Theranostics in Radiation Medicine: Radiopharmaceutical Therapy and Patient-Specific Integration with External-Beam Radiotherapy

1. Introduction

Theranostics links diagnosis and therapy through a shared molecular target, a matched or closely related radiopharmaceutical, and an imaging signal that can guide treatment decisions. In oncology, the concept has become clinically evident through SSTR-directed PRRT for neuroendocrine tumors, PSMA-directed radioligand therapy for prostate cancer, radioiodine for differentiated thyroid cancer, iobenguane for PPGL, and bone-seeking or liver-directed radionuclide therapies. The unique advantage is not simply that radioactive drugs treat cancer, but that biologic targeting and serial imaging allows the radiation dose distribution to be at least partly measurable in each patient [1,2,3,4,5,6]. This is important for radiation medicine because RPT is increasingly being used before, after, or during EBRT. These two distinct modalities have different, but complementary strengths for improved treatment efficacy. EBRT provides geometrically localized treatment to the tumor with high conformity while RPT offers systemic therapy through a biologically distributed intervention that can reach multifocal disease, microscopic disease, or anatomically difficult targets when sufficient target uptake exists. The combined strategy is therefore attractive when the modalities solve different parts of the same clinical problem, such as diffuse intrahepatic tumor plus a dominant lesion, recurrent head and neck cancer near dose-limited structures, pelvic or metastasis-directed treatment in prostate cancer, or SSTR-positive meningioma adjacent to critical neural structures [7,8,9,10,11,12].

The main challenge is that RPT and EBRT cannot be combined reasonably by absorbed dose alone. RPT absorbed dose is governed by biodistribution, residence time, target density, clearance, particle range, and microdistribution. EBRT dose is governed by beam arrangement, fractionation, image guidance, setup uncertainty, and planned target geometry. Combination planning must therefore distinguish three related but distinct questions: (1) where energy was deposited, (2) what biologic effect it is expected to produce, and (3) how the EBRT plan should be adapted for desirable outcomes during the treatment course. [5,6,7,8,9,10,11,12].

In this narrative review first, we focus on the current theranostic radiopharmaceutical development, clinical translation, and combination planning and cumulative dosimetry for RPT-EBRT. The emphasis is on the clinical and dosimetric relevance: the inclusion criteria are patient selection, quantitative imaging, RPT absorbed dose, biologic dose conversion, EBRT adaptation, organ-at-risk risk assessment, or multidisciplinary implementation. Throughout this review we use RPT as the preferred term for therapeutic radiopharmaceutical delivery, while acknowledging that molecular radiotherapy, radionuclide therapy, targeted radionuclide therapy, PRRT, radioembolization, and radioligand therapy remain common in disease-specific communities. The term theranostics is used broadly to denote a paired diagnostic-therapeutic strategy based on a shared target or pharmacologic behavior, not necessarily an identical chemical structure.

2. Molecular and Radiopharmaceutical Foundations

Most theranostic radiopharmaceuticals combine three functional components: a targeting vector, a radionuclide, and a linker or chelator that determines labeling stability and in vivo behavior. The targeting vector may be a small molecule, peptide, antibody, antibody fragment, transporter substrate, nanoparticle, or microsphere. The radionuclide determines photon or positron imaging properties, emission type, half-life, particle range, and dosimetric feasibility. Clinical performance depends on the integrated pharmacology of the entire construct, not on target expression alone [1,2,3,4].

Diagnostic radionuclides are selected for image quality, logistics, and quantitative reliability; therapeutic radionuclides are selected for dose delivery and radiobiologic effect. Beta emitters such as Lu-177, Y-90, and I-131 provide crossfire over millimeter-scale distances and can compensate partly for heterogeneous uptake. Alpha emitters such as Ra-223 and Ac-225 deliver high-LET radiation over short ranges 40-100 micrometer, about 2 to 10 cell diameters wide) and may be advantageous for micrometastatic or cell-cluster disease when uptake is adequate. Auger and conversion electrons, including those from Tb-161, have very short path lengths (0.5 to 30 micrometers) and may provide cell-level intensification when intracellular localization is favorable [1,2,3,4,24,25,26,27,28,29,30,31].

A positive theranostic scan should not be reduced to a binary interpretation. Uptake intensity, lesion-to-background ratio, intrapatient heterogeneity, target-negative discordant lesions, tumor volume, renal or salivary uptake, marrow reserve, previous systemic therapy, and prior EBRT all influence the therapeutic index. The modern theranostic question is therefore: can enough tumor dose be delivered safely in this patient, and what additional local radiation, if any, remains necessary? [5,6,13,14,15,16,17,18,19,20,21,22,23]

3. Established Clinical Platforms

3.1. SSTR-Directed PRRT

SSTR-directed PRRT is a leading proof of principle for therapeutic theranostics. In the NETTER-1 trial, patients with progressive metastatic midgut neuroendocrine tumors treated with Lu-177-DOTATATE plus standard-dose octreotide had an estimated 20-month progression-free survival of 65.2%, compared with 10.8% with high-dose octreotide, and an objective response rate of 18% versus 3% [13]. Final NETTER-1 follow-up showed numerically longer median overall survival with Lu-177-DOTATATE, although the comparison was affected by crossover and subsequent therapies [14]. Regulatory approval of Lu-177-DOTATATE made SSTR imaging a practical gate to systemic radiopharmaceutical therapy [15].

The SSTR platform is also instructive for combination planning. Patients may have widespread receptor-positive disease treated systemically, while a dominant lesion, threatened spinal canal, painful bone metastasis, or organ-compromising mass may still require EBRT. Conversely, patients who have had previous EBRT may need PRRT dosimetry to avoid excessive marrow, kidney, or organ-at-risk exposure. For these reasons, PRRT should be understood as part of a radiation continuum rather than as an isolated nuclear medicine administration [5,6,13,14,15].

3.2. PSMA-Directed Radioligand Therapy

PSMA-directed theranostics has transformed advanced prostate cancer management. In VISION trial, there was a significant improvement in the overall survival in the patients who received 177Lu-PSMA-617 and standard care compared to standard care alone (15.3 months vs. 11.3 months with PSMA-positive metastatic castration-resistant prostate cancer after androgen receptor pathway inhibition and taxane chemotherapy [16]. PSMAfore moved the platform earlier, demonstrating improved radiographic progression-free survival compared with changing androgen receptor pathway inhibitor therapy in taxane-naive patients after one prior androgen receptor pathway inhibitor [17]. In 2025, the U.S. Food and Drug Administration expanded the indication for Lu-177-vipivotide tetraxetan to adults with PSMA-positive mCRPC previously treated with an androgen receptor pathway inhibitor and considered appropriate to delay taxane chemotherapy [18]. Health-related quality-of-life and pain analyses support the practical relevance of this earlier-line positioning [19].

For radiation medicine, PSMA is especially important because imaging can be used at several decision points: staging, EBRT target delineation, selection for RPT, assessment of target-negative disease, response evaluation, and planning of metastasis-directed EBRT. The same patient may receive pelvic EBRT, prostate-bed salvage EBRT, stereotactic treatment to oligometastases, and systemic PSMA RPT over the disease course. Cumulative organ at risk (OAR) doses to marrow, salivary, renal, and lesion-level dose therefore become clinically relevant as RPT moves into earlier lines with longer expected survival [16,17,18,19,51,52,53].

3.3. Radioiodine and Transporter-Based Theranostics

Radioiodine remains the prototype clinical theranostics. Diagnostic iodine imaging, thyroglobulin trends, post-therapy scans, and clinical risk factors guide differentiated thyroid cancer treatment across remnant ablation, adjuvant therapy, surveillance, and metastatic disease management. Modern innovation has not displaced this paradigm; rather, it has renewed it through redifferentiation strategies intended to restore iodine uptake in selected radioiodine-refractory tumors [20,21].

Transporter-based theranostics also includes high-specific-activity I-131-iobenguane for MIBG-avid unresectable or metastatic PPGL. FDA approval was supported by a phase 2 experience in which durable reduction in antihypertensive medication burden and radiographic responses occurred in a subset of patients [22,23]. From a radiation-planning perspective, these therapies illustrate a general principle: a biologic uptake mechanism can define the therapeutic field more accurately than anatomy alone, but the delivered dose remains patient-specific and must be interpreted alongside marrow and normal-organ tolerance.

3.4. Bone-Targeted and Alpha-Emitting Therapy

Ra-223 dichloride established the survival relevance of an alpha-emitting bone-targeted therapy in metastatic prostate cancer with symptomatic bone metastases [24]. Alpha emitters have since expanded into targeted constructs such as Ac-225-PSMA ligands and antibodies, with early clinical studies and multicenter retrospective data showing activity in heavily pretreated mCRPC while also highlighting toxicity challenges such as xerostomia and marrow suppression [25,26,27].

The appeal of alpha therapy in combined-modality radiation medicine is its high-LET, short-range energy deposition. This may complement EBRT in microscopic or marrow-sparing settings, but it also makes microdistribution decisive. Unlike photon EBRT, a uniform organ mean dose may poorly represent cellular hit probability for short-range particles. The field therefore needs not only organ-level absorbed-dose reporting, but also radiobiologic models that can relate uptake pattern, particle range, repair, and toxicity to clinical decisions [24,25,26,27,36,37,38,39,40,41,42,43,44,45].

4. Emerging Theranostic Platforms

FAP-targeted ligands have attracted substantial interest because fibroblast activation protein is expressed in cancer-associated fibroblasts across many solid tumors. Early FAP-targeted RPT experiences, including Lu-177-EB-FAPI in metastatic radioiodine-refractory thyroid cancer and first-in-human FAPI-XT studies, suggest feasibility while underscoring the need for durable tumor retention and normal-tissue safety data [28,29]. These agents are especially relevant to EBRT integration because many FAP-avid tumors are anatomically complex, locally advanced, or previously irradiated.

Terbium radionuclides provide a compelling theranostic concept because different isotopes can support PET, SPECT, beta, alpha, and Auger-like therapeutic applications. Tb-161 is particularly interesting as a beta and conversion/Auger electron emitter; early PSMA-targeted clinical data suggest feasibility and motivate further dose-effect work [30,31]. Nanoparticle and supramolecular radiopharmaceuticals add another layer of design control by altering circulation, multivalency, clearance, and payload delivery [32,33]. Their value for combined RPT-EBRT care will depend on whether these engineering advantages translate into predictable tumor dose, controllable normal-organ exposure, and feasible quantitative imaging.

Table 1 summarizes representative theranostic pairs and radiation-medicine integration issues.

5. Dosimetry: From Administered Activity to Absorbed Dose

Administered activity is not equal to absorbed dose. Patient-specific RPT dosimetry requires quantitative imaging, calibration, activity recovery correction, time-activity modeling, absorbed-dose calculation, and uncertainty evaluation. Quantitative SPECT/CT and PET/CT are essential because most clinically relevant therapeutic distributions are heterogeneous across organs, lesions, and substructures [5,6,32,33,34,35].

From multi-time point imaging, RPT absorbed dose rate $\dot{D}\left(rT,t\right)$and absorbed dose to a specific target organ (r_T) can be obtained using the following equations

Absorbed dose rate per time point

$$\dot{D}\left(rT,t\right)=\sum _{rS}A\left(rS\right).S(rT\leftarrow rS)$$

Absorbed dose

$$D\left(rT\right)={\displaystyle \underset{0}{\overset{\infty }{\int }}}\dot{D}\left(rT,t\right)dt$$

where, $A\left(rS\right)$ is cumulative activity in the source organ, $S(rT\leftarrow rS)$ is the S-value for a given source and target organ pair, t is time.

The practical burden in obtaining absorbed dose in RPT is nontrivial. Multi-time-point imaging provides more robust time-integrated activity than single-time-point methods, but it increases patient inconvenience, camera use, staffing demands, and costs. Recent work has therefore focused on workflow simplification, including optimized sparse imaging schedules, two-time-point methods, population pharmacokinetic approaches, and artificial intelligence-assisted segmentation or prediction [32,33,34,35,61,62,63]. These methods should not be treated as interchangeable: each has assumptions that must be validated for the isotope, agent, tumor type, scanner, reconstruction protocol, and endpoint of interest.

For EBRT integration, the dose map must be placed into the treatment-planning geometry. This step includes rigid and, where appropriate, deformable registration of post-therapy SPECT/PET/CT to the EBRT planning CT or MRI, contour harmonization, dose-grid resampling, and quality assurance by a physicist familiar with both modalities. The most important planning question should drive the level of sophistication. If the question is whether liver mean dose remains within a conservative normal-tissue limit, structure-level dosimetry may suffice. If the question is whether RPT dose replaces EBRT fractions near the spinal cord, optic pathway, salivary gland, brainstem, or mucosa, voxel-level methods and more explicit uncertainty analysis are needed [8,9,10,11,12,46,47,48,49,50].

6. Radiobiology of EBRT and RPT

EBRT and RPT share the same absorbed dose, but they do not share the same temporal, spatial, or microscopic exposure pattern. EBRT usually delivers high dose-rate fractions over minutes, separated by hours or days for repair and normal-tissue recovery. RPT often delivers continuously over hours to days as radionuclides decay and biologic clearance changes local activity. The total dose-rate history may vary across lesions and organs in the same patient [8,9,10,11,12,36,37,38,39,40,41].

The linear-quadratic model remains the most common framework for translating dose and fractionation into biologic effect. For conventional EBRT, a simplified expression is

$$BED=nd\left(1+{\displaystyle \frac{d}{\raisebox{1ex}{$\alpha $}\!\left/ \!\raisebox{-1ex}{$\beta $}\right.}}\right)$$

where n is number of fractions, d is dose per fraction, and α/β reflects tissue- or tumor-specific fractionation sensitivity. For protracted RPT, a simplified biologic expression is

$$BED=D\left(1+{\displaystyle \frac{G(\infty )}{\raisebox{1ex}{$\alpha $}\!\left/ \!\raisebox{-1ex}{$\beta $}\right.}}D\right)$$

where D is absorbed dose and G is a repair-weighting term that depends on the dose-rate history and repair half-time. Equivalent 2-Gy fraction (EQD2) for RPT and EBRT can be expressed by the following equations

$$EQD2RPT={\displaystyle \frac{DRPT\left(\raisebox{1ex}{$\alpha $}\!\left/ \!\raisebox{-1ex}{$\beta $}\right.+G\left(\infty \right).DRPT\right)}{\raisebox{1ex}{$\alpha $}\!\left/ \!\raisebox{-1ex}{$\beta $}\right.+2}}$$

$${EQD2}_{EBRT}=D_{EBRT}.{\displaystyle \frac{\raisebox{1ex}{$\alpha $}\!\left/ \!\raisebox{-1ex}{$\beta $}\right.+d_{EBRT}}{\raisebox{1ex}{$\alpha $}\!\left/ \!\raisebox{-1ex}{$\beta $}\right.+2}}$$

These formulas are useful only when assumptions are explicit and clinically meaningful [8,9,10,11,12].

Many factors affect the above equations. First, α/β values used in EBRT are often extrapolated from photon fractionation data and may not capture RPT-specific biology. Second, LET and particle range influence DNA damage complexity and cellular distribution. Third, tumor and normal tissue receive nonuniform dose at voxel and subvoxel scales. Fourth, repair can occur during protracted irradiation. Fifth, the same organ mean dose may have different implications depending on which substructures or stem-cell compartments are irradiated. For these reasons, biologic conversion should be performed to answer a decision-relevant question, not as a decorative transformation applied after the fact [36,37,38,39,40,41,42,43,44,45].

Table 2 summarizes key differences between EBRT and RPT that affect cumulative dose assessment.

7. Practical Framework for RPT-EBRT Integration

A combined RPT-EBRT plan should start with a clinical hypothesis. Examples include reducing EBRT dose to a previously irradiated mucosal surface because tumor-selective RPT has delivered meaningful dose, escalating SBRT to a residual cold region after Y-90 radioembolization, using PSMA RPT to cover microscopic disease while EBRT treats macroscopic oligometastases, or using PRRT before fractionated EBRT to intensify dose to SSTR-positive meningioma. Without a hypothesis, dose accumulation risks becoming a mathematical exercise that does not change patient care [7,8,9,10,11,12,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60].

The safest workflow includes: (1) define the clinical decision and relevant target/OAR endpoints; (2) acquire quantitative pre-therapy and post-therapy imaging using a calibrated protocol; (3) calculate RPT absorbed dose with the level of granularity required by the decision; (4) register dose maps to the EBRT planning data set; (5) review registration and contour uncertainty; (6) convert to BED or EQD2 only if the question requires biologic equivalence; (7) adapt EBRT target dose, avoidance structures, or margins; and (8) document uncertainty and follow-up toxicity. This workflow should be implemented by a multidisciplinary team rather than delegated to either nuclear medicine or radiation oncology alone [5,6,7,8,9,10,11,12,32,33,34,35,46,47,48,49,50,51,52,53].

In practice, the clinician often faces three possible outputs. The first is no EBRT adaptation: RPT is delivered, but EBRT proceeds as planned because dose contribution to critical structures or target is too uncertain or too small. The second is descriptive adaptation: RPT dose informs risk discussion, toxicity monitoring, or selection of sites for focal EBRT without formal biologic subtraction. The third is prescriptive adaptation: RPT dose directly changes EBRT dose, fraction number, target coverage, or organ-at-risk constraints. Prescriptive adaptation demands the strongest evidence, the best imaging, and the most transparent assumptions.

8. Disease-Specific Synthesis

8.1. Liver-Directed Y-90 and Focal EBRT

The liver is the strongest current template for planned RPT-EBRT dosimetry because Y-90 microspheres create a measurable, heterogeneous intrahepatic dose distribution that can be imaged after treatment and integrated with focal EBRT planning. Wang and colleagues described combined Y-90 SIRT and EBRT in hepatocellular carcinoma from clinical and dosimetric perspectives, and subsequent inverse-planning work showed how SBRT could be shaped after radioembolization to account for delivered tumor and normal-liver dose [46,47]. Dose-response modeling studies further illustrate why normal-liver and tumor control assumptions can materially change planning conclusions [48].

The liver paradigm is important beyond hepatocellular carcinoma. It demonstrates that RPT is not always systemic drug therapy; it can be a regional radiation intervention with a post-therapy dose map. When a residual lesion remains, EBRT can be used to boost underdosed areas. When normal liver has already received substantial microsphere dose, EBRT may need to be de-escalated or reshaped. This is the most concrete example of RPT informing an EBRT plan rather than simply being counted as previous treatment.

8.2. Head and Neck Re-Irradiation

Recurrent head and neck cancer is a compelling but high-risk setting because EBRT re-irradiation is constrained by mucosa, salivary glands, spinal cord, mandible, swallowing structures, carotid arteries, optic pathways, and prior dose. Adam and colleagues developed a voxel-level dosimetry framework for I-131 radiopharmaceutical therapy combined with EBRT, showing how Monte Carlo RPT dose maps could be brought into EBRT planning paradigms [49]. A phase 1 study of I-131 iopofosine with EBRT in recurrent or metastatic head and neck cancer provided early clinical safety and activity data [50].

This setting illustrates the highest-stakes version of combined dosimetry: the question is not only how much total dose was delivered, but whether RPT dose in tumor-adjacent normal tissue should modify re-irradiation. Because serial anatomy, prior dose, tumor shrinkage, and organ motion can all be uncertain, prescriptive fraction replacement should be approached cautiously and reported with detailed uncertainty analysis.

8.3. Prostate Cancer

Prostate cancer is likely to become the most common RPT-EBRT integration setting because many patients receive EBRT at several phases of disease and PSMA radioligand therapy is moving earlier. PROQURE-I addressed concurrent Lu-177-PSMA-617, EBRT, and ADT in node-positive prostate cancer, while lesion-level dosimetry studies have explored Lu-177-PSMA-617 with SBRT in oligometastatic castration-sensitive disease [51,52]. Contemporary reviews now frame the combination of EBRT and Lu-177-labeled PSMA ligands as a developing field with specific trial, dosimetry, and toxicity questions [53].

Several use cases are plausible. PSMA RPT may treat occult systemic disease while SBRT ablates visible oligometastases. Pelvic EBRT may sterilize nodal basins while RPT treats PSMA-positive disease outside the field. RPT dose maps may identify lesions that already received meaningful dose and lesions that remain cold or undertreated. The field should resist assuming that more radiation is automatically better: marrow exposure, salivary toxicity, renal uptake, fracture risk, and cumulative EBRT history all shape patient selection.

8.4. Meningioma and Other SSTR-Positive Tumors

Advanced meningioma provides a biologically rational example because SSTR expression can be imaged and targeted, while EBRT remains a central local therapy. Kreissl and colleagues reported PRRT combined with fractionated EBRT in advanced symptomatic meningioma, and long-term follow-up of the same multimodal strategy suggested feasibility and durable stabilization in a small cohort [54,55].

The dosimetric opportunity in meningioma differs from systemic metastatic disease. Many tumors are near optic nerves, chiasm, cranial nerves, brainstem, pituitary, cochlea, or normal brain. Even a modest RPT contribution may matter if it overlaps a high-risk substructure or if it supports EBRT dose de-escalation in a previously treated region. However, the evidence base remains small and largely nonrandomized, so PRRT-EBRT planning should be individualized and transparent.

8.5. Lymphoma, Bone Metastases, and Historical Combined-Modality Lessons

Historical lymphoma experience with EBRT followed by Y-90 ibritumomab tiuxetan demonstrated spatial cooperation: focal EBRT could address bulky disease that was likely to respond less well to systemic radioimmunotherapy, while RPT treated disseminated disease [56]. Bone-metastasis studies with Sm-153 plus local EBRT and trials of Ra-223 plus SABR similarly emphasize the complementary logic of systemic skeletal irradiation and focal high-dose treatment [57,58,59]. A metastatic osteosarcoma experience with Ra-223, systemic agents, and EBRT further illustrates that combined radionuclide and external-beam approaches can be clinically feasible in rare, high-need settings, although evidence is limited [60].

These reports are important because they broaden the discussion beyond modern PSMA and PRRT. They show that the clinical intuition behind combination therapy has existed for decades. What has changed is the expectation that modern molecular imaging, quantitative reconstruction, and computational planning should allow the combination to be measured, adapted, and reported more rigorously.

Table 3 summarizes selected disease settings in which RPT-EBRT integration has been explored.

9. Artificial Intelligence, Automation, and Infrastructure

Theranostic radiation medicine is data-intensive. Quantitative imaging, segmentation, time-activity fitting, Monte Carlo or dose-kernel calculations, deformable registration, plan adaptation, and toxicity modeling all create opportunities for automation. Artificial intelligence may improve lesion detection, organ segmentation, dosimetry workload, absorbed-dose prediction, radiomics-based response assessment, and EBRT plan generation [61,62,63].

However, automation should not weaken accountability. Models used for RPT dosimetry or EBRT adaptation must be auditable, validated on appropriate scanner and reconstruction protocols, and tested against clinically meaningful endpoints. An algorithm that performs well for organ segmentation may fail for small lesions; a dose predictor trained on fixed-activity therapy may not generalize to adaptive dosing; and a deformable registration algorithm may produce visually plausible but dosimetrically misleading maps near surgical defects or tumor shrinkage. Human review by trained nuclear medicine physicians, radiation oncologists, and medical physicists remains essential.

Institutional infrastructure is as important as computation. A credible RPT-EBRT program needs radiopharmacy support, calibrated quantitative imaging, therapy rooms and radiation-safety procedures, a dosimetry workflow, treatment-planning system compatibility, multidisciplinary contour review, prospective toxicity capture, and a shared language for communicating uncertainty. In many centers the limiting step will not be a new radiopharmaceutical, but the absence of a practical bridge between nuclear medicine dosimetry and EBRT planning systems.

10. Reporting Standards and Research Objectives

The literature would be more interpretable if combined RPT-EBRT studies reported a minimum data set. This should include the clinical sequence, all prior radiation, target and OAR definitions, RPT agent and administered activity, imaging time points, scanner calibration, reconstruction settings, activity quantification method, time-activity curve model, absorbed-dose calculation method, dose-grid resolution, registration method, biologic conversion assumptions, adaptation rules, toxicity grading, and follow-up duration. Trial reports should specify whether dosimetry was exploratory, descriptive, or prescriptive.

Dose constraints require special caution. Extrapolating EBRT constraints directly to RPT may be misleading because RPT is protracted, heterogeneous, and agent-specific. Conversely, dismissing EBRT-derived knowledge entirely would ignore decades of organ tolerance data. The most defensible approach is contextual: use EBRT constraints as reference points when appropriate, but state when RPT-specific dose-rate, substructure, microdosimetry, or clinical dose-response data are inadequate [44,45].

Prospective trials should move beyond feasibility and ask testable questions: Does RPT dose-guided EBRT adaptation improve tumor control or reduce toxicity compared with standard sequencing? Can post-therapy imaging identify lesions that need SBRT boost? Can marrow, salivary, kidney, liver, or bowel toxicity be predicted better by composite biologic dose than by administered activity? Can simplified dosimetry protocols preserve clinically relevant accuracy? Can AI reduce workload without introducing unacceptable uncertainty? These questions require collaboration among nuclear medicine, radiation oncology, radiology, medical physics, radiobiology, radiopharmacy, biostatistics, and data science.

Table 4 provides a suggested minimum reporting checklist for combined RPT-EBRT studies.

11. Conclusions

Theranostics is reshaping radiation medicine by making biologically targeted radiation visible, measurable, and potentially adaptable. The next step is not simply more radiopharmaceuticals or more combinations, but more rigorous integration. RPT and EBRT should be planned together when they address complementary spatial or biologic problems, and cumulative dose should be interpreted with respect for the differences in dose-rate, heterogeneity, particle quality, repair, and normal-tissue exposure. The most mature model is ⁹⁰Y liver therapy integrated with focal EBRT, but head and neck, prostate, meningioma, lymphoma, and bone-dominant approaches show the breadth of the field. The publication standard should now move toward patient-specific quantitative imaging, transparent dosimetry, biologically explicit modeling, uncertainty reporting, and prospective trials in which RPT dose can genuinely modify EBRT decisions. If these standards are met, theranostic radiation medicine can evolve from empiric sequencing to individualized, evidence-based multimodality radiation planning.