high dose rate during the short radiation pulses. We summarize the objectives and plans of the UHDpulse project and present the 16 participating partners.     

Technical challenges for FLASH proton therapy

There is growing interest in the radiotherapy community in the application of FLASH radiotherapy, wherein the dose is delivered to the entire treatment volume in less than a second. Early pre-clinical evidence suggests that these extremely high dose rates provide significant sparing of healthy tissue compared to conventional radiotherapy without reducing the damage to cancerous cells. This interest has been reflected in the proton therapy community, with early tests indicating that the FLASH effect is also present with high dose rate proton irradiation.In order to deliver clinically relevant doses at FLASH dose rates significant technical hurdles must be overcome in the accelerator technology before FLASH proton therapy can be realised. Of these challenges, increasing the average current from the present clinical range of 1–10 nA to in excess of 100 nA is at least feasible with existing technology, while the necessity for rapid energy adjustment on the order of a few milliseconds is much more challenging, particularly for synchrotron-based systems. However, the greatest challenge is to implement full pencil beam scanning, where scanning speeds 2 orders of magnitude faster than the existing state-of-the-art will be necessary, along with similar improvements in the speed and accuracy of associated dosimetry. Hybrid systems utilising 3D-printed patient specific range modulators present the most likely route to clinical delivery. However, to correctly adapt and develop existing technology to meet the challenges of FLASH, more pre-clinical studies are needed to properly establish the beam parameters that are necessary to produce the FLASH effect.     

External beam radiation therapy with kilovoltage x-rays

Kilovoltage (kV) x-rays are most commonly used for diagnostic imaging due to their sensitivity to tissue composition. In radiation therapy (RT), due to their fast attenuation, kV x-rays are typically only used for superficial irradiation of skin cancer and for intra-operative RT (IORT). Recently, however, a number of kV RT techniques have emerged. In this review article, we provide a brief overview of the use of kV x-rays for RT.Various kV x-ray source technologies suitable for RT, such as conventional x-ray tubes as well as novel x-ray sources, are first described. This x-ray source section is then followed by a section on their implementation in terms of clinical, veterinary and preclinical applications. Specifically, IORT, superficial RT and dose enhancement with iodine and gold nanoparticles, as well as microbeam RT and FLASH RT are discussed in this context. Then, a number of kV x-ray RT applications in modeling and proof-of-principle stages, such as breast external beam RT with rotational sources, kilovoltage arc therapy and the BriXS Compton pulsed x-ray sources, are reviewed. Finally, some clinical and economic considerations for the development of kV RT techniques are discussed.     

Treatment-integrated imaging,radiomics, and personalised radiotherapy: the future is at hand

Since the introduction of computed tomography for planning purposes in the 1970s, we have been observing a continuous development of different imaging methods in radiotherapy. The current achievements of imaging technologies in radiotherapy enable more than just improvement of accuracy on the planning stage. Through integrating imaging with treatment machines, they allow advanced control methods of dose delivery during the treatment. This article reviews how the integration of existing and novel forms of imaging changes radiotherapy and how these advances can allow a more individualised approach to cancer therapy.We believe that the significant challenge for the next decade is the continued integration of a range of different imaging devices into linear accelerators. These imaging modalities should show intra-fraction changes in body morphology and inter-fraction metabolic changes. As the use of these more advanced, integrated machines grows, radiotherapy delivery will become more accurate, thus resulting in better clinical outcomes: higher cure rates with fewer side effects.     

Recent advances in clinical studies of selenium supplementation in radiotherapy

BackgroundRadiotherapy is one of the most important and common therapies for cancer patients. Selenium has been shown to be capable of reducing the side effects of radiotherapy because selenoproteins have anti-oxidative functions against reactive oxygen species that are induced by the radiation. They also function in DNA-repair and cytokine control.PurposeWe explored the benefits and risks of selenium supplementation in radiotherapy in our previous review to establish guidelines. In the current study, we expanded the search to cover recent advances in clinical studies of selenium supplementation in radiotherapy.MethodsWe conducted an initial screening in the PubMed using the MeSH terms and keywords “selenium”, “radiation”, “therapy”, and “radiotherapy” using the same methodology applied in our previous review. We identified 121 articles published between January 2013 and December 2019. We then identified eight articles (six studies) on selenium and radiotherapy by excluding 113 articles.ResultsIn selenium supplementation studies, selenium doses of 300−500 μg/day with duration of 10 days to 6 months were used. Selenium supplementation improved the selenium nutritional conditions of the patients and reduced the side effects of radiotherapy. Selenium supplementation did not reduce the effectiveness of radiotherapy, and no toxicities were reported.ConclusionThe results of our previous and current reviews showed that selenium supplementation offers specific benefits for several cancer types treated with radiotherapy. Here, we suggest a new guideline for selenium supplementation in radiotherapy. We recommend determining the selenium status of the patients before radiotherapy, and in cases of deficiency (<100 μg/L serum selenium level), selenium supplement can be beneficial.     

Impact of Pelvic Radiotherapy on Gut Microbiota of Gynecological Cancer Patients Revealed by Massive Pyrosequencing

Although pelvic irradiation is effective for the treatment of various cancer types, many patients who receive radiotherapy experience serious complications. Gut microbial dysbiosis was hypothesized to be related to the occurrence of radiation-induced complications in cancer patients. Given the lack of clinical or experimental data on the impact of radiation on gut microbiota, a prospective observational study of gut microbiota was performed in gynecological cancer patients receiving pelvic radiotherapy. In the current study, the overall composition and alteration of gut microbiota in cancer patients receiving radiation were investigated by 454 pyrosequencing. Gut microbial composition showed significant differences (P < 0.001) between cancer patients and healthy individuals. The numbers of species-level taxa were severely reduced after radiotherapy (P < 0.045), and the abundance of each community largely changed. In particular, the phyla Firmicutes and Fusobacterium were significantly decreased by 10% and increased by 3% after radiation therapy, respectively. In addition, overall gut microbial composition was gradually remolded after the full treatment course of pelvic radiotherapy. In this set of cancer patients, dysbiosis of the gut microbiota was linked to health status, and the gut microbiota was influenced by pelvic radiotherapy. Although further studies are needed to elucidate the relationship between dysbiosis and complications induced by pelvic radiotherapy, the current study may offer insights into the treatment of cancer patients suffering from complications after radiation therapy.     

Clinical,Molecular- and Cytogenetic Analysis of a Case of Severe Radio-Sensitivity

In radiotherapy the normal tissue reaction is often a limiting factor for radiation treatment. Still there is no screening method, which predicts normal tissue reaction on radiotherapy, especially in comparison to tumor tissue, and therefore allows tailoring of the radiation dose to each patient. Here, we present a case of severe radiation-related side effects. We applied classical cytogenetic techniques (Giemsa-banding and staining of centromeric regions), the comet assay as well as multicolor fluorescence in situ hybridization on peripheral blood lymphocytes of this patient in order to determine the radio-sensitivity on the DNA level and to correlate these findings with the clinical outcome. Our investigations revealed abnormalities on chromosome 9, deficiencies in the DNA-repair capacity after radiation exposure and a high number of radiation induced chromosomal aberrations. A detected high amount of residual damage two or three hours after radiation exposure and repair as well as the high number of chromosomal aberrations (ChAs) suggests a correlation between repair capacity and radiation induced ChAs. We concluded that the detected abnormalities might serve as a genetic basis for the radio-sensitive phenotype of this patient. Taken together this report strengthens the idea that intensive DNA genomic analysis of individual patients can serve as the basis for more favourable treatment of cancer patients.     

The role of medical physics in prostate cancer radiation therapy

Medical physics, both as a scientific discipline and clinical service, hugely contributed and still contributes to the advances in the radiotherapy of prostate cancer. The traditional translational role in developing and safely implementing new technology and methods for better optimizing, delivering and monitoring the treatment is rapidly expanding to include new fields such as quantitative morphological and functional imaging and the possibility of individually predicting outcome and toxicity. The pivotal position of medical physicists in treatment personalization probably represents the main challenge of current and next years and needs a gradual change of vision and training, without losing the traditional and fundamental role of physicists to guarantee a high quality of the treatment. The current focus issue is intended to cover traditional and new fields of investigation in prostate cancer radiation therapy with the aim to provide up-to-date reference material to medical physicists daily working to cure prostate cancer patients. The papers presented in this focus issue touch upon present and upcoming challenges that need to be met in order to further advance prostate cancer radiation therapy. We suggest that there is a smart future for medical physicists willing to perform research and innovate, while they continue to provide high-quality clinical service. However, physicists are increasingly expected to actively integrate their implicitly translational, flexible and high-level skills within multi-disciplinary teams including many clinical figures (first of all radiation oncologists) as well as scientists from other disciplines.     

Radiotherapy: Brightness and darkness in the era of immunotherapy

The introduction of immunotherapy into cancer treatment has radically changed clinical management of tumors. However, only a minority of patients (approximately 10 to 30%) exhibit long-term response to monotherapy with immunotherapy. Moreover, there are still many cancer types, including pancreatic cancer and glioma, which are resistant to immunotherapy. Due to the immunomodulatory effects of radiotherapy, the combination of radiotherapy and immunotherapy has achieved better therapeutic effects in a number of clinical trials. However, radiotherapy is a double-edged sword in the sense that it also attenuates the immune system under certain doses and fractionation schedules, not all clinical trials show improved survival in the combination of radiotherapy and immunotherapy. Therefore, elucidation of the interactions between radiotherapy and the immune system is warranted to optimize the synergistic effects of radiotherapy and immunotherapy. In this review, we highlight the dark side as well as bright side of radiotherapy on tumor immune microenvironment and immune system. We also elucidate current status of radioimmunotherapy, both in preclinical and clinical studies, and highlight that combination of radiotherapy and immunotherapy attenuates combinatorial effects in some circumstances. Moreover, we provide insights for better combination of radiotherapy and immunotherapy.     

Radiotherapy after Radical Prostatectomy: Treatment Recommendations Differ between Urologists and Radiation Oncologists

Purpose

There is no consensus on optimal use of radiotherapy following radical prostatectomy. The purpose of this study was to describe opinions of urologists and radiation oncologists regarding adjuvant and salvage radiotherapy following radical prostatectomy.

Methods

Urologists and genitourinary radiation oncologists were solicited to participate in an online survey. Respondent characteristics included demographics, training, practice setting, patient volume/experience, and access to radiotherapy. Participant practice patterns and attitudes towards use of adjuvant and salvage radiotherapy in standardized clinical scenarios were assessed.

Results

One hundred and forty-six staff physicians participated in the survey (104 urologists and 42 genitourinary radiation oncologists). Overall, high Gleason score (Gleason 7 vs. 6, RR 1.37 95% CI 1.19-1.56, p<0.0001 and Gleason 8-10 vs. 6, RR 1.56 95% CI 1.37-1.78, p<0.0001), positive surgical margin (RR 1.43 95% CI 1.26-1.62, p<0.0001), and extraprostatic tumour extension (RR 1.16 95% CI 1.05-1.28, p<0.002) conferred an increased probability of recommending adjuvant radiotherapy. Radiation oncologists were more likely to recommend adjuvant radiotherapy across all clinical scenarios (RR 1.48, 95% CI 1.39, 1.60, p <0.001). Major differences were found for patients with Gleason 6 and isolated positive surgical margin (radiotherapy selected by 21% of urologists vs. 70% of radiation oncologists), and patients with extraprostatic extension and negative surgical margins (radiotherapy selected by 18% of urologist vs. 57% of radiation oncologists).

Conclusions

Urologists and radiation oncologists frequently disagree about recommendation for post-prostatectomy adjuvant radiotherapy. Since clinical equipoise exists between adjuvant versus early salvage post-operative radiotherapy, support of clinical trials comparing these approaches is strongly encouraged.     

3′-End processing of histone pre-mRNAs in Drosophila: U7 snRNP is associated with FLASH and polyadenylation factors

3′-End cleavage of animal replication-dependent histone pre-mRNAs is controlled by the U7 snRNP. Lsm11, the largest component of the U7-specific Sm ring, interacts with FLASH, and in mammalian nuclear extracts these two proteins form a platform that recruits the CPSF73 endonuclease and other polyadenylation factors to the U7 snRNP. FLASH is limiting, and the majority of the U7 snRNP in mammalian extracts exists as a core particle consisting of the U7 snRNA and the Sm ring. Here, we purified the U7 snRNP from Drosophila nuclear extracts and characterized its composition by mass spectrometry. In contrast to the mammalian U7 snRNP, a significant fraction of the Drosophila U7 snRNP contains endogenous FLASH and at least six subunits of the polyadenylation machinery: symplekin, CPSF73, CPSF100, CPSF160, WDR33, and CstF64. The same composite U7 snRNP is recruited to histone pre-mRNA for 3′-end processing. We identified a motif in Drosophila FLASH that is essential for the recruitment of the polyadenylation complex to the U7 snRNP and analyzed the role of other factors, including SLBP and Ars2, in 3′-end processing of Drosophila histone pre-mRNAs. SLBP that binds the upstream stem–loop structure likely recruits a yet-unidentified essential component(s) to the processing machinery. In contrast, Ars2, a protein previously shown to interact with FLASH in mammalian cells, is dispensable for processing in Drosophila. Our studies also demonstrate that Drosophila symplekin and three factors involved in cleavage and polyadenylation—CPSF, CstF, and CF I_m—are present in Drosophila nuclear extracts in a stable supercomplex.     

FLASH is required for the endonucleolytic cleavage of histone pre-mRNAs but is dispensable for the 5' exonucleolytic degradation of the downstream cleavage product

3'-end cleavage of histone pre-mRNAs is catalyzed by CPSF-73 and requires the interaction of two U7 snRNP-associated proteins, FLASH and Lsm11. Here, by using scanning mutagenesis we identify critical residues in human FLASH and Lsm11 that are involved in the interaction between these two proteins. We also demonstrate that mutations in the region of FLASH located between amino acids 50 and 99 do not affect binding of Lsm11. Interestingly, these mutations convert FLASH into an inhibitory protein that reduces in vitro processing efficiency of highly active nuclear extracts. Our results suggest that this region in FLASH in conjunction with Lsm11 is involved in recruiting a yet-unknown processing factor(s) to histone pre-mRNA. Following endonucleolytic cleavage of histone pre-mRNA, the downstream cleavage product (DCP) is degraded by the 5'-3' exonuclease activity of CPSF-73, which also depends on Lsm11. Strikingly, while cleavage of histone pre-mRNA is stimulated by FLASH and inhibited by both dominant negative mutants of FLASH and anti-FLASH antibodies, the 5'-3' degradation of the DCP is not affected. Thus, the recruitment of FLASH to the processing complex plays a critical role in activating the endonuclease mode of CPSF-73 but is dispensable for its 5'-3' exonuclease activity. These results suggest that CPSF-73, the catalytic component in both reactions, can be recruited to histone pre-mRNA largely in a manner independent of FLASH, possibly by a separate domain in Lsm11.     

The Evolution of Tumour Composition During Fractionated Radiotherapy: Implications for Outcome

Current protocols for delivering radiotherapy are based primarily on tumour stage and nodal and metastases status, even though it is well known that tumours and their microenvironments are highly heterogeneous. It is well established that the local oxygen tension plays an important role in radiation-induced cell death, with hypoxic tumour regions responding poorly to irradiation. Therefore, to improve radiation response, it is important to understand more fully the spatiotemporal distribution of oxygen within a growing tumour before and during fractionated radiation. To this end, we have extended a spatially resolved mathematical model of tumour growth, first proposed by Greenspan (Stud Appl Math 51:317–340, 1972), to investigate the effects of oxygen heterogeneity on radiation-induced cell death. In more detail, cell death due to radiation at each location in the tumour, as determined by the well-known linear-quadratic model, is assumed also to depend on the local oxygen concentration. The oxygen concentration is governed by a reaction-diffusion equation that is coupled to an integro-differential equation that determines the size of the assumed spherically symmetric tumour. We combine numerical and analytical techniques to investigate radiation response of tumours with different intratumoral oxygen distribution profiles. Model simulations reveal a rapid transient increase in hypoxia upon regrowth of the tumour spheroid post-irradiation. We investigate the response to different radiation fractionation schedules and identify a tumour-specific relationship between inter-fraction time and dose per fraction to achieve cure. The rich dynamics exhibited by the model suggest that spatial heterogeneity may be important for predicting tumour response to radiotherapy for clinical applications.     

Role of modern radiation therapy in early stage Hodgkin's lymphoma: A young radiation oncologists’ perspective

The role of radiotherapy is well established in combined modality programs for early stage Hodgkin's lymphoma, but still debated with regards to late toxicity issues. Modern radiotherapy prescribing attitudes include lower doses and smaller fields, together with the implementation of sophisticated and dedicated delivery techniques. Aim of this review is to briefly discuss the current role of radiotherapy in this field and the potential future developments. Major trials conducted in recent years in early stage Hodgkin's lymphoma are critically reviewed and discussed with a focus on radiotherapy-related issues and with an attention to current treatment options by a “young” radiation oncologists’ perspective.     

Medical physics in radiotherapy: The importance of preserving clinical responsibilities and expanding the profession's role in research,education, and quality control

Medical physicists have long had an integral role in radiotherapy. In recent decades, medical physicists have slowly but surely stepped back from direct clinical responsibilities in planning radiotherapy treatments while medical dosimetrists have assumed more responsibility. In this article, I argue against this gradual withdrawal from routine therapy planning. It is essential that physicists be involved, at least to some extent, in treatment planning and clinical dosimetry for each and every patient; otherwise, physicists can no longer be considered clinical specialists. More importantly, this withdrawal could negatively impact treatment quality and patient safety. Medical physicists must have a sound understanding of human anatomy and physiology in order to be competent partners to radiation oncologists. In addition, they must possess a thorough knowledge of the physics of radiation as it interacts with body tissues, and also understand the limitations of the algorithms used in radiotherapy. Medical physicists should also take the lead in evaluating emerging challenges in quality and safety of radiotherapy. In this sense, the input of physicists in clinical audits and risk assessment is crucial. The way forward is to proactively take the necessary steps to maintain and advance our important role in clinical medicine.