Radiation Oncology Training in the Philippines: Bridging Gaps for Improved Cancer Care in Low- and Middle-Income Countries.

PURPOSE: Radiation oncology in the Philippines, a large lower- and middle-income country in Southeast Asia, is facing a critical shortage in manpower, with only 113 radiation oncologists (ROs) over 55 radiotherapy (RT) centers serving 100 million population. Paramount to workforce expansion is ensuring that training programs can produce adequately trained specialists. In this study, we describe the current state of radiation oncology training programs in the Philippines. METHODS: This is a cross-sectional observational analysis of the nine radiation oncology residency training programs in the Philippines. Data were collected from a survey of the program directors, the Philippine Radiation Oncology Society database, and a PubMed literature search. RESULTS: Eight of the nine programs are in the National Capital Region. Since program standardization in 2005, there have been 82 four-year residency graduates, with up to 18 new graduates annually. Faculty-to-trainee ratio ranges from 0.5 to 2.67. In terms of technology, all programs have intensity-modulated RT and high-dose-rate brachytherapy, but only six are equipped with computed tomography-based image guidance and stereotactic capabilities. Clinical education schemes vary per institution regarding curriculum implementation, resident activities, and methods of evaluation. Required resident case logs are not met for lung, GI, genitourinary, bone and soft tissue, and hematologic malignancies. In total, there are only 22 resident-led publications from 10 unique individuals in two training programs. CONCLUSION: Program expansions are warranted to meet the projected demand for ROs in the Philippines, but training programs must first improve key aspects of staffing, technology, clinical education, and research. Addressing training challenges related to resource limitations necessitates local and international collaborations with higher-capacity centers to bridge gaps for continued quality improvement with the aim of ultimately delivering better overall cancer care.

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.

Designing combination therapies for cancer treatment: application of a mathematical framework combining CAR T-cell immunotherapy and targeted radionuclide therapy.

Introduction: Cancer combination treatments involving immunotherapies with targeted radiation therapy are at the forefront of treating cancers. However, dosing and scheduling of these therapies pose a challenge. Mathematical models provide a unique way of optimizing these therapies. Methods: Using a preclinical model of multiple myeloma as an example, we demonstrate the capability of a mathematical model to combine these therapies to achieve maximum response, defined as delay in tumor growth. Data from mice studies with targeted radionuclide therapy (TRT) and chimeric antigen receptor (CAR)-T cell monotherapies and combinations with different intervals between them was used to calibrate mathematical model parameters. The dependence of progression-free survival (PFS), overall survival (OS), and the time to minimum tumor burden on dosing and scheduling was evaluated. Different dosing and scheduling schemes were evaluated to maximize the PFS and optimize timings of TRT and CAR-T cell therapies. Results: Therapy intervals that were too close or too far apart are shown to be detrimental to the therapeutic efficacy, as TRT too close to CAR-T cell therapy results in radiation related CAR-T cell killing while the therapies being too far apart result in tumor regrowth, negatively impacting tumor control and survival. We show that splitting a dose of TRT or CAR-T cells when administered in combination is advantageous only if the first therapy delivered can produce a significant benefit as a monotherapy. Discussion: Mathematical models are crucial tools for optimizing the delivery of cancer combination therapy regimens with application along the lines of achieving cure, maximizing survival or minimizing toxicity.

Nutritional Prognosis of Patients Submitted to Radiotherapy and Its Implications in Treatment.

Oncological patients show intense catabolic activity, as well as a susceptibility to higher nutritional risk and clinical complications. Thus, tools are used for monitoring prognosis. Our objective was to analyze the nutrition prognosis of patients who underwent radiotherapy, correlating it with outcomes and complications. We performed a retrospective transversal study based on secondary data from hospital records of patients who started radiotherapy between July 2022 and July 2023. We established Prognostic Scores through a combination of Prognostic Nutritional Index (PNI) and a Subjective Global Assessment (SGA), assessed at the beginning and end of treatment. Score 3 patients, with PNI ≤ 45.56 and an SGA outcome of malnutrition, initially presented a higher occurrence of odynophagia, later also being indicative of reduced diet volume, treatment interruption, and dysphagia. SGA alone showed sensitivity to altered diet volume, dysphagia, and xerostomia in the second assessment. Besides this, PNI ≤ 45.56 also indicated the use of alternative feeding routes, treatment interruption, and hospital discharge with more complications. We conclude that the scores could be used to indicate complications; however, further studies on combined biomarkers are necessary.

A high-resolution large-area detector for quality assurance in radiotherapy.

Hadron therapy is an advanced radiation modality for treating cancer, which currently uses protons and carbon ions. Hadrons allow for a highly conformal dose distribution to the tumour, minimising the detrimental side-effects due to radiation received by healthy tissues. Treatment with hadrons requires sub-millimetre spatial resolution and high dosimetric accuracy. This paper discusses the design, fabrication and performance tests of a detector based on Gas Electron Multipliers (GEM) coupled to a matrix of thin-film transistors (TFT), with an active area of 60 × 80 mm2 and 200 ppi resolution. The experimental results show that this novel detector is able to detect low-energy (40 kVp X-rays), high-energy (6 MeV) photons used in conventional radiation therapy and protons and carbon ions of clinical energies used in hadron therapy. The GEM-TFT is a compact, fully scalable, radiation-hard detector that measures secondary electrons produced by the GEMs with sub-millimetre spatial resolution and a linear response for proton currents from 18 pA to 0.7 nA. Correcting known detector defects may aid in future studies on dose uniformity, LET dependence, and different gas mixture evaluation, improving the accuracy of QA in radiotherapy.

Radiotherapy and immunology.

The majority of cancer patients receive radiotherapy during the course of treatment, delivered with curative intent for local tumor control or as part of a multimodality regimen aimed at eliminating distant metastasis. A major focus of research has been DNA damage; however, in the past two decades, emphasis has shifted to the important role the immune system plays in radiotherapy-induced anti-tumor effects. Radiotherapy reprograms the tumor microenvironment, triggering DNA and RNA sensing cascades that activate innate immunity and ultimately enhance adaptive immunity. In opposition, radiotherapy also induces suppression of anti-tumor immunity, including recruitment of regulatory T cells, myeloid-derived suppressor cells, and suppressive macrophages. The balance of pro- and anti-tumor immunity is regulated in part by radiotherapy-induced chemokines and cytokines. Microbiota can also influence radiotherapy outcomes and is under clinical investigation. Blockade of the PD-1/PD-L1 axis and CTLA-4 has been extensively investigated in combination with radiotherapy; we include a review of clinical trials involving inhibition of these immune checkpoints and radiotherapy.

[Spatially fractionated radiotherapy : introduction into clinical practice]. / Radiothérapie fractionnée dans l'espace : introduction en pratique clinique.

Spatially fractionated radiotherapy is a new concept involving partial irradiation of tumor volumes. Different techniques are described: mini-beam and micro-beam radiotherapy (pre-clinical) and LATTICE radiotherapy (L-RT) (clinical). Although L-RT is emergent in clinical practice and its evidence is still limited, it has still revealed excellent outcomes. At least three clinical situations can be discussed: definitive palliative radiotherapy, dose escalation (boost) or salvage radiotherapy. The interaction between L-RT and the immune system is still under investigation. Preclinical observations have already demonstrated a strong interaction, with tumor response dependent on immune system stimulation and the generation of an abscopal effect.

La radiothérapie fractionnée dans l'espace est un nouveau concept consistant en une irradiation partielle des volumes tumoraux. Plusieurs techniques sont ainsi décrites : les radiothérapies mini-beam et micro-beam (pré-clinique) et la radiothérapie LATTICE (L-RT) (clinique). Bien que la L-RT soit relativement nouvelle dans la pratique clinique et que les preuves quant à son utilisation soient encore limitées, elle montre des résultats prometteurs. Au moins trois situations cliniques peuvent être examinées en détail : la radiothérapie palliative définitive, l'escalade de dose (boost) ou encore la radiothérapie de sauvetage. L'interaction entre la L-RT et le système immunitaire est encore en cours d'investigation, mais des observations précliniques ont déjà démontré une interaction forte, avec notamment la dépendance de la réponse tumorale à la stimulation du système immunitaire et la génération d'un effet abscopal.

A review and bibliometric analysis of global research on proton radiotherapy.

Proton beam therapy (PBT) has great advantages as tumor radiotherapy and is progressively becoming a more prevalent choice for individuals undergoing radiation therapy. The objective of this review is to pinpoint collaborative efforts among countries and institutions, while also exploring the hot topics and future outlook in the field of PBT. Data from publications were downloaded from the Web of Science Core Collection. CiteSpace and Excel 2016 were used to conduct the bibliometric and knowledge map analysis. A total of 6516 publications were identified, with the total number of articles steadily increasing and the United States being the most productive country. Harvard University took the lead in contributing the highest number of publications. Paganetti Harald published the most articles and had the most cocitations. PHYS MED BIOL published the greatest number of PBT-related articles, while INT J RADIAT ONCOL received the most citations. Paganetti Harald, 2012, PHYS MED BIOL can be classified as classic literature due to its high citation rate. We believe that research on technology development, dose calculation and relative biological effectiveness were the knowledge bases in this field. Future research hotspots may include clinical trials, flash radiotherapy, and immunotherapy.

Second Chance for Cure: Stereotactic Ablative Radiotherapy in Oligometastatic Disease.

PURPOSE: Local ablative therapy, such as radiotherapy or surgery, plays a key role in treatment of patients with oligometastatic disease. Stereotactic ablative body radiotherapy (SABR) comes to the fore as a safe and effective treatment for patients with a limited number of metastases, even those located in hard-to-reach body sites. Many researchers have suggested that metastatsis-directed therapy could improve long-term progression-free survival (PFS) and overall survival (OS) in patients with oligometastases. PATIENTS AND METHODS: This was a retrospective, single-arm, observational study conducted between July 2015 and February 2022. In our institute, 60 patients with controlled primary tumors and one to five metastases were treated with SABR. Prescribed radiation doses ranged from 12 to 60 Gy administered in one to seven fractions. We aimed to determine whether metastatic-directed therapy using SABR for all oligometastases affects OS and PFS and whether the primary tumor or metastatic site influences OS/PFS. RESULTS: The most common primary malignancy types were prostate (n = 14), colorectal (n = 10), lung (n = 7), and breast cancers (n = 6). The median follow-up was 30 months, ranging from 9 to 79. The 1-, 3-, and 5-year PFS and OS rates were 54.9%, 37.0%, and 37.0% and 98.3%, 84.4%, and 73.8%, respectively, and the median time to first progression was 15 (range, 2-32) months. Twenty-four (40%) patients had no recurrence. In our analysis, primary tumor site was not an independent prognostic factor. The metastatic site may influence on patient outcome in cases of localized bone and liver metastases. CONCLUSION: In our retrospective analysis, SABR was associated with favorable levels of PFS and OS in patients with oligometastases. The limitations of our study were lacking high-level evidence, and randomized studies to compare SABR and palliative standard of care are mandatory.

Advancements and future directions in positron emission tomography-guided radiotherapy: a narrative review.

BACKGROUND AND OBJECTIVE: Positron emission tomography (PET) imaging has been useful in delineating tumor volumes and allowing for improved radiation treatment. The field of PET-guided radiotherapy is rapidly growing and will have significant impact on radiotherapy delivery in the future. This narrative review provides an overview of the current state of PET-guided radiotherapy as well as the future directions of the field. METHODS: For this narrative review, PubMed was searched for articles from 2010-2023. A total of 18 keywords or phrases were searched to provide an overview of PET-guided radiotherapy, radiotracers, the role of PET-guided radiotherapy in oligometastatic disease, and biology-guided radiotherapy (BgRT). The first 300 results for each keyword were searched and relevant articles were extracted. The references of these articles were also reviewed for relevant articles. KEY CONTENT AND FINDINGS: In radiotherapy, 18F-2-fluoro-2-deoxy-D-glucose (F-FDG or FDG) is the major radiotracer for PET and when combined with computed tomography (CT) scan allows for anatomic visualization of metabolically active malignancy. Novel radiotracers are being explored to delineate certain cell types and numerous tumor metrics including metabolism, hypoxia, vascularity, and cellular proliferation. This molecular and functional imaging will provide improved tumor characterization. Through these radiotracers, radiation plans can employ dose painting by creating different dose levels based upon specific risk factors of the target volume. Additionally, biologic imaging during radiotherapy can allow for adaptation of the radiation plan based on response to treatment. Dose painting and adaptive radiotherapy should improve the therapeutic ratio through more selective dose delivery. The novel PET-linear accelerator hopes to combine these techniques and more by using radiotracers to deliver BgRT. The areas of radiotracer uptake will serve as fiducials to guide radiotherapy to themselves. This technique may prove promising in the growing area of oligometastatic radiation treatment. CONCLUSIONS: Significant challenges exist for the future of PET-guided radiotherapy. However, with the advancements being made, PET imaging is set to change the delivery of radiotherapy.

Travel-Time Disparities in Access to Proton Beam Therapy for Cancer Treatment.

Importance: Proton beam therapy is an emerging radiotherapy treatment for patients with cancer that may produce similar outcomes as traditional photon-based therapy for many cancers while delivering lower amounts of toxic radiation to surrounding tissue. Geographic proximity to a proton facility is a critical component of ensuring equitable access both for indicated diagnoses and ongoing clinical trials. Objective: To characterize the distribution of proton facilities in the US, quantify drive-time access for the population, and investigate the likelihood of long commutes for certain population subgroups. Design, Setting, and Participants: This population-based cross-sectional study analyzed travel times to proton facilities in the US. Census tract variables in the contiguous US were measured between January 1, 2017, and December 31, 2021. Statistical analysis was performed from September to November 2023. Exposures: Drive time in minutes to nearest proton facility. Population totals and prevalence of specific factors measured from the American Community Survey: age; race and ethnicity; insurance, disability, and income status; vehicle availability; broadband access; and urbanicity. Main Outcomes and Measures: Poor access to proton facilities was defined as having a drive-time commute of at least 4 hours to the nearest location. Median drive time and percentage of population with poor access were calculated for the entire population and by population subgroups. Univariable and multivariable odds of poor access were also calculated for certain population subgroups. Results: Geographic access was considered for 327 536 032 residents of the contiguous US (60 594 624 [18.5%] Hispanic, 17 974 186 [5.5%] non-Hispanic Asian, 40 146 994 [12.3%] non-Hispanic Black, and 195 265 639 [59.6%] non-Hispanic White; 282 031 819 [86.1%] resided in urban counties). The median (IQR) drive time to the nearest proton facility was 96.1 (39.6-195.3) minutes; 119.8 million US residents (36.6%) lived within a 1-hour drive of the nearest proton facility, and 53.6 million (16.4%) required a commute of at least 4 hours. Persons identifying as non-Hispanic White had the longest median (IQR) commute time at 109.8 (48.0-197.6) minutes. Multivariable analysis identified rurality (odds ratio [OR], 2.45 [95% CI, 2.27-2.64]), age 65 years or older (OR, 1.09 [95% CI, 1.06-1.11]), and living below the federal poverty line (OR, 1.22 [1.20-1.25]) as factors associated with commute times of at least 4 hours. Conclusions and Relevance: This cross-sectional study of drive-time access to proton beam therapy found that disparities in access existed among certain populations in the US. These results suggest that such disparities present a barrier to an emerging technology in cancer treatment and inhibit equitable access to ongoing clinical trials.

A perspective on tumor radiation resistance following high-LET radiation treatment.

High-linear energy transfer (LET) radiation is a promising alternative to conventional low-LET radiation for therapeutic gain against cancer owing to its ability to induce complex and clustered DNA lesions. However, the development of radiation resistance poses a significant barrier. The potential molecular mechanisms that could confer resistance development are translesion synthesis (TLS), replication gap suppression (RGS) mechanisms, autophagy, epithelial-mesenchymal transition (EMT) activation, release of exosomes, and epigenetic changes. This article will discuss various types of complex clustered DNA damage, their repair mechanisms, mutagenic potential, and the development of radiation resistance strategies. Furthermore, it highlights the importance of careful consideration and patient selection when employing high-LET radiotherapy in clinical settings.

Safety and Tolerability of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy.

Importance: In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy. Objective: To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach). Design, Setting, and Participants: This cohort study included adults with solid tumors treated with a 1.5-T MR-Linac enrolled in Multi Outcome Evaluation for Radiation Therapy Using the MR-Linac (MOMENTUM), a large prospective international study of MRgRT between February 2019 and October 2021. Included were adults with solid tumors treated with a 1.5-T MR-Linac. Data were collected in Canada, Denmark, The Netherlands, United Kingdom, and the US. Data were analyzed in August 2023. Exposure: All patients underwent MRgRT using a 1.5-T MR-Linac. Radiation prescriptions were consistent with institutional standards of care. Main Outcomes and Measures: Patterns of care, tolerability, and technical feasibility (ie, treatment completed as planned). Acute high-grade radiotherapy-related toxic effects (ie, grade 3 or higher toxic effects according to Common Terminology Criteria for Adverse Events version 5.0) occurring within the first 3 months after treatment delivery. Results: In total, 1793 treatment courses (1772 patients) were included (median patient age, 69 years [range, 22-91 years]; 1384 male [77.2%]). Among 41 different treatment sites, common sites were prostate (745 [41.6%]), metastatic lymph nodes (233 [13.0%]), and brain (189 [10.5%]). ATS was used in 1050 courses (58.6%). MRgRT was completed as planned in 1720 treatment courses (95.9%). Patient withdrawal caused 5 patients (0.3%) to discontinue treatment. The incidence of radiotherapy-related grade 3 toxic effects was 1.4% (95% CI, 0.9%-2.0%) in the entire cohort and 0.4% (95% CI, 0.1%-1.0%) in the subset of patients treated with ATS. There were no radiotherapy-related grade 4 or 5 toxic effects. Conclusions and Relevance: In this cohort study of patients treated on a 1.5-T MR-Linac, radiotherapy was safe and well tolerated. Online adaptation of the radiation plan at each treatment session to account for anatomic variations was associated with a low risk of acute grade 3 toxic effects.

Fibroblast Activation Protein Inhibitor Tracers and Their Preclinical, Translational, and Clinical Status in China.

Quinoline-based fibroblast activation protein (FAP) inhibitors (FAPIs) have recently emerged as a focal point in global nuclear medicine, underscored by their promising applications in cancer theranostics and the diagnosis of various nononcological conditions. This review offers an in-depth summary of the existing literature on the evolution and use of FAPI tracers in China, tracing their journey from preclinical to clinical research. Moreover, this review also assesses the diagnostic accuracy of FAPI PET for the most common cancers in China, analyzes its impact on oncologic management paradigms, and investigates the potential of FAP-targeted radionuclide therapy in patients with advanced or metastatic cancer. This review also summarizes studies using FAPI PET for nononcologic disorders in China. Thus, this qualitative overview presents a snapshot of China's engagement with FAPI tracers, aiming to guide future research endeavors.

Recent Advances in Radiotracers Targeting Novel Cancer-Specific Biomarkers in China: A Brief Overview.

Radiopharmaceuticals play a critical role in nuclear medicine, providing novel tools for specifically delivering radioisotopes for the diagnosis and treatment of cancers. As the starting point for developing radiopharmaceuticals, cancer-specific biomarkers are important and receive worldwide attention. This field in China is currently experiencing a rapid expansion, with multiple radiotracers targeting novel targets being developed and translated into clinical studies. This review provides a brief overview of the exploration of novel imaging targets, preclinical evaluation of their targeting ligands, and translational research in China from 2020 to 2023, for detecting cancer, guiding targeted therapy, and visualizing the immune microenvironment. We believe that China will play an even more important role in the development of nuclear medicine in the world in the future.

Advances in personalized radiotherapy.

Radiotherapy is a mainstay of cancer treatment. The clinical response to radiotherapy is heterogeneous, from a complete response to early progression. Recent studies have explored the importance of patient characteristics in response to radiotherapy. In this editorial, we invite contributions for a BMC Cancer collection of articles titled 'Advances in personalized radiotherapy' towards the improvement of treatment response.

Imaging Assessment of Radiation Therapy-Related Normal Tissue Injury in Children: A PENTEC Visionary Statement.

The Pediatric Normal Tissue Effects in the Clinic (PENTEC) consortium has made significant contributions to understanding and mitigating the adverse effects of childhood cancer therapy. This review addresses the role of diagnostic imaging in detecting, screening, and comprehending radiation therapy-related late effects in children, drawing insights from individual organ-specific PENTEC reports. We further explore how the development of imaging biomarkers for key organ systems, alongside technical advancements and translational imaging approaches, may enhance the systematic application of imaging evaluations in childhood cancer survivors. Moreover, the review critically examines knowledge gaps and identifies technical and practical limitations of existing imaging modalities in the pediatric population. Addressing these challenges may expand access to, minimize the risk of, and optimize the real-world application of, new imaging techniques. The PENTEC team envisions this document as a roadmap for the future development of imaging strategies in childhood cancer survivors, with the overarching goal of improving long-term health outcomes and quality of life for this vulnerable population.

Radiation Dose-Volume-Response Relationships for Adverse Events in Childhood Cancer Survivors: Introduction to the Scientific Issues in PENTEC.

At its very core, radiation oncology involves a trade-off between the benefits and risks of exposing tumors and normal tissue to relatively high doses of ionizing radiation. This trade-off is particularly critical in childhood cancer survivors (CCS), in whom both benefits and risks can be hugely consequential due to the long life expectancy if the primary cancer is controlled. Estimating the normal tissue-related risks of a specific radiation therapy plan in an individual patient relies on predictive mathematical modeling of empirical data on adverse events. The Pediatric Normal-Tissue Effects in the Clinic (PENTEC) collaborative network was formed to summarize and, when possible, to synthesize dose-volume-response relationships for a range of adverse events incident in CCS based on the literature. Normal-tissue clinical radiation biology in children is particularly challenging for many reasons: (1) Childhood malignancies are relatively uncommon-constituting approximately 1% of new incident cancers in the United States-and biologically heterogeneous, leading to many small series in the literature and large variability within and between series. This creates challenges in synthesizing data across series. (2) CCS are at an elevated risk for a range of adverse health events that are not specific to radiation therapy. Thus, excess relative or absolute risk compared with a reference population becomes the appropriate metric. (3) Various study designs and quantities to express risk are found in the literature, and these are summarized. (4) Adverse effects in CCS often occur 30, 50, or more years after therapy. This limits the information content of series with even very extended follow-up, and lifetime risk estimates are typically extrapolations that become dependent on the mathematical model used. (5) The long latent period means that retrospective dosimetry is required, as individual computed tomography-based radiation therapy plans gradually became available after 1980. (6) Many individual patient-level factors affect outcomes, including age at exposure, attained age, lifestyle exposures, health behaviors, other treatment modalities, dose, fractionation, and dose distribution. (7) Prospective databases with individual patient-level data and radiation dosimetry are being built and will facilitate advances in dose-volume-response modeling. We discuss these challenges and attempts to overcome them in the setting of PENTEC.