Integrating Positron Emission Tomography Combined with Computed Tomography Imaging into Advanced Radiation Therapy Planning: Clinical Applications, Innovations, and Challenges

Abstract

Positron emission tomography combined with computed tomography (PET/CT) has revolutionized radiation oncology by merging functional and anatomical imaging to enhance tumor characterization, guide treatment precision, and support individualized patient care. This review critically evaluates the clinical applications of PET/CT-guided radiation therapy, highlighting its evolving impact, technical innovations, limitations, and future research directions. Key clinical uses – such as improved target delineation, adaptive therapy, and treatment response monitoring – are explored alongside the diagnostic performance of diverse radiotracers including 18F-fluorodeoxyglucose, prostate-specific membrane antigen-targeted agents, and hypoxia-specific probes. We examine advanced methodologies such as deformable image registration, radiomics, and artificial intelligence (AI)-driven segmentation for their potential to reduce interobserver variability and streamline radiotherapy (RT) workflows. The review also addresses persistent barriers, including limited tracer specificity, spatial resolution constraints, integration complexity, and high implementation costs. Beyond technical discussions, we reflect on emerging ethical considerations, such as transparency in AI-driven planning, patient consent in algorithm-assisted treatment decisions, and the need for equitable access to PET/CT technologies. We emphasize the importance of interdisciplinary collaboration and standardized imaging protocols to optimize clinical adoption. With continuous innovation and global access initiatives, PET/CT-guided RT is poised to play a leading role in shaping the future of precision oncology.

INTRODUCTION

Positron emission tomography combined with computed tomography (PET/CT) has profoundly transformed oncological imaging by integrating functional and anatomical information, thereby significantly enhancing tumor characterization, staging, and therapeutic response monitoring.[1,2] Initially developed primarily for tumor staging and evaluating treatment responses, PET/CT has evolved into an indispensable component of advanced radiation therapy planning. This powerful imaging modality provides critical metabolic and molecular tumor characteristics, which facilitates precise tumor delineation and individualized patient management.

Positron emission tomography (PET)-guided radiotherapy (RT) planning markedly improves tumor delineation accuracy, minimizing radiation exposure to healthy tissues, and contributes substantially to adaptive therapeutic strategies. The integration of PET imaging with conventional imaging techniques, including computed tomography (CT) and magnetic resonance imaging (MRI), allows sophisticated image fusion capabilities that significantly refine RT treatment precision. The availability of novel radiotracers beyond the conventional 18F-fluorodeoxyglucose (FDG) expands PET imaging’s applicability, offering more tumor-specific biological insights and facilitating more informed clinical decision-making.[3,4]

Despite substantial advancements, several notable challenges remain. These include variability in image registration methodologies, limited standardization of PET-based tumor contouring protocols, and disparities in accessibility to advanced radiotracers and hybrid imaging technologies. In addition, the increased application of artificial intelligence (AI) in tasks such as tumor segmentation and radiation dose prediction has introduced critical ethical and clinical considerations. Addressing these factors is crucial to ensuring the safe, ethical, and equitable integration of PET/CT into clinical RT practice.

This comprehensive review critically evaluates the evolving role of PET/CT in modern radiation oncology. We systematically explore key clinical applications of PET-guided radiation therapy, developments in radiotracer technology, state-of-the-art image fusion methodologies, and emerging AI-driven innovations. Furthermore, we discuss persistent barriers such as limited tracer specificity, spatial resolution constraints, complexity of technology integration, and high implementation costs. Beyond technical considerations, this review also highlights patient-centered ethical issues, including transparency in AI-driven decision-making, informed patient consent in algorithm-assisted therapy planning, and equitable access to advanced PET/CT technologies.

By providing a multidimensional perspective that encompasses clinical applications, technological innovations, and ethical considerations, this review aims to deliver a comprehensive understanding of the potential and limitations of PET-guided RT. This approach aligns with the broader goals of precision oncology, emphasizing interdisciplinary collaboration, standardized imaging protocols, and equitable global access to advanced imaging technologies. Ultimately, ongoing innovation and collaborative global efforts position PET/CT-guided RT as a pivotal element in future landscape of personalized cancer care.

THE EVOLVING ROLE OF POSITRON EMISSION TOMOGRAPHY COMBINED WITH COMPUTED TOMOGRAPHY IN RADIATION ONCOLOGY

Advancements in radiotracer development

The field of radiotracer development has significantly advanced beyond the commonly used 18F-FDG, which exploits the Warburg effect by detecting increased glucose metabolism in cancer cells. Newer tracers target diverse biological processes, substantially expanding the clinical utility of PET imaging. For example, radiotracers such as 11C-choline and 18F-fluoromethylcholine have improved visualization of lipid metabolism in malignancies, while 18F-fluciclovine enhances amino acid transport imaging, particularly for prostate cancer detection. Hypoxia-specific tracers like 18F-fluoromisonidazole (FMISO) identify radioresistant tumor regions, thereby guiding adaptive RT strategies. In addition, prostate-specific membrane antigen (PSMA)-targeted agents such as 68Ga-PSMA-11 have revolutionized prostate cancer imaging by detecting subclinical metastases and facilitating focused radiation boosts.[5,6] These tracer innovations exemplify a shift toward biologically adaptive RT, allowing treatment customization based on individual tumor biology rather than relying solely on anatomical imaging.

Clinical integration of positron emission tomography combined with computed tomography into radiotherapy workflows

PET/CT has become indispensable in contemporary RT by addressing significant limitations inherent to conventional CT-based imaging. Its primary clinical contribution is enhancing target delineation accuracy due to the metabolic contrast provided by PET. Research indicates that semi-automated PET segmentation tools reduce interobserver variability in tumor contouring by up to 40%, notably in anatomically complex regions such as the head and neck.[7] Moreover, adaptive RT approaches have evolved, utilizing serial PET/CT imaging to dynamically assess tumor response and facilitate real-time plan adjustments. For instance, negative interim PET scans in early-stage Hodgkin’s lymphoma are increasingly used to justify reducing radiation doses, effectively minimizing long-term toxicities without compromising treatment efficacy.[8] Hypoxia-guided planning, using tracers such as 18F-FMISO, further exemplifies PET/CT’s clinical value by enabling biologically targeted dose painting, concentrating radiation delivery on treatment-resistant tumor subvolumes.[9]

Ongoing challenges and strategic outlook

Despite the transformative potential of PET/CT-guided RT, several persistent challenges require resolution. First, variability in PET image interpretation, particularly distinguishing malignant from inflammatory FDG uptake, poses a risk of false-positive tumor delineation.[10] Second, technical challenges in integrating deformable image registration (DIR) and ensuring patient positioning accuracy necessitate rigorous quality assurance protocols and advanced software solutions.[11] Third, optimal timing and tracer selection remain subjects of ongoing debate, with experts deliberating the most effective scheduling for PET/CT scans – before, during, or after treatment – and validating tracer-specific protocols tailored to different tumor types and clinical objectives.[12] Addressing these integration challenges necessitates standardized acquisition protocols, improved software compatibility, and targeted training for radiation oncologists and medical physicists to maximize the clinical utility and precision of PET/CT in radiation therapy.

RADIOTRACER FOUNDATIONS AND INNOVATIONS IN POSITRON EMISSION TOMOGRAPHY-GUIDED RADIOTHERAPY

Fluorodeoxyglucose in oncology: Strengths, mechanisms, and clinical limitations

18F-FDG remains a cornerstone radiotracer in oncology PET imaging, primarily due to its effectiveness in identifying increased glucose metabolism characteristics of cancer cells (the Warburg effect). FDG is highly valuable in detecting malignancies such as cervical, colorectal, lung, esophageal, head-and-neck cancers, and lymphomas.[13,14] The mechanism involves FDG uptake through glucose transporters (GLUT-1 and GLUT-3), followed by phosphorylation by hexokinase, trapping it intracellularly without further metabolism.[15] However, clinical limitations include nonspecific uptake in inflammatory conditions, benign tissues, and normal physiological processes, potentially leading to false positives. In addition, FDG demonstrates limited effectiveness in imaging prostate cancers, neuroendocrine tumors, and sarcomas due to inherently low tracer uptake. Bladder artifacts caused by renal excretion can further complicate image interpretation.[16,17] These limitations have driven the development of alternative, more specific radiotracers.

FDG’s limitations have spurred the development of new tracers, which are summarized in Table 1.

Table 1.

Summarizing fluorodeoxyglucose’s advantages and limitations

Aspect	FDG-PET strengths	FDG-PET limitations
Sensitivity	High sensitivity in detecting metabolic activity	Limited specificity in inflammation/infection
Tumor identification	Effective for most cancers	Less effective in prostate cancer
Clinical utility	Guides treatment response	May miss well-differentiated tumors

Sodium 18F-fluoride for bone metabolism imaging

18F-sodium fluoride (18F-NaF), a Food and Drug Administration (FDA)-approved PET radiotracer, is highly sensitive for identifying bone metastases, particularly in prostate, lung, and breast cancers. It surpasses traditional 99mTc bone scans and FDG in detecting sclerotic metastatic lesions, playing a significant role in adaptive RT for metastatic bone disease.[18,19] However, its uptake reflects general osteoblastic activity rather than tumor-specific metabolism, limiting its specificity. Thus, 18F-NaF PET is best utilized when structural bone changes directly inform RT dose planning.

Amino acid and neuroendocrine imaging

Novel amino acid tracers, such as 18F-fluciclovine, have significantly advanced prostate cancer imaging, notably in biochemical recurrence scenarios. Compared to PSMA tracers, 18F-fluciclovine shows reduced urinary excretion, improving pelvic lesion visualization.[20,21] In addition, 18F-DOPA, approved initially for Parkinson’s disease imaging, has demonstrated utility in neuroendocrine tumors, particularly medullary thyroid carcinoma, highlighting the tracer’s versatility beyond neurological applications.[22]

Tumor-specific tracers: Prostate-specific membrane antigen, fibroblast activation protein inhibitor, and emerging agents

PSMA-targeted radiotracers, notably 68Ga-PSMA-11 and 18F-PSMA-1007, have dramatically improved prostate cancer imaging accuracy. These agents enhance metastatic lesion detection and support focal dose escalation in RT.[23,24] In addition, novel tracers targeting fibroblast activation protein (FAP), such as 68Ga-FAP inhibitor (FAPI), provide superior tumor-to-background contrast, especially beneficial in desmoplastic tumors such as pancreatic, breast, and head-and-neck cancers.[25] Hybrid PET/MRI further complements tracer specificity, particularly benefiting soft-tissue imaging and treatment personalization through advanced radiomics and AI-driven analysis.[26]

Choline tracers for lipid metabolism imaging

Choline-based PET tracers, including 11C-choline and fluorinated derivatives like 18F-fluoroethylcholine and 18F-fluorocholine, have historically facilitated prostate cancer imaging. Although increasingly superseded by PSMA tracers, choline PET remains valuable where lipid metabolism imaging can refine radiation therapy targeting or dose modulation.[27,28]

Ligand-specific and hormonal tracers

Ligand-specific tracers, such as somatostatin receptor-targeting agents (68Ga-DOTATATE, 68Ga-DOTATOC), are instrumental in neuroendocrine tumor imaging due to their high specificity and sensitivity.[29,30] Hormone receptor-specific tracers, notably 18F-fluoroestradiol, have gained FDA approval for guiding endocrine therapy in estrogen receptor-positive breast and ovarian cancers, especially when biopsy procedures are challenging.[31]

Hypoxia, apoptosis, and immune positron emission tomography imaging

Hypoxia-specific tracers such as 18F-FMISO and ¹⁸F-fluoroazomycin arabinoside (18F-FAZA) significantly aid in identifying radioresistant tumor areas, enabling targeted dose painting and adaptive RT.[32,33] Apoptosis-imaging tracers (e.g., 18F-Annexin V and 18F-ICMT-11) offer noninvasive assessment of early therapy response by distinguishing apoptotic from necrotic tissue, potentially minimizing unnecessary toxicity through early therapeutic adjustments. Immuno-PET tracers targeting immune checkpoint molecules or FAPs (e.g., 68Ga-FAPI) further provide insights into tumor microenvironment (TME) interactions, guiding combined RT and immunotherapy strategies.[34]

EXPANDING RADIOTRACER HORIZONS IN PRECISION RADIOTHERAPY

Targeting DNA synthesis and cellular proliferation

Radiotracers targeting DNA synthesis, such as 18F-fluorothymidine (18F-FLT), are becoming increasingly significant due to their specificity in marking cellular proliferation. Unlike FDG, which reflects metabolic activity, 18F-FLT is directly incorporated into the DNA synthesis pathway, making it a precise marker for identifying active tumor cell division. This specificity has proven particularly valuable in evaluating early treatment responses and adapting RT regimens in cancers such as gliomas and head-and-neck malignancies, where rapid cellular proliferation is indicative of aggressive tumor behavior.[35]

Imaging tumor angiogenesis

Tumor angiogenesis, essential for cancer growth and metastasis, has become a critical imaging target. PET tracers that bind to angiogenesis markers such as vascular endothelial growth factor receptors and integrins like αvβ3 provide insight into tumor vascularity and aggressiveness. Radiotracers such as 68Ga-NODAGA-RGD specifically target αvβ3 integrins, aiding in identifying highly vascularized tumors. Incorporating angiogenesis imaging into radiation therapy planning facilitates dose intensification strategies, particularly beneficial in aggressive tumor types requiring focused therapeutic interventions.[36]

Hypoxia-responsive dose painting with emerging tracers

While established hypoxia tracers such as 18F-FMISO and 18F-FAZA have significantly contributed to identifying hypoxic regions resistant to RT, newer agents such as 18F-HX4 offer improved pharmacokinetics and clearer delineation of hypoxic areas. These advances support sophisticated dose painting techniques, where radiation doses are dynamically adjusted at the voxel level based on hypoxia imaging. This approach is especially promising for tumors such as head-and-neck cancers, cervical carcinomas, and non-small cell lung cancer (NSCLC), known for containing challenging hypoxic regions.[37]

Apoptosis and therapy response monitoring

Innovative PET tracers such as 18F-Annexin V and 18F-ICMT-11 are designed to detect apoptotic cell death, providing critical information for assessing therapeutic effectiveness noninvasively. These tracers can differentiate between actively treated tumor tissue and necrotic or residual cancerous regions, allowing early adaptation of RT protocols. The ability to rapidly and accurately evaluate therapy response can significantly reduce unnecessary treatment-related toxicity and optimize therapeutic outcomes.[38]

Immuno-positron emission tomography and microenvironmental targeting

Immuno-PET tracers have emerged as powerful tools for visualizing the TME, particularly in the context of combined RT and immunotherapy strategies. Monoclonal antibody-based tracers such as 89Zr-labeled anti-PD-L1 provide detailed spatial maps of immune checkpoint expression within tumors, enabling targeted and personalized immunoradiotherapy. This capability is particularly advantageous in tumors with heterogeneous immune infiltration, offering clinicians the ability to tailor treatments to patient-specific tumor biology.[39]

Fibroblast activation protein imaging and tumor microenvironment assessment

FAPI tracers, notably 68Ga-FAPI and 18F-FAPI, have gained attention for their remarkable ability to visualize cancer-associated fibroblasts (CAFs), crucial elements within the tumor stroma. These tracers provide superior contrast in imaging desmoplastic tumors, significantly enhancing target delineation accuracy in RT planning. FAPI imaging is particularly promising for refining radiation treatments in cancers with substantial stromal involvement, such as pancreatic, breast, and head-and-neck malignancies, facilitating precision oncology.[40]

TRANSLATIONAL IMPACT OF POSITRON EMISSION TOMOGRAPHY TRACERS IN RADIATION THERAPY PLANNING AND ADAPTATION

Enhancing tumor characterization and volume definition

Recent advancements in PET radiotracers have significantly reshaped radiation therapy planning and delivery. By incorporating functional imaging that assesses tumor proliferation, hypoxia, and apoptosis, radiation oncologists can now develop biologically adapted treatment plans. Tracers such as 18F-FMISO and 18F-FAZA have become central in hypoxia imaging, enabling precise dose modulation strategies like dose painting to target radioresistant regions effectively. In addition, apoptosis-specific PET tracers offer real-time insights into therapeutic efficacy, allowing clinicians to adjust treatments dynamically, reducing unnecessary toxicity, and optimizing patient outcomes.[41,42]

Mapping the tumor microenvironment for combination therapies

PET imaging extends beyond tumor tissue itself, also mapping nontumoral components of the TME, which critically influence treatment efficacy. Radiotracers like 68Ga-FAPI provide superior imaging of CAFs, revealing stromal involvement in fibrotic tumors. This stromal imaging capability is invaluable for informing combination treatment strategies, particularly immunotherapy combined with RT. Immuno-PET tracers, including those targeting T-cell activity or immune checkpoint molecules, further facilitate personalized immunoradiotherapy strategies in refractory solid tumors.[43]

Adjusting therapy plans based on functional imaging

The real-time integration of PET imaging into RT workflows has transformed the traditional static treatment approach into a more dynamic, adaptive process. For instance, PSMA-targeted PET tracers have revolutionized prostate cancer treatment planning by enabling substantial therapeutic adjustments in patients experiencing biochemical recurrence. These adjustments include expanding target coverage, focal dose escalation to PSMA-positive sites, or omitting previously assumed metastatic regions. Moreover, PET-guided delineation has significantly refined gross tumor volume definition across diverse cancers, enhancing targeting precision and sparing normal tissues from unnecessary exposure.[44]

Adaptive radiotherapy: Toward responsive oncology

PET imaging also plays a pivotal role in the emerging adaptive RT paradigm, characterized by ongoing modifications to treatment based on serial or interim PET scans. This approach allows clinicians to observe evolving tumor biology during treatment, adjusting doses, target volumes, or treatment intensity in response to early signs of progression or response. PET-derived functional imaging biomarkers increasingly support predictive models, enabling clinicians and patients to align therapy intensity with individual disease progression risks. This strategy particularly benefits tumors with rapid responses, such as lymphomas and aggressive head-and-neck malignancies, driving forward the concept of truly personalized oncology.[45]

CHALLENGES IN COMBINING POSITRON EMISSION TOMOGRAPHY IMAGES FOR CANCER TREATMENT PLANNING

Limitations of rigid registration and the role of deformable image registration

Accurate integration of functional PET imaging with anatomical modalities such as CT and MRI is critical for precise RT planning. However, rigid image registration methods, commonly used due to their simplicity, frequently encounter difficulties in accurately aligning images from different modalities, especially in regions exhibiting significant motion or deformation. To overcome this, DIR methods have emerged, offering improved accuracy by providing voxel-level adaptation to anatomical changes. DIR significantly enhances spatial accuracy in tumor localization, especially valuable in head-and-neck and thoracic cancers where anatomical shifts are common due to respiration or tumor shrinkage during treatment. Nonetheless, DIR requires rigorous validation and quality assurance, as inaccuracies could lead to errors in treatment delivery.[46,47]

Positron emission tomography/magnetic resonance imaging integration and the challenge of synthetic computed tomography

While PET/MRI provides excellent soft-tissue contrast and functional imaging capabilities, particularly beneficial for neurological, pediatric, and pelvic malignancies, it poses a unique challenge in RT planning due to the absence of direct electron density information required for accurate dose calculations. Synthetic CT (sCT) generation techniques, using deep learning algorithms to predict CT-equivalent densities from MRI images, have emerged as a promising solution. Recent studies demonstrate that sCT models achieve comparable accuracy to traditional CT-based planning. However, widespread clinical adoption of these techniques requires extensive validation across different anatomical sites and imaging protocols to ensure their robustness and accuracy.[48] Figure 1 illustrates the workflow integrating PET/CT, PET/MRI, and MRI in RT planning. It highlights the critical steps involved, such as RT immobilization, treatment positioning, image registration, generation of pseudo-CT from MRI sequences, and the subsequent dose calculation and treatment execution. The diagram emphasizes the importance of cross-modality image fusion and the adaptation of imaging protocols to ensure precision in tumor targeting and radiation dose delivery.

Figure 1.

Schematic workflow depicting the integration of positron emission tomography (PET)/magnetic resonance imaging (MRI), PET/computed tomography (CT), and MRI into radiotherapy treatment planning. Arrows demonstrating the image registration process and the flow from image acquisition to planning CT, synthetic pseudo-CT creation, and the final treatment planning phase. The figure emphasizes the critical role of image fusion and modality-specific preparation in optimizing radiation therapy. PET: Positron emission tomography, CT: Computed tomography, MRI: Magnetic resonance imaging

Harmonization of protocols and multicenter consistency

A significant challenge to effective PET-guided RT planning is the variability in imaging protocols, image registration methods, and software across different institutions. These inconsistencies can significantly affect tumor delineation accuracy and ultimately impact patient outcomes. To address this, international bodies such as the European Association of Nuclear Medicine (EANM) and the International Atomic Energy Agency (IAEA) have proposed standardized protocols and guidelines. Adherence to these standardized procedures is crucial for ensuring the consistency, reliability, and reproducibility of PET-guided radiation therapy, especially important in multicenter clinical trials and international research collaborations.[49]

Addressing these challenges through ongoing research, standardized training, and robust quality control protocols is essential for realizing the full potential of PET imaging in precision oncology.

TOWARD PERSONALIZED ONCOLOGY: POSITRON EMISSION TOMOGRAPHY-DRIVEN INNOVATION IN RADIOTHERAPY

Radiation oncology is progressively shifting toward personalized medicine through the integration of advanced PET tracers, sophisticated radiomics, and AI techniques. These innovations allow oncologists to transition beyond purely anatomical imaging, employing biological and functional markers for more precise and tailored treatment plans.

Hypoxia imaging using PET tracers such as 18F-FMISO and 18F-FAZA has proven valuable in identifying radioresistant tumor regions, enabling targeted radiation dose escalation – commonly known as dose painting – which has demonstrated improved local control rates, particularly in challenging tumors such as head-and-neck cancers. Similarly, apoptosis-specific PET tracers provide insights into early treatment responses, facilitating dynamic adaptations in therapy that help avoid overtreatment and reduce patient toxicity.[50,51]

The advent of immune-PET tracers, notably 68Ga-FAPI, targeting FAPs, has significantly advanced the imaging of the TME. These tracers provide critical insights into immunosuppressive regions within tumors, enhancing combined immunoradiotherapy strategies. Such integration has shown promise in optimizing therapeutic synergy between RT and immunotherapy in tumors resistant to conventional therapies.[52]

Concurrently, radiomics and machine learning technologies are revolutionizing PET interpretation by extracting quantitative imaging features, including texture, intensity, and shape characteristics. These features enhance predictive modeling of treatment outcomes, risk stratification, and individualized dosing strategies. AI-driven radiomics analyses have notably improved the accuracy of tumor segmentation, dose prediction, and treatment response evaluation, significantly influencing personalized treatment planning.[38]

Deep learning models, particularly convolutional neural networks, are now extensively employed to automate tumor contouring and enhance PET image reconstruction, significantly reducing manual labor, variability, and planning time. However, integrating AI technologies into clinical practice introduces challenges concerning interpretability, robustness, and external validation. Ethical considerations related to patient consent, data privacy, and algorithmic transparency also need to be rigorously addressed to ensure ethical and equitable use.[39,53]

The integration of innovative PET tracers, sophisticated image analysis methods, and AI-driven personalization represents a transformative step toward responsive, biologically informed RT. Future research and clinical efforts must continue focusing on tracer validation, development of explainable AI tools, and equitable access to these advanced technologies, ensuring precision oncology’s continued evolution and improved patient outcomes globally.

CLINICAL APPLICATIONS OF POSITRON EMISSION TOMOGRAPHY IMAGING ACROSS TUMOR TYPES

Lymphomas

PET/CT imaging plays a critical role in managing lymphomas, particularly Hodgkin’s and non-Hodgkin’s lymphomas. Interim PET scans have become essential for response-adapted treatment approaches, significantly influencing therapeutic decision-making. Early PET negativity allows clinicians to safely omit or reduce radiation exposure, minimizing long-term treatment-related toxicities, especially crucial for younger patients.[54]

Esophageal and gastrointestinal tumors

PET imaging markedly improves the management of esophageal and gastrointestinal malignancies by enhancing occult lymph node involvement detection and refining tumor delineation. PET’s ability to differentiate active tumor tissue from inflammatory changes substantially improves local tumor control, reduces marginal misses, and optimizes RT planning.[55]

Lung cancer

In NSCLC, PET imaging significantly contributes to accurate lymph node staging and improved tumor delineation. It effectively distinguishes viable tumor tissue from nonmalignant conditions such as atelectasis or fibrosis, enabling targeted radiation dose escalation and adherence to dose constraints for critical thoracic structures, ultimately improving therapeutic outcomes.[56]

Central nervous system tumors

Advanced PET tracers, including 18F-FET and 11C-MET, provide superior discrimination between tumor recurrence and radiation-induced necrosis compared to conventional MRI. This enhanced diagnostic accuracy facilitates optimal re-irradiation strategies, minimizes neurologic toxicity, and guides precise radiation therapy adjustments for central nervous system malignancies.[57]

Prostate cancer

PSMA-targeted PET imaging, particularly with tracers such as 68Ga-PSMA-11, has substantially transformed prostate cancer management, especially in biochemical recurrence cases. PET-guided imaging allows precise delineation of salvage RT targets and supports focal boosting strategies, significantly improving therapeutic accuracy and patient outcomes.[58,59]

Head-and-neck malignancies

Hypoxia PET imaging using tracers like 18F-FAZA enhances head-and-neck cancer treatment by enabling functional dose painting strategies. Targeting hypoxic, radiation-resistant tumor subvolumes with higher radiation doses while sparing critical adjacent organs reduces treatment toxicity and improves tumor control, demonstrating PET imaging’s vital role in personalized RT.[60]

OPERATIONAL AND ETHICAL CONSIDERATIONS IN POSITRON EMISSION TOMOGRAPHY-GUIDED RADIOTHERAPY

Infrastructure and access gaps

Despite PET-guided RT becoming commonplace in developed countries, significant disparities persist globally, particularly in low- and middle-income countries. Barriers include limited access to cyclotrons, insufficient availability of specialized radiotracers, and the high financial costs associated with PET/CT technologies. Innovative solutions such as centralized PET services, international radiotracer distribution networks, and AI-enabled cloud platforms are emerging as viable options to bridge these access gaps, ensuring broader equitable implementation of advanced RT worldwide.[61]

Quality control and protocol standardization

Variability in image registration methodologies and tumor contouring techniques significantly hampers the reliability of PET-based RT planning. The lack of standardized acquisition protocols, fusion algorithms, and observer training can lead to inconsistent results and diminished comparability across institutions. International bodies, including the EANM and the IAEA, have outlined comprehensive guidelines emphasizing uniformity and consistency in PET imaging practices. Adherence to these guidelines is critical for achieving robust, reproducible PET-guided RT outcomes, especially in multicenter clinical trials and collaborative research settings.[62]

Ethical use and clinical justification

Given the inherent radiation exposure and substantial associated costs, the clinical use of PET imaging must be carefully justified based on clear medical necessity and demonstrated clinical benefit. The integration of AI into PET imaging processes introduces additional ethical considerations, particularly concerning patient consent, data privacy, and the transparency of decision-making algorithms. Clinicians have an ethical obligation to ensure that patients fully understand how AI algorithms influence their treatment planning and outcomes. Robust regulatory frameworks and interdisciplinary collaboration between clinicians, researchers, and policymakers are necessary to uphold ethical standards and ensure safe, effective, and equitable clinical practice.[63]

CONCLUSION

PET has become integral to modern radiation oncology, facilitating a paradigm shift from anatomy-based to biology-driven RT. Through advancements in radiotracer diversity, sophisticated image fusion techniques, and AI-powered analytics, PET imaging significantly enhances tumor targeting precision, adaptive dose modulation, and treatment response evaluation.

Clinically, PET-guided RT has improved outcomes across various malignancies, including lymphomas, gliomas, prostate, lung, and head-and-neck cancers, by enabling precise treatment volume delineation and reducing normal tissue toxicity. Innovations such as hypoxia-targeting tracers, PSMA agents, and immune-PET tracers further support personalized dose escalation strategies, preserving organ function and improving local tumor control rates.

However, critical challenges remain. Unequal global access to advanced PET technologies, inconsistent imaging workflows, and limited validation of AI-driven methodologies continue to hinder broader adoption. Addressing these barriers requires interdisciplinary collaboration, ongoing training and education, robust regulatory oversight of AI applications, and global efforts to standardize imaging protocols and quality control procedures.

Future research should emphasize:

• Validation and clinical implementation of emerging PET tracers

• Development of explainable, standardized AI tools

• Expanding cost-effective solutions to improve global PET accessibility

• Comprehensive education and training programs on functional imaging and AI ethics.

By addressing these strategic priorities, PET-guided RT will continue to evolve, significantly contributing to precision oncology’s advancement, promoting equitable global access, and ultimately improving patient outcomes worldwide.

Ethical statement

This study did not involve human participants or animal subjects and therefore did not require ethical approval. All data and literature referenced in this review are from publicly available sources.

Data availability

All data supporting the findings of this review are included within the manuscript. Additional datasets or referenced materials are publicly accessible through the sources cited in the references section.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.