Timely and comprehensive analyses of causes of death stratified by age, sex, and location are essential for shaping effective health policies aimed at reducing global mortality. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides cause-specific mortality estimates measured in counts, rates, and years of life lost (YLLs). GBD 2023 aimed to enhance our understanding of the relationship between age and cause of death by quantifying the probability of dying before age 70 years (70q0) and the mean age at death by cause and sex. This study enables comparisons of the impact of causes of death over time, offering a deeper understanding of how these causes affect global populations. GBD 2023 produced estimates for 292 causes of death disaggregated by age-sex-location-year in 204 countries and territories and 660 subnational locations for each year from 1990 until 2023. We used a modelling tool developed for GBD, the Cause of Death Ensemble model (CODEm), to estimate cause-specific death rates for most causes. We computed YLLs as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. Probability of death was calculated as the chance of dying from a given cause in a specific age period, for a specific population. Mean age at death was calculated by first assigning the midpoint age of each age group for every death, followed by computing the mean of all midpoint ages across all deaths attributed to a given cause. We used GBD death estimates to calculate the observed mean age at death and to model the expected mean age across causes, sexes, years, and locations. The expected mean age reflects the expected mean age at death for individuals within a population, based on global mortality rates and the population's age structure. Comparatively, the observed mean age represents the actual mean age at death, influenced by all factors unique to a location-specific population, including its age structure. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 250-draw distribution for each metric. Findings are reported as counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2023 include a correction for the misclassification of deaths due to COVID-19, updates to the method used to estimate COVID-19, and updates to the CODEm modelling framework. This analysis used 55 761 data sources, including vital registration and verbal autopsy data as well as data from surveys, censuses, surveillance systems, and cancer registries, among others. For GBD 2023, there were 312 new country-years of vital registration cause-of-death data, 3 country-years of surveillance data, 51 country-years of verbal autopsy data, and 144 country-years of other data types that were added to those used in previous GBD rounds. The initial years of the COVID-19 pandemic caused shifts in long-standing rankings of the leading causes of global deaths: it ranked as the number one age-standardised cause of death at Level 3 of the GBD cause classification hierarchy in 2021. By 2023, COVID-19 dropped to the 20th place among the leading global causes, returning the rankings of the leading two causes to those typical across the time series (ie, ischaemic heart disease and stroke). While ischaemic heart disease and stroke persist as leading causes of death, there has been progress in reducing their age-standardised mortality rates globally. Four other leading causes have also shown large declines in global age-standardised mortality rates across the study period: diarrhoeal diseases, tuberculosis, stomach cancer, and measles. Other causes of death showed disparate patterns between sexes, notably for deaths from conflict and terrorism in some locations. A large reduction in age-standardised rates of YLLs occurred for neonatal disorders. Despite this, neonatal disorders remained the leading cause of global YLLs over the period studied, except in 2021, when COVID-19 was temporarily the leading cause. Compared to 1990, there has been a considerable reduction in total YLLs in many vaccine-preventable diseases, most notably diphtheria, pertussis, tetanus, and measles. In addition, this study quantified the mean age at death for all-cause mortality and cause-specific mortality and found noticeable variation by sex and location. The global all-cause mean age at death increased from 46·8 years (95% UI 46·6-47·0) in 1990 to 63·4 years (63·1-63·7) in 2023. For males, mean age increased from 45·4 years (45·1-45·7) to 61·2 years (60·7-61·6), and for females it increased from 48·5 years (48·1-48·8) to 65·9 years (65·5-66·3), from 1990 to 2023. The highest all-cause mean age at death in 2023 was found in the high-income super-region, where the mean age for females reached 80·9 years (80·9-81·0) and for males 74·8 years (74·8-74·9). By comparison, the lowest all-cause mean age at death occurred in sub-Saharan Africa, where it was 38·0 years (37·5-38·4) for females and 35·6 years (35·2-35·9) for males in 2023. Lastly, our study found that all-cause 70q0 decreased across each GBD super-region and region from 2000 to 2023, although with large variability between them. For females, we found that 70q0 notably increased from drug use disorders and conflict and terrorism. Leading causes that increased 70q0 for males also included drug use disorders, as well as diabetes. In sub-Saharan Africa, there was an increase in 70q0 for many non-communicable diseases (NCDs). Additionally, the mean age at death from NCDs was lower than the expected mean age at death for this super-region. By comparison, there was an increase in 70q0 for drug use disorders in the high-income super-region, which also had an observed mean age at death lower than the expected value. We examined global mortality patterns over the past three decades, highlighting-with enhanced estimation methods-the impacts of major events such as the COVID-19 pandemic, in addition to broader trends such as increasing NCDs in low-income regions that reflect ongoing shifts in the global epidemiological transition. This study also delves into premature mortality patterns, exploring the interplay between age and causes of death and deepening our understanding of where targeted resources could be applied to further reduce preventable sources of mortality. We provide essential insights into global and regional health disparities, identifying locations in need of targeted interventions to address both communicable and non-communicable diseases. There is an ever-present need for strengthened health-care systems that are resilient to future pandemics and the shifting burden of disease, particularly among ageing populations in regions with high mortality rates. Robust estimates of causes of death are increasingly essential to inform health priorities and guide efforts toward achieving global health equity. The need for global collaboration to reduce preventable mortality is more important than ever, as shifting burdens of disease are affecting all nations, albeit at different paces and scales. Gates Foundation.
To describe the management of a 5-day downtime event of a multi-room ProteusPLUS (P-PLUS) proton therapy (PT) system, including the triage and treatment of patients on a single-room ProteusONE (P-ONE) system and 2 linear accelerators. Following the failure of a radiofrequency (RF) coupler, patients were triaged for PT on the P-ONE according to medical necessity and available capacity, aiming to minimize the complexity of the P-ONE workload while ensuring each patient received at least 4 fractions of radiotherapy that week. Replanning was required across non-beam matched systems (P-ONE, TrueBeam, and Synergy) and rapidly accomplished primarily via remote planning. Treatment adaptations included extending PT availability from 12 to 19 hours, the suspension of training of students and new therapists, the delay of new starts, and the use of kV oblique imaging for brain cases in lieu of cone-beam CT (CBCT). A total of 42 patients were replanned within 30 hours, with an additional 5 patients replanned thereafter. The P-ONE averaged 60 patient treatments per day during the downtime event and achieved 61 treatments in 17.5 hours on a given day. Overall, 73% of scheduled PT fractions across all systems were treated with PT, with an additional 8% treated with photon therapy (XT), 13% postponed, and 6% canceled. All patients currently under treatment received at least 4 fractions of radiation therapy, with 73.6% receiving a full 5 fractions. The case mix on the P-ONE shifted towards less complex treatments overall (+13.4% prostate). Swift triage, extended operating hours, and cross-platform re-planning enabled high-throughput and continuity of care during a significant downtime event. The event offers an early look at how downtime events can be successfully managed in a multi-system PT environment.
Charged particle therapy (PT), including proton beam therapy (PBT) and carbon ion radiation therapy (CIRT), offers potential advantages for selected patients. A key challenge remains in how to expand access to PT to maximize clinical benefit. Eighty-one international PT leaders convened at the 2nd World Forum to discuss strategies for advancing PT globally. Recent PBT trials have shown reduced toxicity in oropharyngeal and advanced esophageal cancer, improved local control in hepatocellular carcinoma, and improved survival in patients with leptomeningeal and oropharygeal cancer. In contrast, there was no difference in toxicity nor progression-free survival in low-to-intermediate risk prostate cancer, and no cognitive benefit seen in adult glioblastoma. Additional trials results are awaited. Vendor financial support has been instrumental in enabling many studies.CIRT trials remain limited, though several are ongoing. Further development and harmonization of relative biological effectiveness (RBE) models is crucial. Helium therapy and oxygen therapy require exploration. Heavy ions may enhance immune response through more complex DNA damage than X-rays. This potential synergy with immunotherapy should be explored further.Second-generation trials should leverage the biological advantages of PT, target promising sites and diseases, include molecular diagnostics, and explore hypofractionation.Indications for PBT are expanding, supported by emerging evidence. More studies are needed, including developments in clinical endpoints and integration of biological data on tumors and normal tissues. Follow up of all PT patients is needed, with pooling of international data. Trials are needed to define the role of heavier ions and their immune effects. Large, definitive, "Champion Studies," demonstrating survival benefit over established therapy are essential. International collaboration with strong administrative and financial support will be key. A meeting to develop such a study is strongly recommended. The faster and more efficiently the community can work, the more patients will benefit.
To overview the status and trends in the current rapidly evolving field of ocular particle therapy (OPT). The Particle Therapy Co-Operative Group Ocular Subcommittee developed an online survey, including 127 questions, made available to treatment centers worldwide, between April 2022 and January 2024. The survey covered a broad range of topics from general program organization and beamline description, to diagnoses and patient numbers treated, treatment planning and set-up, quality assurance techniques, as well as insights into anticipated future developments. Twenty facilities offered OPT by the end of 2023: 3 in Asia, 9 in Europe, and 8 in the USA. Combined, they treated, on average, 1800 patients per year, with uveal melanoma being the most common indication. The vast majority of treatments continue to be delivered on dedicated horizontal beamlines, both high (>120 Mev) and low (<75 MeV) energy. Five of the 7 recently established programs (n = 7, since 2015) use high-energy general-purpose beamlines, where some beam characteristics, including penumbrae size and dose delivery rate, differ from those typically achieved on dedicated beamlines. The evolution of the ocular treatment framework is ongoing as 9 centers reported the intent to upgrade their systems within five years, to engage state-of-the-art developments in beam delivery, imaging, and planning tools. Common protocols in dosimetry, dose, and fractionation have largely been adopted worldwide, while variability persists in planning, quality assurance, and delivery workflows. The obsolescence of dedicated ocular proton systems and key planning tools, and a lack of standardization, remain as pressing challenges. The adoption of non-dedicated high-energy systems on gantries and integration into multipurpose treatment environments enhances OPT accessibility, but this transition requires ongoing critical evaluation of dosimetric trade-offs and clinical outcomes. Multicenter collaboration, technological innovation, and clinical validation are essential to continued assurance of the safe and effective delivery of OPT worldwide.
For more than three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has provided a framework to quantify health loss due to diseases, injuries, and associated risk factors. This paper presents GBD 2023 findings on disease and injury burden and risk-attributable health loss, offering a global audit of the state of world health to inform public health priorities. This work captures the evolving landscape of health metrics across age groups, sexes, and locations, while reflecting on the remaining post-COVID-19 challenges to achieving our collective global health ambitions. The GBD 2023 combined analysis estimated years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 375 diseases and injuries, and risk-attributable burden associated with 88 modifiable risk factors. Of the more than 310 000 total data sources used for all GBD 2023 (about 30% of which were new to this estimation round), more than 120 000 sources were used for estimation of disease and injury burden and 59 000 for risk factor estimation, and included vital registration systems, surveys, disease registries, and published scientific literature. Data were analysed using previously established modelling approaches, such as disease modelling meta-regression version 2.1 (DisMod-MR 2.1) and comparative risk assessment methods. Diseases and injuries were categorised into four levels on the basis of the established GBD cause hierarchy, as were risk factors using the GBD risk hierarchy. Estimates stratified by age, sex, location, and year from 1990 to 2023 were focused on disease-specific time trends over the 2010-23 period and presented as counts (to three significant figures) and age-standardised rates per 100 000 person-years (to one decimal place). For each measure, 95% uncertainty intervals [UIs] were calculated with the 2·5th and 97·5th percentile ordered values from a 250-draw distribution. Total numbers of global DALYs grew 6·1% (95% UI 4·0-8·1), from 2·64 billion (2·46-2·86) in 2010 to 2·80 billion (2·57-3·08) in 2023, but age-standardised DALY rates, which account for population growth and ageing, decreased by 12·6% (11·0-14·1), revealing large long-term health improvements. Non-communicable diseases (NCDs) contributed 1·45 billion (1·31-1·61) global DALYs in 2010, increasing to 1·80 billion (1·63-2·03) in 2023, alongside a concurrent 4·1% (1·9-6·3) reduction in age-standardised rates. Based on DALY counts, the leading level 3 NCDs in 2023 were ischaemic heart disease (193 million [176-209] DALYs), stroke (157 million [141-172]), and diabetes (90·2 million [75·2-107]), with the largest increases in age-standardised rates since 2010 occurring for anxiety disorders (62·8% [34·0-107·5]), depressive disorders (26·3% [11·6-42·9]), and diabetes (14·9% [7·5-25·6]). Remarkable health gains were made for communicable, maternal, neonatal, and nutritional (CMNN) diseases, with DALYs falling from 874 million (837-917) in 2010 to 681 million (642-736) in 2023, and a 25·8% (22·6-28·7) reduction in age-standardised DALY rates. During the COVID-19 pandemic, DALYs due to CMNN diseases rose but returned to pre-pandemic levels by 2023. From 2010 to 2023, decreases in age-standardised rates for CMNN diseases were led by rate decreases of 49·1% (32·7-61·0) for diarrhoeal diseases, 42·9% (38·0-48·0) for HIV/AIDS, and 42·2% (23·6-56·6) for tuberculosis. Neonatal disorders and lower respiratory infections remained the leading level 3 CMNN causes globally in 2023, although both showed notable rate decreases from 2010, declining by 16·5% (10·6-22·0) and 24·8% (7·4-36·7), respectively. Injury-related age-standardised DALY rates decreased by 15·6% (10·7-19·8) over the same period. Differences in burden due to NCDs, CMNN diseases, and injuries persisted across age, sex, time, and location. Based on our risk analysis, nearly 50% (1·27 billion [1·18-1·38]) of the roughly 2·80 billion total global DALYs in 2023 were attributable to the 88 risk factors analysed in GBD. Globally, the five level 3 risk factors contributing the highest proportion of risk-attributable DALYs were high systolic blood pressure (SBP), particulate matter pollution, high fasting plasma glucose (FPG), smoking, and low birthweight and short gestation-with high SBP accounting for 8·4% (6·9-10·0) of total DALYs. Of the three overarching level 1 GBD risk factor categories-behavioural, metabolic, and environmental and occupational-risk-attributable DALYs rose between 2010 and 2023 only for metabolic risks, increasing by 30·7% (24·8-37·3); however, age-standardised DALY rates attributable to metabolic risks decreased by 6·7% (2·0-11·0) over the same period. For all but three of the 25 leading level 3 risk factors, age-standardised rates dropped between 2010 and 2023-eg, declining by 54·4% (38·7-65·3) for unsafe sanitation, 50·5% (33·3-63·1) for unsafe water source, and 45·2% (25·6-72·0) for no access to handwashing facility, and by 44·9% (37·3-53·5) for child growth failure. The three leading level 3 risk factors for which age-standardised attributable DALY rates rose were high BMI (10·5% [0·1 to 20·9]), drug use (8·4% [2·6 to 15·3]), and high FPG (6·2% [-2·7 to 15·6]; non-significant). Our findings underscore the complex and dynamic nature of global health challenges. Since 2010, there have been large decreases in burden due to CMNN diseases and many environmental and behavioural risk factors, juxtaposed with sizeable increases in DALYs attributable to metabolic risk factors and NCDs in growing and ageing populations. This long-observed consequence of the global epidemiological transition was only temporarily interrupted by the COVID-19 pandemic. The substantially decreasing CMNN disease burden, despite the 2008 global financial crisis and pandemic-related disruptions, is one of the greatest collective public health successes known. However, these achievements are at risk of being reversed due to major cuts to development assistance for health globally, the effects of which will hit low-income countries with high burden the hardest. Without sustained investment in evidence-based interventions and policies, progress could stall or reverse, leading to widespread human costs and geopolitical instability. Moreover, the rising NCD burden necessitates intensified efforts to mitigate exposure to leading risk factors-eg, air pollution, smoking, and metabolic risks, such as high SBP, BMI, and FPG-including policies that promote food security, healthier diets, physical activity, and equitable and expanded access to potential treatments, such as GLP-1 receptor agonists. Decisive, coordinated action is needed to address long-standing yet growing health challenges, including depressive and anxiety disorders. Yet this can be only part of the solution. Our response to the NCD syndemic-the complex interaction of multiple health risks, social determinants, and systemic challenges-will define the future landscape of global health. To ensure human wellbeing, economic stability, and social equity, global action to sustain and advance health gains must prioritise reducing disparities by addressing socioeconomic and demographic determinants, ensuring equitable health-care access, tackling malnutrition, strengthening health systems, and improving vaccination coverage. We live in times of great opportunity. Gates Foundation and Bloomberg Philanthropies.
Cardiovascular diseases (CVDs) are the leading cause of mortality and are among the foremost causes of disability globally. CVD burden has continued to increase in most countries since 1990, with trends driven by changing exposures to harmful risk factors, population growth, and population aging. We report estimates of global, national, and subnational CVD burden, including 18 subdiseases and 12 associated modifiable risk factors. We analyzed change in CVD burden from 1990 to 2023 and identified drivers of change including population growth, population aging, and risk factor exposure. The Global Burden of Disease (GBD) 2023 study, a multinational collaborative research study, quantified burden due to 375 diseases including CVD burden and identified drivers of change from 1990 to 2023 using all available data and statistical models. GBD 2023 estimated the population-level burden of diseases in 204 countries and territories from 1990 to 2023. CVDs were the leading cause of disability-adjusted life years (DALYs) and deaths estimated in the GBD. As of 2023, there were 437 million (95% UI: 401 to 465 million) CVD DALYs globally, a 1.4-fold increase from the number in 1990 of 320 million (292 to 344 million). Ischemic heart disease, intracerebral hemorrhage, ischemic stroke, and hypertensive heart disease were the leading cardiovascular causes of DALYs in 2023 globally. As of 2023, age-standardized CVD DALY rates were highest in low and low-middle Socio-demographic Index (SDI) settings and lowest in high SDI settings. The number of CVD deaths increased globally from 13.1 million (95% UI: 12.2 to 14.0 million) in 1990 to 19.2 million (95% UI: 17.4 to 20.4 million) in 2023. The number of prevalent cases of CVD more than doubled since 1990, with 311 million (95% UI: 294 to 333 million) prevalent cases of CVD in 1990 and 626 million (95% UI: 591 to 672 million) prevalent cases in 2023 globally. A total of 79.6% (95% UI: 75.7% to 82.5%) of CVD burden is attributable to modifiable risk factors 347 million [95% UI: 318 to 373 million] DALYs in 2023). Globally, high systolic blood pressure, dietary risks, high low-density lipoprotein cholesterol, and air pollution were the modifiable risks responsible for most attributable CVD burden in 2023. Since 1990, changes in exposure to modifiable risk factors have had mixed effects on CVD burden, with increases in high body mass index, high fasting plasma glucose, and low physical activity leading to higher burden, while reductions in tobacco usage have mitigated some of these increases. Population growth and population aging were the main drivers of the increasing burden since 1990, adding 128 million (95% UI: 115 to 139 million) and 139 million (95% UI: 126 to 151 million) CVD DALYs to the increase in CVD burden since 1990. CVD remains the leading cause of disease burden and death worldwide with the greatest burden in low, low-middle, and middle SDI regions. Large variation exists in CVD burden even for countries at similar levels of development, a gap explained substantially by known, modifiable risk factors that are inadequately controlled. The decades-long increase in CVD burden was the result of population growth, population aging, and increased exposure to a subset of risk factors led by metabolic risks. Countries will need to adopt effective health system and public health strategies if they are to progress in achieving global goals to reduce the burden of CVD.
Carbon ion radiotherapy (CIRT) combines the physical precision of charged particles with high-linear energy transfer (LET) biological effectiveness, enabling superior control of radioresistant or anatomically complex tumors. Initially developed in Japan, CIRT is slowly expanding globally with increasing institutional and clinical maturity. To summarize current clinical evidence, operational strategies, and expansion plans for carbon ion facilities worldwide, as discussed during the "Hadrontherapy-for-Life" symposium held in Caen, France (March 2025). This white paper compiles presentations and institutional reports from major CIRT centers in Japan (QST, Gunma), Europe (HIT, CNAO, MedAustron, Cyclhad), and other emerging sites. Data sources include institutional registries, peer-reviewed studies, and national frameworks for hadrontherapy development. Over 50,000 patients have received CIRT worldwide. Japan remains the leading contributor through the J-CROS network, emphasizing registry-based research, hypofractionation, and treatment of mobile tumors. European centers adopt translational programs aimed at further exploiting biological properties of carbon and helium ions. Major barriers include heterogeneous dose-modeling (local effect model vs modified microdosimetric kinetic model), limited image guidance, lack of standardized indications, and funding disparities. Ongoing efforts emphasize registry harmonization, pragmatic trials, and cost-effectiveness modeling. New multi-ion facilities such as Cyclhad (Caen) aim to propose multi-ion therapy, increase the level of evidence for clinical use, and promote research. CIRT is transitioning from pioneering programs to a coordinated global network. Collaborative initiatives and shared data platforms are essential to establish evidence-based indications, optimize biological modeling, and ensure economic sustainability. The "Hadrontherapy-for-Life" initiative calls for a strategic step toward internationally standardized, clinically integrated heavy-ion therapy.
Comprehensive, comparable, and timely estimates of demographic metrics-including life expectancy and age-specific mortality-are essential for evaluating, understanding, and addressing trends in population health. The COVID-19 pandemic highlighted the importance of timely and all-cause mortality estimates for being able to respond to changing trends in health outcomes, showing a strong need for demographic analysis tools that can produce all-cause mortality estimates more rapidly with more readily available all-age vital registration (VR) data. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) is an ongoing research effort that quantifies human health by estimating a range of epidemiological quantities of interest across time, age, sex, location, cause, and risk. This study-part of the latest GBD release, GBD 2023-aims to provide new and updated estimates of all-cause mortality and life expectancy for 1950 to 2023 using a novel statistical model that accounts for complex correlation structures in demographic data across age and time. We used 24 025 data sources from VR, sample registration, surveys, censuses, and other sources to estimate all-cause mortality for males, females, and all sexes combined across 25 age groups in 204 countries and territories as well as 660 subnational units in 20 countries and territories, for the years 1950-2023. For the first time, we used complete birth history data for ages 5-14 years, age-specific sibling history data for ages 15-49 years, and age-specific mortality data from Health and Demographic Surveillance Systems. We developed a single statistical model that incorporates both parametric and non-parametric methods, referred to as OneMod, to produce estimates of all-cause mortality for each age-sex-location group. OneMod includes two main steps: a detailed regression analysis with a generalised linear modelling tool that accounts for age-specific covariate effects such as the Socio-demographic Index (SDI) and a population attributable fraction (PAF) for all risk factors combined; and a non-parametric analysis of residuals using a multivariate kernel regression model that smooths across age and time to adaptably follow trends in the data without overfitting. We calibrated asymptotic uncertainty estimates using Pearson residuals to produce 95% uncertainty intervals (UIs) and corresponding 1000 draws. Life expectancy was calculated from age-specific mortality rates with standard demographic methods. For each measure, 95% UIs were calculated with the 25th and 975th ordered values from a 1000-draw posterior distribution. In 2023, 60·1 million (95% UI 59·0-61·1) deaths occurred globally, of which 4·67 million (4·59-4·75) were in children younger than 5 years. Due to considerable population growth and ageing since 1950, the number of annual deaths globally increased by 35·2% (32·2-38·4) over the 1950-2023 study period, during which the global age-standardised all-cause mortality rate declined by 66·6% (65·8-67·3). Trends in age-specific mortality rates between 2011 and 2023 varied by age group and location, with the largest decline in under-5 mortality occurring in east Asia (67·7% decrease); the largest increases in mortality for those aged 5-14 years, 25-29 years, and 30-39 years occurring in high-income North America (11·5%, 31·7%, and 49·9%, respectively); and the largest increases in mortality for those aged 15-19 years and 20-24 years occurring in Eastern Europe (53·9% and 40·1%, respectively). We also identified higher than previously estimated mortality rates in sub-Saharan Africa for all sexes combined aged 5-14 years (87·3% higher in GBD 2023 than GBD 2021 on average across countries and territories over the 1950-2021 period) and for females aged 15-29 years (61·2% higher), as well as lower than previously estimated mortality rates in sub-Saharan Africa for all sexes combined aged 50 years and older (13·2% lower), reflecting advances in our modelling approach. Global life expectancy followed three distinct trends over the study period. First, between 1950 and 2019, there were considerable improvements, from 51·2 (50·6-51·7) years for females and 47·9 (47·4-48·4) years for males in 1950 to 76·3 (76·2-76·4) years for females and 71·4 (71·3-71·5) years for males in 2019. Second, this period was followed by a decrease in life expectancy during the COVID-19 pandemic, to 74·7 (74·6-74·8) years for females and 69·3 (69·2-69·4) years for males in 2021. Finally, the world experienced a period of post-pandemic recovery in 2022 and 2023, wherein life expectancy generally returned to pre-pandemic (2019) levels in 2023 (76·3 [76·0-76·6] years for females and 71·5 [71·2-71·8] years for males). 194 (95·1%) of 204 countries and territories experienced at least partial post-pandemic recovery in age-standardised mortality rates by 2023, with 61·8% (126 of 204) recovering to or falling below pre-pandemic levels. There were several mortality trajectories during and following the pandemic across countries and territories. Long-term mortality trends also varied considerably between age groups and locations, demonstrating the diverse landscape of health outcomes globally. This analysis identified several key differences in mortality trends from previous estimates, including higher rates of adolescent mortality, higher rates of young adult mortality in females, and lower rates of mortality in older age groups in much of sub-Saharan Africa. The findings also highlight stark differences across countries and territories in the timing and scale of changes in all-cause mortality trends during and following the COVID-19 pandemic (2020-23). Our estimates of evolving trends in mortality and life expectancy across locations, ages, sexes, and SDI levels in recent years as well as over the entire 1950-2023 study period provide crucial information for governments, policy makers, and the public to ensure that health-care systems, economies, and societies are prepared to address the world's health needs, particularly in populations with higher rates of mortality than previously known. The estimates from this study provide a robust framework for GBD and a valuable foundation for policy development, implementation, and evaluation around the world. Gates Foundation.
The "Hadrontherapy for Life" symposium in Caen, France, highlighted that a new era of radiobiology is fundamental for advancing particle therapy to the next level. A radiobiology capable of integrating molecular biology and omics technologies is needed to deeply analyze treatment responses and underlying mechanisms. Key challenges discussed at the symposium included tumor hypoxia, which remains only partially mitigated by high-LET radiation, and the specificity of carbon ions, or more broadly, high-LET particles, considered as "new drugs" capable of providing systemic benefits beyond local tumor control, including their potential to promote immunogenicity. Moreover, emerging modalities, such as Ultra High Dose Rate irradiation and spatial fractionated beams, were also discussed, with consensus that all require dedicated and coordinated radiobiological investigations. Infrastructure presentations highlighted the international capabilities of leading centers in Europe and Asia, emphasizing the importance of integrating radiobiology into clinical programs, advancing multi-ion experimentation, and adopting innovative experimental models, such as organoids and/or 3D cell cultures. Participants also stressed the need for greater access to animal experimentation facilities, which are essential for accelerating progress in the field. Furthermore, the meeting underscored translational endpoints such as biomarker development, a hot topic in current radiotherapy. The C400 accelerator enables Caen to incorporate radiobiology from its very inception, establishing a European hub for collaborative research. Round-table discussions emphasized the importance of harmonized protocols, dedicated in vivo irradiation rooms, international training programs with exchange of students and researchers, and comprehensive patient biobanking. In summary, the symposium reinforced the essential role of radiobiology in advancing hadron therapy (HT), providing strategic directions for translational research, infrastructure development, and international collaborations to accelerate personalized and effective particle therapy.
Surface-guided radiotherapy (SGRT) is a real-time, non-ionizing optical imaging technology that monitors patient surfaces during radiation treatment by creating 3D reconstructions from surface coordinate measurements. LAP has recently released a new SGRT solution, and we are the first proton therapy center to adopt this SGRT solution in a full rotating gantry. This work aims to present the commissioning results and quality assurance procedures at our center and to highlight the challenges of installing SGRT on a full rotating gantry. Following closely the recommendations in TG-302, 6 different measurements were performed during the commissioning of the SGRT system, which was mounted linearly on the same beam due to space constraints. These measurements included spatial drift measurement, static localization accuracy, dynamic localization accuracy, end-to-end localization accuracy, field-of-view (FOV) characterization of different treatment sites, and stability upon gantry rotation. These measurements subsequently served as baseline values for the different quality assurance procedures recommended in TG-302. The moving average for spatial drift measurement across 200 minutes was 0.0233 mm, while the average deviation for static and dynamic localization was less than 0.2 mm across. The largest deviation was 0.182 mm in the LR direction at 40 mm for static localization, while dynamic localization has a maximum deviation from the Anzai laser tracking at 0.1 minute point with a value of 0.734 mm. End-to-end localization test reported a difference of 0.08 cm between x-ray imaging and LUNA 3D's isocenter. The FOV was in general mostly visible for all treatment sites except for the lower neck region and lateral prostate surfaces due to the placement of the cameras. Stability during gantry rotation is kept within 0.2 mm with gantry angle 30.4° and 335.8° having the largest magnitude deviations of 0.151 and 0.156 mm, respectively. The successful commissioning of the LUNA 3D SGRT system at our center can serve as a reference for other particle therapy centers with a full rotating gantry. This work will allow them to include the relevant tests as well as understand the limitations of FOV for different treatment sites when adopting similar camera arrangement like ours in a full rotating gantry.
Base of tongue (BOT) adenoid cystic carcinoma (ACC) is a rare, locally aggressive malignancy that is typically associated with a high rate of disease recurrence. Surgery alone is rarely curative and highly morbid. Outcomes of systemic therapies and low linear energy transfer radiation therapy (RT) are generally poor. Fast neutron therapy (NRT), a form of high linear energy transfer radiation, is advantageous in treating radioresistant salivary gland malignancies. Long-term cancer control and swallowing outcomes in patients with BOT ACC treated with NRT were retrospectively reviewed. Between 1994 and 2023, 63 patients ≥18 years (median age 61) with biopsy-confirmed BOT ACC, not treated previously with surgery or RT, underwent 3D-conformal NRT or intensity-modulated neutron therapy (IMNT) for localized M0 (77.8%) or M1 (22.2%) disease. Most patients had (T3-4) primary tumors. Kaplan-Meier method was used to estimate locoregional recurrence-free (LRFS), distant metastasis-free, and overall survival. Late toxicities (≥90 days after NRT) were reported per Common Terminology Criteria for Adverse Events v5.0. Treatment-related and post-treatment percutaneous endoscopic gastrotomy (PEG) tube utilization was evaluated. For the entire cohort, 5-year LRFS was 53.4%, and 5-year overall survival was 75.1%. Among M0 patients, 3-year LRFS was 72.4%, 5-year LRFS was 59.4%, and 5-year distant metastasis-free was 44.1%. Prophylactic PEG tubes were placed in 58.1% of patients; 14.5% remained PEG-dependent ≥90 days post-treatment. Common toxicities included xerostomia and dysphagia. Among evaluable patients, 33.3% required PEG placement after 90 days due to disease or salvage therapy. Neither patient treated with IMNT required long-term PEG use. This is the first study to report clinical outcomes of NRT for BOT ACC. Swallowing outcomes were acceptable, with a low rate of persistent PEG dependence. NRT achieved significant locoregional control in many locally advanced primary tumors. Additional improvements in the therapeutic ratio and functional outcomes may be achievable with IMNT.
Evidence for the efficacy of proton beam therapy (PBT) for liver metastases of pancreatic cancer remains unclear. Therefore, we analyzed outcomes using data from a multicenter prospective study on particle therapy (PT) by the Japanese Society for Radiation Oncology (JASTRO). We enrolled patients who underwent PBT at all facilities in Japan between 2016 and 2019. Patient selection criteria included liver recurrence without recurrence at the primary pancreatic tumor site after curative treatment, no other metastatic tumors in other organs, and up to three liver lesions. Moreover, inoperability and refractoriness to chemotherapy were part of the treatment eligibility criteria. The PBT dose and fractionation corresponded to the JASTRO treatment policy. The local recurrence (LR), overall survival (OS), and progression-free survival (PFS) rates were calculated using the Kaplan-Meier method. Factors potentially associated with LR and OS were analyzed. Adverse events (AEs) were also investigated. Twenty-four patients with a median age of 64 years (range, 40-82 years) and 40 lesions were enrolled in the study. The median tumor size was 11.7 (0.74-901.2 mL). Seven patients underwent concurrent chemotherapy; meanwhile, the median biological effective dose was 109.6 (range, 88.8-115.2) Gy. The median follow-up period was 9.2 (range, 2.1-41.4) months. The 1-year LR rate was 16.7%. The 1-year OS and PFS rates were 37.5% and 4.2%, respectively, with median survival times of 9.3 and 4.7 months. However, no factors were related to LR. In multivariate analysis, levels of anti-carbohydrate determinant 19-9 (P < .01) and PFS duration after PBT (P < .01) were identified as statistically significant factors influencing OS. The only AE noted was radiation-induced dermatitis in 2 patients. PBT was safe with few AEs, and patients likely to achieve long-term survival could be identified under appropriate conditions.
Classical Hodgkin lymphoma (cHL) is associated with favorable prognosis and high overall survival (OS). Consolidative proton therapy (cPT) represents a modality recommended for young patients due to its reduction in exit dose, with a goal to minimize late effects. We present outcomes of pediatric patients with cHL receiving cPT at initial diagnosis or relapse/refractory (R/R) disease. From 10/2007 to 12/2022, 74 patients between the ages of 6 and 22 with cHL treated with cPT after systemic therapy (ST) were included. Risk groups were classified by ST into low, intermediate, and high risk. Involved-site radiotherapy was used for most patients (90%). OS and relapse-free survival (RFS) were estimated using the Kaplan-Meier method; crude cumulative incidence estimates were used to describe recurrence patterns. Median follow-up was 5.5 years (30% > 8 years). Sixty-one (82.4%) patients were treated at initial diagnosis, and 13 (17.6%) received cPT for R/R disease. Median age at diagnosis was 16 years (range, 6.3-21.7), with most being female (58.1%), nodular sclerosing subtype (82.4%), and bulky disease (78.4%). 10-year OS was 96% overall (97% initial, 92% R/R); 10-year RFS was 84% overall (82% initial, 92% R/R). 10-year RFS was 100%, 82%, and 72% for low, intermediate, and high-risk groups. Of the 61 patients treated for initial diagnosis, 8 experienced relapse, with 4 (6.6%) out-of-field & in-field, 3 (4.9%) out-of-field, and 1 (1.6%) in-field. Of the 13 patients treated for R/R disease, 1 experienced an out-of-field recurrence. One patient developed papillary thyroid carcinoma 11.9 years post-cPT (in-field); no other grade 3+ radiation-related late toxicities were observed. cPT is an effective and well-tolerated treatment for young patients with cHL, demonstrating excellent 10-year OS and RFS, even for those treated at relapse. These findings support cPT as a treatment modality, warranting further studies to assess long-term outcomes.
Monte Carlo (MC) simulations provide gold standard dose calculations in radiation therapy but generate large phase space (PHSP) files that limit clinical implementation. We developed NeRP-MC, the first neural representation learning approach for PHSP data modeling, and evaluated its ability to model particle distributions from minimal training data. We investigated proton PHSP modeling at 242 and 140 MeV. For both energies, a reference proton pencil beam PHSP containing 25 million particles was generated using TOPAS. A multi-layer perceptron with Fourier feature encoding was trained to predict particle energies from spatial and momentum inputs. We evaluated NeRP-MC in 3 scenarios: 1) compact energy modeling given full spatial and momentum information, 2) energy modeling from sparse PHSP data (1.25 million particles, 20-fold reduction), and 3) replacing the PHSP with parametric Gaussian spatial/momentum distributions and network-predicted energies conditioned on the Gaussian-sampled inputs. Validation used in-water dose distributions compared via gamma index analysis. The trained network requires only 600 KB for storage versus 3 GB for the original PHSP and predicts 25 million particle energies in under 0.5 seconds on an NVIDIA A100 GPU. NeRP-MC generated energies showed close agreement with reference data across all 3 scenarios. Depth-dose profiles, lateral profiles, and penumbra regions were accurately reproduced. Gamma pass rates exceeded 99% at 3%/2 mm and 90% at the strictest 1%/1 mm criterion. NeRP-MC offers compact modeling and fast prediction of particle energies from particle spatial and momentum information and promises to replace the large-scale PHSP with a parametric Gaussian model of spatial and angular variables and the NeRP model of particle energy variables. NeRP-MC has the potential to advance MC simulation efficiency for radiation therapy through a substantial reduction in computational and storage requirements while maintaining dosimetric accuracy.
Multimodality therapy, including surgery, radiotherapy, and systemic therapy, has significantly improved overall survival for patients with brain metastases. However, treatment-related neurocognitive sequelae remain a major challenge in survivorship. Although advances in radiotherapy delivery techniques have reduced toxicity, the potential interaction with chemotherapy, targeted therapy, and immunotherapy, and the consequent effect on neurocognitive outcomes is poorly characterised. We conducted a systematic review of clinical trials reporting neurocognitive endpoints in patients with brain metastases receiving radiotherapy with or without other concurrent systemic therapies. Neurocognitive outcomes were manually extracted from published reports. 39 studies from 1997 to 2024 involving 6617 patients met inclusion criteria (n=27 whole-brain radiotherapy; n=12 radiosurgery), including six studies evaluating combined-modality therapy. Baseline neurocognitive disability was frequently observed, and the majority of randomised trials evaluating advanced radiotherapy delivery techniques (hippocampal avoidance and radiosurgery) compared with whole-brain radiotherapy reported reduced cognitive decline and improved quality of life. There was no signal for increased toxicity with combined-modality therapy, including radiotherapy with concurrent systemic therapy, although evaluable trials were few in number. Given improvements in survival for patients with brain metastases, characterisation of long-term neurocognitive outcomes is growing in importance. There is an urgent need for targeted research to resolve evidence gaps around modality-specific neurocognitive toxicity and optimal sequencing of therapies. Systemic issues, such as integration of routine neuropsychological screening or assessment and incorporation of rehabilitation strategies into neuro-oncology care pathways, warrant evaluation. Exploration of emerging strategies, ranging from neuroprotectants to dose-sparing radiotherapy techniques, could further mitigate long-term adverse effects.
Proton therapy, with its high conformality and superior dose distribution, is becoming an increasingly prevalent modality in radiation oncology. Although a generic relative biological effectiveness (RBE) value of 1.1 for treatment planning has been adopted, evidence suggests that RBE varies with dose, linear energy transfer (LET), and biological endpoints. This variation raises concerns about underestimating the RBE-weighted dose, which may significantly impact treatment outcomes. To assess the awareness and management of RBE variability in clinical practice, we conducted a survey among US proton therapy centers. The survey consisted of 32 questions grouped into subtopics, such as awareness of RBE variability, practices to account for variability, and future needs. It was distributed among 29 centers through the auspices of the Particle Therapy Co-Operative Group - North America. The response rate was 80% and revealed significant apprehension about the assumption of a constant RBE. All respondents used a fixed RBE of 1.1, yet expressed varying degrees of concern about its appropriateness. Most centers report unanticipated toxicities and local recurrences potentially linked to an underestimation of RBE, highlighting the need for revisiting current practices. The survey indicated that nearly all centers consider RBE variability during beam arrangement, and some perform LET and variable RBE calculations for patient-specific treatments. There is a strong consensus on the need for multi-institutional databases, studies to accumulate clinical evidence, and education on proton RBE to better understand RBE's clinical implications. This study is an overview of current clinical practices regarding proton RBE and identifies key priorities for future research. Although deviations from the generic RBE of 1.1 is commonly considered in treatment planning, the absence of standardized approaches leads to inconsistencies. Developing consensus guidelines and integrating advanced RBE and LET-based models into treatment planning could improve the precision and safety of proton therapy.
Magnetic resonance imaging (MRI) offers superior soft-tissue contrast for prostate delineation, and MR-only radiotherapy eliminates computed tomography (CT)-MRI registration errors. Although synthetic CT (sCT) has been validated for photon and proton therapy, its clinical feasibility in carbon ion radiotherapy (CIRT) remains unclear, particularly because dose accuracy in CIRT is highly sensitive to stopping-power ratio (SPR) errors. This study evaluated the dosimetric accuracy of MRI-derived sCT for prostate CIRT, including the effect of a thermoplastic fixation shell used clinically but not visualized on MRI. Twenty patients with prostate cancer underwent same-day planning CT (pCT) and MRI. sCT images were generated using the MRCAT algorithm (Philips Healthcare). Bone pseudo-Hounsfield units were replaced with institution-specific SPR values to improve range accuracy. Treatment plans were created on the pCT and recalculated on the sCT using identical beam parameters. Dose agreement was assessed using carbon-ion depth and lateral dose profiles, 3D gamma analysis (3%/3 mm, 2%/2 mm, 1%/1 mm), and key Dose-volume histogram indices. To evaluate the fixation-shell impact, a 3-mm virtual shell was added to the sCT and compared with a corresponding pCT containing the physical shell. The sCT-based distal range was longer than that of the pCT by 2.7 ± 1.6 mm, reduced to 1.2 ± 1.6 mm with shell inclusion. Lateral dose differences were <1 mm for all patients. Gamma passing rates exceeded 90% for 2%/2 mm and 3%/3 mm criteria, and the 1%/1 mm pass rate at the 50% threshold improved by ∼6% with shell inclusion. CTV D99% and PTV D1% agreed within ±1%, whereas PTV D95% decreased by up to 8% at the target periphery. Organs at risk (OAR) dose differences were clinically negligible. With bone SPR adjustment and fixation-shell consideration, Magnetic Resonance for Calculating ATtenuation-based sCT provides clinically acceptable dose-calculation accuracy for prostate CIRT, supporting the feasibility of MR-only planning.
Proton FLASH radiotherapy offers the potential to enhance normal tissue sparing while maintaining tumor control. This study investigates the dosimetric advantages of spread-out Bragg peak (SOBP) FLASH compared to standard intensity modulated proton therapy (IMPT) for re-irradiation in recurrent head-and-neck (HN) cancer. Eight recurrent HN cancer cases were retrospectively analyzed using hypofractionated proton therapy plans (5 × 8 Gy fractions). FLASH plans were designed using a single energy layer and patient-specific modulation devices implemented in the RayStation. Robust optimizations accounted for setup (±3 mm) and range (±3.5%) uncertainties. A biologically effective dose model incorporating a FLASH-modifying factor (FMF) of 0.7 for normal tissues meeting dose (≥5 Gy) and dose rate (≥40 Gy/s) thresholds was used to assess the therapeutic potential of FLASH. Dosimetric parameters such as target coverage, homogeneity index (HI), conformity index (CI), and organ-at-risk (OAR) sparing were compared between FLASH and standard IMPT plans. Compared to standard IMPT, SOBP-based FLASH plans demonstrated reduced target homogeneity (p < .05) and slightly lower dose conformity, with the effects more pronounced for targets near the neck region due to larger center-to-axis distances to avoid collisions. Despite these limitations, FLASH plans maintained robust target coverage (D95% > 96.6% ± 1.2%) in robustness scenarios. The FLASH effective dose model indicated a reduction in the maximum dose to OARs within 2 cm of the target volume; for instance, the maximum dose to the larynx decreased from 29.9 Gy (IMPT) to 25.4 Gy (FLASH). SOBP-based FLASH plans preserved the dosimetric advantages of IMPT for sparing distal normal tissues while offering potential reductions in high-dose exposure to OARs near the target volume. Incorporating an FMF of 0.7, these plans showed comparable dosimetric profiles to IMPT with the added benefit of enhanced normal tissue protection under uncertainty, a unique advantage over conventional radiotherapy.
This study aims to analyze the trends in institutional performance on Imaging and Radiation Oncology Core (IROC) proton phantoms and to investigate the impact of treatment parameters on proton therapy delivery accuracy. We analyzed 402 IROC anthropomorphic phantom audits performed by 57 institutions worldwide between 2009 and 2024, including brain, head and neck (H&N), spine, prostate, lung, and liver phantoms. Dosimetric assessments included thermoluminescent dosimeters (TLDs) for dose comparison and gamma analysis of radiochromic film. The lung and liver phantoms were irradiated with simulated motion. Univariate analysis was performed to evaluate the relationships between treatment parameters and phantom outcomes (pass/fail, TLD-to-treatment planning systems (TPS) ratio, and gamma passing rate). Linear regression was used to analyze the long-term trends in the institutional delivery accuracy across the 6 phantoms. The inter-institutional dose variation in the target was approximately 3% across all phantoms. Of the participating institutions, 66.7% failed at least one IROC proton phantom. Pass rates were 97% for brain, 91% for H&N, 89% for spine, 76% for prostate, 63% for lung, and 57% for liver phantoms. Phantoms incorporating motion exhibited the poorest performance, particularly in gamma analysis, with 33 (N = 91) lung and 33 (N = 76) liver irradiations showing gamma values below 85%. No linear temporal trends were observed in the overall passing rates of the six phantoms, while TLD results improved for brain, liver, spine, and prostate phantoms (P < .05). Machine type was correlated with pass rates for H&N and liver phantoms (P < .05). Overall institutional phantom performance has not significantly improved over time. In particular, the proton lung and liver phantoms continuously demonstrate suboptimal results, likely due to complex geometries and motion management challenges. These findings underscore the need for careful selection of treatment parameters and optimization of motion management strategies. The IROC phantom program remains crucial for characterizing proton therapy systems and identifying clinically significant errors.
This study aimed to evaluate the efficacy of respiratory-gated irradiation using visual feedback (VF) in carbon-ion radiotherapy (CIRT). Furthermore, in patients with liver cancer undergoing CIRT, the treatment times of treatments with and without VF (non-VF) were compared. Thirty-three patients with liver cancer were analyzed. VF system was applied in 10 patients with liver tumors. To evaluate the efficacy of VF, patients treated non-VF were selected as a control group. All treatments were performed under free-breathing conditions in both the VF and non-VF groups. For each VF patient, 1-3 candidate non-VF patients were identified by matching the CTV size and irradiation gate width (amplitude). From these candidates, 1 non-VF patient was selected as a matched control for each VF patient. The average treatment time for each VF patient was compared with that of the corresponding non-VF patient. The effect of the reduced treatment time for VF was calculated by comparing each VF patient with the corresponding non-VF patient. To quantify respiratory variability, the root mean square error and standard deviation were calculated. The treatment time was reduced in 8 of 10 pairs. Further, in 6 of 8 pairs, the treatment time was reduced by more than 5 minutes when using VF compared with non-VF. The RMSE value was significantly reduced at 50% and 100% (P < .05). The RMSE value decreased by 28.2% in the VF compared with non-VF. VF was effective in improving respiratory waveform reproducibility in most pairs. The results suggest that VF contributes to a reduction in treatment time, indicating improved time efficiency during irradiation sessions. In addition, VF improves respiratory waveform reproducibility, which may contribute to enhanced treatment accuracy. Furthermore, shortening the treatment time may reduce the treatment burden on patients and improve overall treatment workflow.