Magnetic resonance linear accelerator technology and adaptive radiation therapy: An overview for clinicians.

Radiation therapy (RT) continues to play an important role in the treatment of cancer. Adaptive RT (ART) is a novel method through which RT treatments are evolving. With the ART approach, computed tomography or magnetic resonance (MR) images are obtained as part of the treatment delivery process. This enables the adaptation of the irradiated volume to account for changes in organ and/or tumor position, movement, size, or shape that may occur over the course of treatment. The advantages and challenges of ART maybe somewhat abstract to oncologists and clinicians outside of the specialty of radiation oncology. ART is positioned to affect many different types of cancer. There is a wide spectrum of hypothesized benefits, from small toxicity improvements to meaningful gains in overall survival. The use and application of this novel technology should be understood by the oncologic community at large, such that it can be appropriately contextualized within the landscape of cancer therapies. Likewise, the need to test these advances is pressing. MR-guided ART (MRgART) is an emerging, extended modality of ART that expands upon and further advances the capabilities of ART. MRgART presents unique opportunities to iteratively improve adaptive image guidance. However, although the MRgART adaptive process advances ART to previously unattained levels, it can be more expensive, time-consuming, and complex. In this review, the authors present an overview for clinicians describing the process of ART and specifically MRgART.

Radiation therapy-associated toxicity: Etiology, management, and prevention.

Radiation therapy (RT) is a curative treatment for many malignancies and provides effective palliation in patients with tumor-related symptoms. However, the biophysical effects of RT are not specific to tumor cells and may produce toxicity due to exposure of surrounding organs and tissues. In this article, the authors review the clinical context, pathophysiology, risk factors, presentation, and management of RT side effects in each human organ system. Ionizing radiation works by producing DNA damage leading to tumor death, but effects on normal tissue may result in acute and/or late toxicity. The manifestation of toxicity depends on both cellular characteristics and affected organs' anatomy and physiology. There is usually a direct relationship between the radiation dose and volume to normal tissues and the risk of toxicity, which has led to guidelines and recommended dose limits for most tissues. Side effects are multifactorial, with contributions from baseline patient characteristics and other oncologic treatments. Technological advances in recent decades have decreased RT toxicity by dramatically improving the ability to deliver RT that maximizes tumor dose and minimizes organ dose. Thus the study of RT-associated toxicity is a complex, core component of radiation oncology training that continues to evolve alongside advances in cancer management. Because RT is used in up to one-half of all patients with cancer, an understanding of its acute and late effects in different organ systems is clinically pertinent to both oncologists and nononcologists.

Molecular and cellular consequences of mitochondrial DNA double-stranded breaks.

Mitochondria are subcellular organelles essential for life. Beyond their role in producing energy, mitochondria govern various physiological mechanisms, encompassing energy generation, metabolic processes, apoptotic events, and immune responses. Mitochondria also contain genetic material that is susceptible to various forms of damage. Mitochondrial double-stranded breaks (DSB) are toxic lesions that the nucleus repairs promptly. Nevertheless, the significance of DSB repair in mammalian mitochondria is controversial. This review presents an updated view of the available research on the consequences of mitochondrial DNA DSB from the molecular to the cellular level. We discuss the crucial function of mitochondrial DNA damage in regulating processes such as senescence, integrated stress response, and innate immunity. Lastly, we discuss the potential role of mitochondrial DNA DSB in mediating the cellular consequences of ionizing radiations, the standard of care in treating solid tumors.

Direct visualization of proton beam irradiation effects in liquids by MRI.

The main advantage proton beams offer over photon beams in radiation therapy of cancer patients is the dose maximum at their finite range, yielding a reduction in the dose deposited in healthy tissues surrounding the tumor. Since no direct method exists to measure the beam's range during dose delivery, safety margins around the tumor are applied, compromising the dose conformality and reducing the targeting accuracy. Here, we demonstrate that online MRI can visualize the proton beam and reveal its range during irradiation of liquid-filled phantoms. A clear dependence on beam energy and current was found. These results stimulate research into novel MRI-detectable beam signatures and already find application in the geometric quality assurance for magnetic resonance-integrated proton therapy systems currently under development.

Tumor hypoxia and radiotherapy: A major driver of resistance even for novel radiotherapy modalities.

Hypoxia in solid tumors is an important predictor of poor clinical outcome to radiotherapy. Both physicochemical and biological processes contribute to a reduced sensitivity of hypoxic tumor cells to ionizing radiation and hypoxia-related treatment resistances. A conventional low-dose fractionated radiotherapy regimen exploits iterative reoxygenation in between the individual fractions, nevertheless tumor hypoxia still remains a major hurdle for successful treatment outcome. The technological advances achieved in image guidance and highly conformal dose delivery make it nowadays possible to prescribe larger doses to the tumor as part of single high-dose or hypofractionated radiotherapy, while keeping an acceptable level of normal tissue complication in the co-irradiated organs at risk. However, we insufficiently understand the impact of tumor hypoxia to single high-doses of RT and hypofractionated RT. So-called FLASH radiotherapy, which delivers ionizing radiation at ultrahigh dose rates (> 40 Gy/sec), has recently emerged as an important breakthrough in the radiotherapy field to reduce normal tissue toxicity compared to irradiation at conventional dose rates (few Gy/min). Not surprisingly, oxygen consumption and tumor hypoxia also seem to play an intriguing role for FLASH radiotherapy. Here we will discuss the role of tumor hypoxia for radiotherapy in general and in the context of novel radiotherapy treatment approaches.

The dePARylase NUDT16 promotes radiation resistance of cancer cells by blocking SETD3 for degradation via reversing its ADP-ribosylation.

Poly(ADP-ribosyl)ation (PARylation) is a critical posttranslational modification that plays a vital role in maintaining genomic stability via a variety of molecular mechanisms, including activation of replication stress and the DNA damage response. The nudix hydrolase NUDT16 was recently identified as a phosphodiesterase that is responsible for removing ADP-ribose units and that plays an important role in DNA repair. However, the roles of NUDT16 in coordinating replication stress and cell cycle progression remain elusive. Here, we report that SETD3, which is a member of the SET-domain containing protein (SETD) family, is a novel substrate for NUDT16, that its protein levels fluctuate during cell cycle progression, and that its stability is strictly regulated by NUDT16-mediated dePARylation. Moreover, our data indicated that the E3 ligase CHFR is responsible for the recognition and degradation of endogenous SETD3 in a PARP1-mediated PARylation-dependent manner. Mechanistically, we revealed that SETD3 associates with BRCA2 and promotes its recruitment to stalled replication fork and DNA damage sites upon replication stress or DNA double-strand breaks, respectively. Importantly, depletion of SETD3 in NUDT16-deficient cells did not further exacerbate DNA breaks or enhance the sensitivity of cancer cells to IR exposure, suggesting that the NUDT16-SETD3 pathway may play critical roles in the induction of tolerance to radiotherapy. Collectively, these data showed that NUDT16 functions as a key upstream regulator of SETD3 protein stability by reversing the ADP-ribosylation of SETD3, and NUDT16 participates in the resolution of replication stress and facilitates HR repair.

Lighting up the tumor fire with low-dose irradiation.

Current efforts combining immunotherapy and radiation have focused on high-dose radiation delivered to few tumor lesions, aiming to generate diffuse abscopal effects; however, these effects are uncommon in patients. Three recent studies in mouse tumor models and human cancer patients show that low-dose radiation (LDRT) delivered to all tumor lesions effectively mobilizes innate and adaptive immunity and synergizes with immunotherapy. These new findings suggest LDRT's potential as an immune amplifier capable of reprogramming the tumor microenvironment, instigating inflammation, and sensitizing 'cold' tumors to immune checkpoint blockade responsiveness.

Enhanced perfusion following exposure to radiotherapy: A theoretical investigation.

Tumour angiogenesis leads to the formation of blood vessels that are structurally and spatially heterogeneous. Poor blood perfusion, in conjunction with increased hypoxia and oxygen heterogeneity, impairs a tumour's response to radiotherapy. The optimal strategy for enhancing tumour perfusion remains unclear, preventing its regular deployment in combination therapies. In this work, we first identify vascular architectural features that correlate with enhanced perfusion following radiotherapy, using in vivo imaging data from vascular tumours. Then, we present a novel computational model to determine the relationship between these architectural features and blood perfusion in silico. If perfusion is defined to be the proportion of vessels that support blood flow, we find that vascular networks with small mean diameters and large numbers of angiogenic sprouts show the largest increases in perfusion post-irradiation for both biological and synthetic tumours. We also identify cases where perfusion increases due to the pruning of hypoperfused vessels, rather than blood being rerouted. These results indicate the importance of considering network composition when determining the optimal irradiation strategy. In the future, we aim to use our findings to identify tumours that are good candidates for perfusion enhancement and to improve the efficacy of combination therapies.

DNA Damage in Stem Cells.

Both embryonic and adult stem cells are endowed with a superior capacity to prevent the accumulation of genetic lesions, repair them, or avoid their propagation to daughter cells, which would be particularly detrimental to the whole organism. Inducible pluripotent stem cells also display a robust DNA damage response, but the stability of their genome is often conditioned by the mutational history of the cell population of origin, which constitutes an obstacle to clinical applications. Cancer stem cells are particularly tolerant to DNA damage and fail to undergo senescence or regulated cell death upon accumulation of genetic lesions. Such a resistance contributes to the genetic drift of evolving tumors as well as to their limited sensitivity to chemo- and radiotherapy. Here, we discuss the pathophysiological and therapeutic implications of the molecular pathways through which stem cells cope with DNA damage.

Radiotherapy: An immune response modifier for immuno-oncology.

The ability of radiotherapy to enhance antigenicity and adjuvanticity of an irradiated tumor has stimulated the interest for its combination with immuno-oncology agents. However, radiotherapy often generates multiple layers of host responses which likely depends on the tumor biology, the immune cell infiltration and the induction of immunosuppressive signals post radiotherapy. Consequently, translation of preclinical findings to the clinic is more convoluted than anticipated which underscore the need to decipher molecular and cellular mechanisms elicited by radiotherapy. Here we review pro-inflammatory and immunosuppressive mechanisms triggered by radiotherapy that impact the outcome of antigen specific T cell killing and discuss how radiation-induced immunostimulatory mechanisms can be exploited to reactivate the host's immune system, especially in the context of immunotherapy.

Radiation-Activated Resiquimod Prodrug Nanomaterials for Enhancing Immune Checkpoint Inhibitor Therapy.

Immune checkpoint inhibitor (ICI) therapy is effectively employed in treating various malignancies. However, the response rate is constrained to 5-30%, which is attributed to differences in immune responses across different tumors. Overcoming all obstacles of multistep immune activation with monotherapy is difficult. Here, maleimide-modified resiquimod (R848) prodrug nanoparticles (MAL-NPs) are reported and combined with radiotherapy (RT) and anti-PD1 to enhance ICI therapy. MAL-NPs can promote antigen endocytosis by dendritic cells and are radio-reduced to produce R848. When combined with RT, MAL-NPs can augment the concentration of nanoparticles at tumor sites and be selectively radio-reduced within the tumor, thereby triggering a potent antitumor immune response. The systemic immune response and long-term memory efficacy induced by MAL-NPs + RT + anti-PD1 significantly inhibit the abscopal tumor growth and prevent tumor recurrence. This strategy can achieve systemic therapy through selective training of the tumor immune microenvironment, offering a new approach to overcome the obstacles of ICI therapy.

Sustained Secretion of CCL21 via an Implantable Cell Reservoir Hydrogel Enhances the Systemic Antitumor Effect of Radiotherapy.

The combination of radiotherapy (RT) and immunotherapy shows promise in improving the clinical treatment of solid tumors; however, it faces challenges of low response rates and systemic toxicity. Herein, an implantable alginate/collagen hydrogel encapsulating C-C motif ligand 21 (CCL21)-expressing dendritic cells (CCL21-DCs@gel) was developed to potentiate the systemic antitumor effects of RT. The hydrogel functioned as a suitable reservoir for in vivo culture and proliferation of CCL21-DCs, thereby enabling sustained CCL21 release. The local CCL21 gradient induced by CCL21-DCs@gel significantly enhanced the efficacy of RT in suppressing primary tumor growth and inhibiting distant metastasis across several mouse models. Furthermore, the combination of RT with CCL21-DCs@gel provided complete prophylactic protection to mice. Mechanistic investigations revealed that CCL21-DCs@gel potentiated RT by promoting tumor lymphangiogenesis and attracting immune cell infiltration into the tumor. Collectively, these results suggest that CCL21-DCs@gel is a promising adjunct to RT for effectively eradicating tumors and preventing tumor recurrence.

Recent advances and impending challenges for the radiopharmaceutical sciences in oncology.

This paper is the first of a Series on theranostics that summarises the current landscape of the radiopharmaceutical sciences as they pertain to oncology. In this Series paper, we describe exciting developments in radiochemistry and the production of radionuclides, the development and translation of theranostics, and the application of artificial intelligence to our field. These developments are catalysing growth in the use of radiopharmaceuticals to the benefit of patients worldwide. We also highlight some of the key issues to be addressed in the coming years to realise the full potential of radiopharmaceuticals to treat cancer.

Quantification of the environmental impact of radiotherapy and associated secondary human health effects: a multi-institutional retrospective analysis and simulation.

BACKGROUND: The health-care industry is a substantial contributor to global greenhouse gas emissions, yet the specific environmental impact of radiotherapy, a cornerstone of cancer treatment, remains under-explored. We aimed to quantify the emissions associated with the delivery of radiotherapy in the USA and propose a framework for reducing the environmental impact of oncology care. METHODS: In this multi-institutional retrospective analysis and simulation study, we conducted a lifecycle assessment of external beam radiotherapy (EBRT) for ten anatomical disease sites, adhering to the International Organization for Standardization's standards ISO 14040 and ISO 14044. We analysed retrospective data from Jan 1, 2017, to Oct 1, 2023, encompassing patient and staff travel, medical supplies, and equipment and building energy use associated with the use of EBRT at four academic institutions in the USA. The primary objective was to measure the environmental impacts across ten categories: greenhouse gases (expressed as kg of carbon dioxide equivalents [CO2e]), ozone depletion, smog formation, acidification, eutrophication, carcinogenic and non-carcinogenic potential, respiratory effects, fossil fuel depletion, and ecotoxicity. Human health effects secondary to these environmental impacts were also estimated as disability-adjusted life years. We also assessed the potential benefits of hypofractionated regimens for breast and genitourinary (ie, prostate and bladder) cancers on US greenhouse gas emissions using an analytic model based on the 2014 US National Cancer Database for fractionation patterns and patient commute distances. FINDINGS: We estimated that the mean greenhouse gas emissions associated with a standard 25-fraction EBRT course were 4310 kg CO2e (SD 2910), which corresponded to 0·0035 disability-adjusted life years per treatment course. Transit and building energy usage accounted for 25·73% (1110 kg CO2e) and 73·95% of (3190 kg CO2e) of total greenhouse gas emissions, respectively, whereas supplies contributed only 0·32% (14 kg CO2e). Across the other environmental impact categories, most of the environmental impact also stemmed from patient transit and energy use within facilities, with little environmental impact contributed by supplies used. Hypofractionated treatment simulations suggested a substantial reduction in greenhouse gas emissions-by up to 42% for breast and 77% for genitourinary cancer-and environmental impacts more broadly. INTERPRETATION: This comprehensive lifecycle assessment of EBRT delineates the environmental and secondary health impacts of radiotherapy, and underscores the urgent need for sustainable practices in oncology. The findings serve as a reference for future decarbonisation efforts in cancer care and show the potential environmental benefits of modifying treatment protocols (when clinical equipoise exists). They also highlight strategic opportunities to mitigate the ecological footprint in an era of escalating climate change and increasing cancer prevalence. FUNDING: Mount Zion Health Fund.

Current and projected gaps in the availability of radiotherapy in the Asia-Pacific region: a country income-group analysis.

BACKGROUND: Cancer incidence and mortality is increasing rapidly worldwide, with a higher cancer burden observed in the Asia-Pacific region than in other regions. To date, evidence-based modelling of radiotherapy demand has been based on stage data from high-income countries (HIC) that do not account for the later stage at presentation seen in many low-income and middle-income countries (LMICs). We aimed to estimate the current and projected demand and supply in megavoltage radiotherapy machines in the Asia-Pacific region, using a national income-group adjusted model. METHODS: Novel LMIC radiotherapy demand and outcome models were created by adjusting previously developed models that used HIC cancer staging data. These models were applied to the cancer case mix (ie, the incidence of each different cancer) in each LMIC in the Asia-Pacific region to estimate the current and projected optimal radiotherapy utilisation rate (ie, the proportion of cancer cases that would require radiotherapy on the basis of guideline recommendations), and to estimate the number of megavoltage machines needed in each country to meet this demand. Information on the number of megavoltage machines available in each country was retrieved from the Directory of Radiotherapy Centres. Gaps were determined by comparing the projected number of megavoltage machines needed with the number of machines available in each region. Megavoltage machine numbers, local control, and overall survival benefits were compared with previous data from 2012 and projected data for 2040. FINDINGS: 57 countries within the Asia-Pacific region were included in the analysis with 9·48 million new cases of cancer in 2020, an increase of 2·66 million from 2012. Local control was 7·42% and overall survival was 3·05%. Across the Asia-Pacific overall, the current optimal radiotherapy utilisation rate is 49·10%, which means that 4·66 million people will need radiotherapy in 2020, an increase of 1·38 million (42%) from 2012. The number of megavoltage machines increased by 1261 (31%) between 2012 and 2020, but the demand for these machines increased by 3584 (42%). The Asia-Pacific region only has 43·9% of the megavoltage machines needed to meet demand, ranging from 9·9-40·5% in LMICs compared with 67·9% in HICs. 12 000 additional megavoltage machines will be needed to meet the projected demand for 2040. INTERPRETATION: The difference between supply and demand with regard to megavoltage machine availability has continued to widen in LMICs over the past decade and is projected to worsen by 2040. The data from this study can be used to provide evidence for the need to incorporate radiotherapy in national cancer control plans and to inform governments and policy makers within the Asia-Pacific region regarding the urgent need for investment in this sector. FUNDING: The Regional Cooperative Agreement for Research, Development and Training Related to Nuclear Science and Technology for Asia and the Pacific (RCA) Regional Office (RCARP03).

Trends in nuclear medicine and the radiopharmaceutical sciences in oncology: workforce challenges and training in the age of theranostics.

Although the promise of radionuclides for the diagnosis and treatment of disease was recognised soon after the discovery of radioactivity in the late 19th century, the systematic use of radionuclides in medicine only gradually increased over the subsequent hundred years. The past two decades, however, has seen a remarkable surge in the clinical application of diagnostic and therapeutic radiopharmaceuticals, particularly in oncology. This development is an exciting time for the use of theranostics in oncology, but the rapid growth of this area of nuclear medicine has created challenges as well. In particular, the infrastructure for the manufacturing and distribution of radiopharmaceuticals remains in development, and regulatory bodies are still optimising guidelines for this new class of drug. One issue of paramount importance for achieving equitable access to theranostics is building a sufficiently trained workforce in high-income, middle-income, and low-income countries. Here, we discuss the key challenges and opportunities that face the field as it seeks to build its workforce for the 21st century.

Addressing challenges in low-income and middle-income countries through novel radiotherapy research opportunities.

Although radiotherapy continues to evolve as a mainstay of the oncological armamentarium, research and innovation in radiotherapy in low-income and middle-income countries (LMICs) faces challenges. This third Series paper examines the current state of LMIC radiotherapy research and provides new data from a 2022 survey undertaken by the International Atomic Energy Agency and new data on funding. In the context of LMIC-related challenges and impediments, we explore several developments and advances-such as deep phenotyping, real-time targeting, and artificial intelligence-to flag specific opportunities with applicability and relevance for resource-constrained settings. Given the pressing nature of cancer in LMICs, we also highlight some best practices and address the broader need to develop the research workforce of the future. This Series paper thereby serves as a resource for radiation professionals.

Radiotherapy, immunity, and immune checkpoint inhibitors.

Radiotherapy exerts immunostimulatory and immunosuppressive effects, both locally, within the irradiated tumour microenvironment, and systemically, outside the radiation field. Inspired by preclinical data that showed synergy between radiotherapy and immune checkpoint inhibitors, multiple clinical trials were initiated with the hypothesis that combined treatment with radiotherapy and immune checkpoint inhibitors could stimulate a robust systemic immune response and improve clinical outcomes. However, despite early optimism, radioimmunotherapy trials in the curative and metastatic settings have met with little success. In this Review, we summarise the immunostimulatory effects of radiotherapy that provided the theoretical basis for trials of combination radiotherapy and immune checkpoint inhibitors. We also discuss findings from clinical trials incorporating radiotherapy and immune checkpoint inhibitors and examine the success of these trials in the context of the immunosuppressive effects of radiotherapy. We conclude by highlighting targets for relieving radiotherapy-induced immunosuppression with the goal of enhancing the combined effects of radiotherapy and immune checkpoint inhibitors.

Low-dose radiation therapy mobilizes antitumor immunity: New findings and future perspectives.

Radiotherapy has unique immunostimulatory and immunosuppressive effects. Although high-dose radiotherapy has been found to have systemic antitumor effects, clinically significant abscopal effects were uncommon on the basis of irradiating single lesion. Low-dose radiation therapy (LDRT) emerges as a novel approach to enhance the antitumor immune response due to its role as a leverage to reshape the tumor immune microenvironment (TIME). In this article, from bench to bedside, we reviewed the possible immunomodulatory role of LDRT on TIME and systemic tumor immune environment, and outlined preclinical evidence and clinical application. We also discussed the current challenges when LDRT is used as a combination therapy, including the optimal dose, fraction, frequency, and combination of drugs. The advantage of low toxicity makes LDRT potential to be applied in multiple lesions to amplify antitumor immune response in polymetastatic disease, and its intersection with other disciplines might also make it a direction for radiotherapy-combined modalities.