Navigating Scientific Progress in Radiation Oncology: Comprehensive Analysis of Clinical Trials From the Past Two Decades Using the ClinicalTrials.gov Database

INTRODUCTION AND BACKGROUND

Over the past two decades, oncology has witnessed major advancements in the understanding, diagnosis, and treatment of cancer, which has led to an era of precision medicine and the proliferation of new therapies that can be tailored to patients. As one of the three pillars of cancer therapy, radiation oncology has undergone profound transformation, driven by advancements in technology, evolving treatment paradigms, and a growing understanding of the intricate interplay between cancer biology, systemic therapy, and radiation.¹ Radiation therapy remains implicated in the treatment of more than 50% of all patients with cancer at least once during the course of their disease,² with an increase in the use of reirradiation.³ Moreover, curative treatment strategies for many malignancies continue to include radiation therapy, further underscoring its importance in interdisciplinary cancer management.⁴

This modern era has also witnessed an unprecedented surge in oncology clinical trials, which serve as a linchpin for translating scientific discoveries into tangible improvements in patient care. Clinical trials in radiation oncology test new treatments, technologies, and strategies to help researchers assess their safety, efficacy, and side effects. Through clinical trials, valuable data that inform evidence-based decision making are generated. Ultimately, clinical trials not only shape the current standard of oncologic care, but also provide a basis for developing more effective treatments in the future.

An important milestone in tracking this scientific progress, formalizing reporting, and enhancing transparency in clinical trial research was the launch of the ClinicalTrials.gov website in February 2000. Initially, the database primarily included information on federally and privately funded clinical trials conducted in the United States. However, over the years, its scope has expanded globally, and now includes trials from all over the world. In 2003, the International Committee of Medical Journal Editors (ICMJE) made it necessary for researchers to register their clinical trials in a public database, with ClinicalTrials.gov being the most widely used platform. Throughout the years, numerous updates and enhancements have been made to ClinicalTrials.gov to improve its usability and scope.

Leveraging ClinicalTrials.gov, several analyses have been conducted recently. In 2017, Trone et al⁵ found reporting limitations in phase III radiation therapy trials. Liu et al⁶ compared radiation therapy with oncology trials and found limited funding for the former. Aggarwal et al,⁷ using a bibliographic approach, analyzed radiation oncology trials in 25 leading research countries, described the diverse trial landscape, and highlighted the need for more investment. Odedina et al⁸ also highlighted the need for more clinical trials in Africa in particular. Park et al⁹ expanded on the analysis by Trone et al,⁵ suggesting diversified funding and more aggressive implementation of hypofractionated treatments. In 2021, Wells et al¹⁰ compared anticancer therapy trial activity from 2014 to 2017 in high-income countries versus low- and middle-income countries, concluding that most trials come from high-income countries and are not aligned with global cancer burden. In a similar effort, Dodkins et al¹¹ looked at radiation oncology randomized trials from 2014 to 2017, and stressed the need for greater investment in trial infrastructure, especially in low- and middle-income countries. Most recently, Kim et al¹² found evidence for challenges in data transparency and harmonization in neuro-oncology trials. All these analyses show that there is much to learn from clinical trial data.

Until today, no comprehensive analysis of the clinical trial landscape in radiation oncology from the past two decades has been conducted. The objectives of this analysis hence encompass an examination of the characteristics of all conducted trials over the past two decades and of all currently ongoing trials by synthesizing ClinicalTrial.gov data, identifying clinical trial patterns, and critically evaluating the identified trends. In looking at research priorities, understanding geographical dominance, assessing trial type, and evaluating funding sources, this analysis aspires to provide clinicians, researchers, and policymakers with a robust understanding of the current state of the clinical trial landscape in radiation oncology. This endeavor will help to highlight potential research domains and to chart the scientific trajectory for this discipline in the future.

MATERIALS AND METHODS

RESULTS

As of February 8, 2024, the ClinicalTrials.gov website compiled data from 482,151 registered studies. Filtering for cancer and radiation therapy trials conducted in the past two decades yielded an initial data set of 12,614 (2.6%) trials. After removing trials with insufficient data reporting, 5,795 (1.2%) trials remained. Subsequently, excluding false-positive trials yielded a remainder of 4,253 (0.9%) clinical trials, which were included in the analysis of this study. The flow diagram in Figure 1 shows a graphical depiction of the inclusion and exclusion criteria.

Open multimedia modal

Over the past two decades, 4,253 radiation oncology trials have been registered at ClinicalTrials.gov. Clinical trial activity has steadily increased: 134 trials in 2003 (n = 4,253/n = 134; 3.2%) and 118 in 2004 (n = 4,253/n = 118; 2.8%), averaging 176 annually from 2005 to 2013 (n = 4,253/n = 176; 4.1%). In 2016, 234 trials were listed (n = 4,253/n = 234; 5.5%), rising to 244 in 2023 (n = 4,253/n = 244; 5.7%). The peak was in 2018, with 274 trials (n = 4,253/n = 274; 6.4%; Fig 2).

Open multimedia modal

Research activity is not uniformly distributed across organ systems. The digestive system emerged in most trials, that is, 972 (n = 4,253/n = 972; 22.9%). CNS and head and neck cancers were each represented in 577 (n = 4,253/n = 577; 13.6%) and 564 (n = 4,253/n = 564; 13.3%) trials, respectively. By contrast, the gynecologic system and breast cancers had the least number of trials, with 190 (n = 4,253/n = 190; 4.5%) and 236 (n = 4,253/n = 236; 5.5%) clinical trials, respectively. OMD was the subject of investigation in 95 (n = 4,253/n = 92; 2.2%) trials, underscoring the growing importance of better understanding and addressing this specific metastatic disease state (Appendix Fig A1A). The rise in trials focusing on OMD from one decade to the next was statistically significant, with an increase from 0.2% to 3.5% (P < .01). Hematology trials experienced a decrease in trial activity, with 175 (4.1%) trials reported for the period from 2013 to 2023 compared with 238 (5.6%) in the previous decade, representing a statistically significant drop from 13% to 7% (P < .01; Appendix Fig A2; Fig 3A).

Open multimedia modal

Phase II studies emerged as the prevailing category throughout the years, with 2,181 (51.3%) registered trials falling into this category. From 2005 to 2014, an annual publication range of 75 (1.7%) to 107 (2.5%) phase II trials was observed, underlining a consistent focus on this particular clinical trial phase (first decade: 50.4%, second decade: 51.9%, P = .36). Phase I and phase III studies exhibited comparable levels of activity over the years, with numbers fluctuating between 15 (0.4%) and 60 (1.4%) clinical trials per year, totaling at 738 (17.4%) and 672 (15.8%) over the past 20 years, respectively. However, it is noteworthy to highlight a substantial deviation observed in the latter decade, characterized by a marked increase in early phase I studies, escalating from 0.6% to 2% (P < .01; Table 1). Phase IV trials manifested as the least published category, amounting to 33 (0.4%) of all registered trials, and maintained an average of approximately two (<0.1%) clinical trials per year (Fig 3B). This general distribution pattern of trial phases can also be observed in the OMD category (Appendix Fig A1B). Fewer trials terminated prematurely during the latter decade, accounting for only 10% of trials compared with the 22% observed in the first decade.

North America contributed the majority of the studies (n = 2,477, 58.2%). The second most trials came from Asia (n = 1,072, 25.2%), while Europe maintained a stable contribution (n = 903, 21.2%). Africa contributed the least number of clinical studies (n = 40, 0.9%; Figs 4A and 4B).

Open multimedia modal

Industry funding remained stable at approximately 6% over the two decades (2003-2012: 6.1%; 2013-2023: 6.4%). Although other funding sources largely remained unchanged, the network funding category experienced a significant decrease (2003-2012: 10.2%; 2013-2023: 2.5%; P-value: <0.01), whereas the other category saw a significant increase over this period (2003-2012: 76.4%; 2013-2023: 85.7%; P value: <.01). For further details, see Appendix Figures A3A and A3B.

DISCUSSION

The sustained increase in the number of trials registered each year on ClinicalTrials.gov indicates growing interest in radiation oncology research. This trend is expected to continue. However, this does not provide a relative measure compared with other oncological disciplines, such as medical or surgical oncology. There is some evidence that radiation oncology trial activities are outnumbered and outfinanced by medical oncology.⁶ Medical oncology benefits significantly from pharmaceutical industry backing, with a focus on drug development, including immunotherapies and targeted treatments, which generates substantial funding and numerous trials. Surgical oncology, while less trial-heavy, emphasizes technical refinements and often collaborates with radiation oncology in multimodal treatment studies. A comparative analysis of oncologic research is required to holistically address this question.

One disease group that stands out, as it opposes this trend, is the hematologic system, where a decline in radiation oncology trial activity was observed. This decline coincides with advancements in systemic therapy for various hematologic diseases. Hodgkin and non-Hodgkin lymphomas have shifted the treatment paradigm away from primary radiation-based approaches.¹³

The growing number of trials focusing on OMD, with an equitable distribution in terms of both publication and leadership between the United States and Europe, represents an important finding of our analysis. This finding reflects increasing recognition of the clinical relevance of OMD and the potential for targeted interventions in this specific patient population. The balanced leadership and publication contributions from the two regions highlight the importance of different research groups within the discipline attributed to the OMD state.

Although phase II trials are crucial for assessing treatment efficacy and generating hypotheses for further investigation, the preponderance of such studies prompts reflection on the lack of phase I trials and the translational gap between phase II and subsequent phase III trials. The abundance of phase II trials may suggest a need for improved strategies to investigate more drug-radiotherapy combinations in preclinical and phase I clinical trial settings and to facilitate the translation of promising therapies into larger, more definitive phase III trials. The prevalence of phase II trials also necessitates a critical evaluation of their role in informing clinical practice and shaping treatment guidelines, emphasizing the importance of well-designed and adequately powered trials in advancing the field.

North America has contributed to the majority of studies over the past two decades, yet other continents have steadily caught up in terms of research output. The remarkable surge in contributions from Asia is particularly noteworthy, signifying a significant leap in the region's involvement in clinical studies. Europe, while maintaining a stable presence, has demonstrated consistent growth in research endeavors. However, Africa remains relatively distant in terms of the number of clinical studies conducted, which in turn is also a reflection of lower patient volume, less cancer care resources, and research capacity. This evolving global distribution underscores the dynamic nature of scientific exploration and the expanding role of diverse regions in advancing medical knowledge.

Industry funding of approximately 6% over the past two decades has been notably low. Unlike medical oncology, which is heavily driven by pharmaceutical companies, radiation oncology relies on capital-intensive technologies, such as linear accelerators and proton therapy systems, which often have limited scalability and fewer repeat customers compared with drugs. Regulatory hurdles, high initial costs, and the lack of robust financial incentives for innovation further deter industry engagement. However, limited private-sector involvement arguably has the advantage of ensuring that most funding comes from publicly funded research institutions, which may reduce the potential biases associated with profit-driven motives. However, the downside is significant, as the private sector plays a crucial role in driving innovation, developing cutting-edge software programs, and advancing hardware technology. Increased industry funding can accelerate technological advancements and foster the development of novel treatment modalities in radiation oncology, ultimately improving patient care.

To our knowledge, the current analysis constitutes the first comprehensive overview of the clinical trial landscape in radiation oncology over the past two decades. One limitation of this analysis was that only trials registered on the ClinicalTrials.gov website were included. Another shortcoming was that only a limited number of parameters per trial were available via the database used, and that the quality and transparency of reported data remains imperfect. One implication for clinical routine and future research activity concerns the generalizability of clinical trial findings and recommendations to a global patient population, particularly considering variations in patient demographics, health care infrastructure, and socioeconomic factors, given the dominant contribution from the United States and Europe collectively shaping the majority of the studies investigated.

In conclusion, our examination of the radiation oncology clinical trial landscape over the past two decades has brought to light a concentration of studies in the United States and Europe, the prevalence of phase II trials, and an increasing emphasis on OMD trials. On the basis of these findings, the global research community should foster collaboration, address regional disparities, and strategically advance therapies from early-phase trials to impactful clinical applications. The field should also work toward attracting more industry funding for its trials.