Radiotheranostics in oncology: Making precision medicine possible

A quintessential setting for precision medicine, theranostics refers to a rapidly evolving field of medicine in which disease is diagnosed followed by treatment of disease‐positive patients using tools for the therapy identical or similar to those used for the diagnosis. Against the backdrop of only‐treat‐when‐visualized, the goal is a high therapeutic index with efficacy markedly surpassing toxicity. Oncology leads the way in theranostics innovation, where the approach has become possible with the identification of unique proteins and other factors selectively expressed in cancer versus healthy tissue, advances in imaging technology able to report these tissue factors, and major understanding of targeting chemicals and nanodevices together with methods to attach labels or warheads for imaging and therapy. Radiotheranostics—using radiopharmaceuticals—is becoming routine in patients with prostate cancer and neuroendocrine tumors who express the proteins PSMA (prostate‐specific membrane antigen) and SSTR2 (somatostatin receptor 2), respectively, on their cancer. The palpable excitement in the field stems from the finding that a proportion of patients with large metastatic burden show complete and partial responses, and this outcome is catalyzing the search for more radiotheranostics approaches. Not every patient will benefit from radiotheranostics; but, for those who cross the target‐detected line, the likelihood of response is very high.


INTRODUCTION
Patients with metastatic cancer, including some with oligometastatic disease (i.e., the spectrum between the cancer being contained to where it originated and widespread dissemination throughout the body), are largely ineligible for curative-intent external-beam radiotherapy (EBRT) or surgery, although the number of ablative procedures for oligometastatic disease is on the ascent for certain cancers, such as prostate cancer, with acceptable rates of acute and late-stage grade 3-5 toxic effects (<13%), and with clinically acceptable rates of local control (95%) and progression-free survival (51%) at 1 year in a recent meta-analysis. [1][2][3] Part of the reason for the imperfect outcomes from treatment for metastatic disease, and for some oligometastatic cancers, is heterogeneity between and within each cancer lesion, the evolution of therapy resistance in lesions, as well as the existence of micrometastatic disease. 4,5 Modern precision oncology attempts to address some of these challenges by matching critical molecular information to specific available targeted therapies, but how can we practice effective precision oncology in the metastatic setting when we have an incomplete understanding of the disease in terms of expressed receptors or the presence of activating mutations in all lesions of each individual patient? This problem is further compounded, in the period leading up to clinical failure, by clonal evolution (the acquisition of genetic or epigenetic changes that selectively affect the fitness of cells), resulting in divergent subclones with mutually exclusive or private mutations that can influence levels of the very cellular proteins or microenvironment factors that these therapies target. 6,7 In this review, we expound the practice of radiotheranostics as a technological advance that addresses therapeutic heterogeneity, together with in-built accounting for tumor molecular target evolution, thus improving patient outcomes in metastatic cancer.
Theranostics was recently suggested as a future cancer research priority in the United States. 8 It refers to the systematic integration of targeted diagnostics and therapeutics, in alignment with the concept of precision medicine. 8 Theranostics can be defined as the use of diagnostic procedures for the identification of patients who are candidates for a specific treatment. This may consist in a broader sense in the use of isotope-based methods for the visualization and quantification of the expression of a target, followed by treatment with compounds, including nonradioactive molecules binding to this target. Contrary to the analysis of biopsies with immunohistochemistry, imaging, especially with positron emission tomography (PET), allows the noninvasive and quantitative analysis of all lesions in the body, not only the biopsied ones. This permits an estimate of both interlesion and intralesion heterogeneity of target expression. In this setting, the molecule used for imaging and the molecule used for therapy may not necessarily be the same; these molecules may even be very different. In a narrower sense, imaging with isotope-labeled molecules is followed by therapy with the same or very similar molecule. In this case, the resulting images show the distribution of the targeting molecule that can be used to estimate the distribution of the same or a very similar molecule during therapy, which is useful information with respect to possible side effects or to possible response/failure.
In the practice of radiotheranostics, the radiotheranostic diagnostic part is typically an imaging method involving quantitative PET or single-photon emission computed tomography (SPECT) conducted with a radiotheranostic compound that identifies whether and by how much a particular molecular target is present in each cancer lesion within the body, hence promulgating which patient would be a candidate for the analogous companion radiotheranostic drug (also referred to as molecular radiotherapy, endoradiotherapy, or radioligand therapy). In keeping with our knowledge of tumor molecular target evolution, the patient is periodically imaged after commencing therapy to verify the levels of target and detect any changes in those levels, so as to appropriately modify the dose of drug in order to improve the therapeutic index (the relation between effectiveness and toxicity) or to consider alternatives in the case of disease progression. This positions the practice of radiotheranostics as the quintessential setting for precision medicine. The field of radiotheranostics is expanding rapidly, and oncology leads the way in innovation, with identification of unique proteins and other factors selectively expressed in cancer versus healthy tissue, advances in imaging technology able to report these tissue factors, and major understanding of targeting chemicals and nanodevices together with methods to attach labels for imaging and therapy. 8 Although the focus here is on classical intravenous injection of a radiotheranostic pair to treat solid tumors and hematologic cancers, the concept of theranostics can be extended to image-guided surgery and photodynamic therapy for oligometastatic disease; treatment of precancerous lesions, such as actinic keratosis and Bowen disease; and beyond oncology to rheumatologic diseases, cardiovascular diseases, and macular degeneration. 9

RADIOISOTOPES AND TARGETS
Currently, most radiotheranostics target receptors that are overexpressed on the cell surface. Typically, the radiolabel accumulates via cellular internalization, concomitant with overexpression of the target on tumor or stromal cells, to permit imaging and therapy. Figure 1A illustrates this concept. For PET, the imaging radioisotopes of choice are fluorine-18 ( 18 F) or gallium-68 ( 68 G), although the use of zirconium-89 is increasing, particularly with antibodies. Regarding the choice of therapeutic theranostics radioisotopes, iodine-131 ( 131 I) has been widely used, particularly with antibodies; however, more recently, lutetium-177 ( 177 L) has been the workhorse radioisotope (Table 1) As with the need to expand the list of targets, radioisotope availability/supply chain will need to match the growing need for F I G U R E 1 The radiotheranostics concept and Theranostics Audit Trail (ThAT) in GEP-NETs when using a radiopharmaceutical. (A) The practice of radiotheranostics involves the injection of radiopharmaceuticals with similar or identical targeting motifs that permit imaging and therapy. Targeting of different cell surface proteins expressed on hematologic cancers and solid tumors is illustrated. Targets include, but are not limited to, neurotensin receptor-1 (NTR1), prostate-specific membrane antigen (PSMA), sodium-iodide symporter (NIS), somatostatin receptor 2 (SSTR2), gastrin-releasing peptide receptor (GRPR), CXC chemokine receptor-4 (CXCR4) alpha v beta 6 integrin (AVB6 or α v β 6 ), B7 homolog 3 protein (B7-H3; CD276), human epidermal growth factor receptor 2 (HER2), norepinephrine transporter (NET), fibroblast activation protein (FAP), CD20, CD37, and CD45. Antigen-mediated internalization and lysosomal processing precede DNA damage. This model illustrates opportunities for combining radiotheranostics with DNA-repair inhibitors or immunotherapy. (B) ThAT provides a framework for patient selection and monitoring.
-257 these alpha-emitters. A less explored area is use of Auger-emitters, exemplified by 123 I, despite their availability. Research to design motifs that localize the internalized radioisotopes close to cell nuclei is needed to expand this field and achieve more localized linear energy transfer, similar to alpha particles. Finally, availability of chelators also determines the choice of radioisotope. This has limited expansion of 223 Ra use beyond treatment of bone disease. The popularity of 225 Ac and 212 Pb partly stems from the availability of efficient DOTA/DOTAMTATE chelators for conjugation. Similarly, thorium-227 uses octadentate 3,2-hydroxypyridinone, whereas halogen radiochemistry exists for 131 I and astatine-211. There is ongoing research to improve chelator efficiency.
To achieve high therapeutic index, the practice of radiotheranostics needs to consider where the radioisotope localizestumor versus healthy organs-and for how long. The target, the pharmacokinetics of the carrier molecule used, and the nature of the radioisotope largely determine this. As aforementioned, a major focus in the field of radiotheranostics relates to two cancer targetssomatostatin receptor 2 (SSTR2) and prostate-specific membrane antigen (PSMA). The excitement in the field of radiotheranostics, however, stems from the burgeoning list of radiotheranostics candidates (Table 2) and the impact realized in ongoing clinical studies regarding the resolution of extensive metastatic burden (vide infra). Table 2, which is by no means exhaustive, attempts to capture current targets being explored, together with their radiotheranostic pairs. Some of the new targets include fibroblast activated protein (FAP), neurotensin receptor type 1, gastrin-releasing peptide receptor/bombesin receptor, norepinephrine transporter, C-X-C chemokine receptor type 4 (CXCR4), CD20, CD37, CD45, and B7-H3/ CD276 ( Figure 1A and Table 2). We envision that future efforts will aim to expand this list of targets substantially for clinical benefit. To allow for rapid and high tumor penetration, together with rapid clearance from organs at risk, most radiotheranostics are designed as small, organic/inorganic compounds or peptides. Antibody radiotheranostics are also in use, with high affinity and high target engagement, but with more off-target toxicity because of their long plasma half-lives. The use of smaller kDa antibody-like recognition domains, including affibodies and nanobodies, as targeting motifs, together with the use of plasma expanders to expedite renal elimination are attempts to overcome off-target effects. 11

RADIOTHERANOSTICS DEVELOPMENT-RATIONAL VERSUS HIGH THROUGHPUT
The tracer development process includes the selection and validation of the target, the selection and performance of the method applied for the ligand identification, and, finally, the evaluation and potential improvement of its binding properties and pharmacologic profile. 12 In general, antibodies for the delivery of therapeutic agents or as radiopharmaceuticals face limitations by their slow blood pool clearance, poor tissue penetration, and thus an unfavorable pharmacokinetic profile. 13 Smaller molecules, including single-domain antibodies, nanobodies, scaffold proteins, and peptides demonstrating high affinity for the target and better tissue penetration but less immunogenicity, represent attractive smaller alternatives for imaging and radiotheranostic drug therapy. 11,14,15 For rational design, knowledge about enzymatic activity and/or substrate binding sites of the target receptor, as well as about the structure of substrates and potential inhibitors, is needed. Because of the high affinity of the peptide for SSTR2, followed by the internalization of the radiolabeled peptide-receptor complex, DOTATOC/DOTATATE has successfully been applied for PET/ computed tomography imaging of and therapy for SSTR2-expressing tumors. Another example is the use of quinoline-based inhibitors of the FAP. [16][17][18] FAP, a membrane-anchored peptidase, is highly expressed in cancer-associated fibroblasts in the stroma of >90% of epithelial tumors and thus is considered a promising pan-cancer target for radionuclide-based theranostic approaches. Preclinically, 68 Ga-FAP inhibitor (FAPI) derivatives demonstrated a high rate of intratumoral internalization and, in clinical PET/computed tomography imaging, tumor-to-nontumor contrast ratios that were equal or even higher compared with the standard tracer in oncology, 18 F-fluorodeoxyglucose ( 18 F-FDG), in an intraindividual comparison. 19 In addition to the approaches described above, more recently, increased use of high-throughput technologies to discover new ligands has been described. These technologies include phage, cell surface, cell-free systems and ribosome and messenger RNA displays. Some of these techniques have found use in the discovery of novel ligands, including α v β 6 integrin selectively expressed in many epithelial-derived carcinomas associated with a poor prognosis, including lung, colorectal, and cervical cancers and delta-like ligand 4, which is overexpressed on endothelial and tumor cells involved in angiogenic balance. 20,21

THE CLINICAL CASE FOR THERANOSTICS
It was estimated that only about one-half of patients with cancer in the United States could be cured with existing therapies, and the remaining one-half were expected to die of their disease. 22,23 Metastasis often characterizes the late stage of incurable cancer, and it will be useful if, for instance, de novo metastatic castration-sensitive prostate cancer (mCRPC) with a 29.8% survival rate, 24 (2) the corresponding radiographic progression-free survival was 8.7 months compared with 3.4 months in the control arm, demonstrating that the therapy prolongs survival. Furthermore, the combination was tolerated, with fatigue, dry mouth, and nausea being the commonly observed side effects; the incidence of grade ≥3 adverse events was greater with 177 Lu-PSMA-617 than without it (52.7% vs. 38.0%, respectively), but quality of life was not adversely affected.
The US Food and Drug Administration (FDA) granted approval to     60 as an initial step in the investigation of future radiotheranostics to select cancer types likely to substantially express the target and accumulate radioligands.

THERANOSTICS AUDIT TRAIL
Here, we present a framework and examples to aid physicians unfamiliar with the field, as well as seasoned practitioners. We coined the term Theranostics Audit Trail (ThAT) to represent a framework for evidence-based decision making when using theranostics analogous to the Pharmacological Audit Trail, which exploits imaging in hypothesis-testing clinical trials. 61 ThAT commences with selecting individual patients for therapy using a radiotheranostic diagnostic ( Figure 1B). Therefore, the first clinical consideration is which patient the therapeutic index, the second question is whether the individual's dosimetry (organ and overall body effective dose) is appropriate (this aspect compares the amount of drug delivered to lesions with that delivered to critical organs, including bone marrow and kidneys). The aim is to optimize lesion outcome and reduce myelotoxicity or nephrotoxicity when a relation between regional uptake and these clinical variables exists. Standard clinical end points-blood count and renal function-may also be used to support the clinical decision ( Figure 1B). 62 A review is conducted (e.g., at the end of every second cycle) to enable decisions to be made on continuation or restriction of further treatment. Implementing a standardized quantitative or semiquantitative approach to determine tumor uptake (and residence time) allows a comparison of data between hospitals. In a study by Sharma and coworkers, the baseline quantitative measurea maximum (voxel) standardized uptake value of 13.0 from somatostatin receptor imaging (SRI; e.g., with 68 Ga-DOTATATE)-defined a threshold below which patients with neuroendocrine cancers have a poor response to 177 Lu-DOTATATE and worse progression-free survival. 63 Not every patient will benefit from radiotheranostics; however, for those, even with large metastatic burden, who favorably cross the target-detected line, the likelihood of response is high (Figure 2A,B). In the practice of radiotheranostics, patients are typically scanned by PET or SPECT at baseline for stratification and at the end of every second cycle to verify disease progression/ response. Further determination of dosimetry, versus the use of fixed-activity regimens, may be used to maximize tumor-absorbed dose while keeping a safe normal organ dose ( Figure 2C). 64 This is not universally implemented in the practice of radiotheranostics; Pandit-Taskar and coworkers suggest an informed approach that supports using dosimetry-based treatments through the provision of evidence of improved outcomes, as indicated above for SRI, so that the benefit of an empiric-activity approach is not undercut. 65 Lu-DOTATATE therapy. Images show excellent response to therapy, with marked reduction in burden of liver metastases. 68 Ga indicates gallium-68; 177 Lu, lutetium-177; CT, computed tomography; NET, neuroendocrine tumor; PSA, prostate-specific antigen; PET, positron emission tomography; SUV, standardized uptake value.

RADIOTHERANOSTICS IN ONCOLOGY
Addressing the issue of interlesion heterogeneity takes center stage in the practice of radiotheranostics. We consider two scenarios.
The first relates to pre-therapy heterogeneity of target expression. This is exemplified in Figure 3A by a patient with prostate cancer who will nominally have crossed the target-detected line but who also harbors lesions that do not express the target. Because these discordant FDG-avid, PSMA-negative lesions are unlikely to respond to the molecular radiotherapy being administered, the patient could be excluded as a candidate for such therapy despite having numerous target-positive lesions. This clinical scenario contrasts to that of a patient with prostate cancer who has multiple bone metastases, showed high 68 Ga-PSMA uptake and only weak/absent FDG avidity F I G U R E 3 Tumor heterogeneity and the role of multitracer imaging-dual 18 F-FDG and 68 Ga-PSMA PET scans. (A) Metastatic prostate cancer in a patient with widespread nodal and bone disease that is intensely 18 F-FDG-avid and 68 Ga-PSMA-avid. MIP, axial fused, and axial PET images, respectively. Some lesions are discordant (blue, red, and green circles) 18 F-FDG-avid and 68 Ga-PSMA-negative disease include a cervical spine bone metastasis (blue arrows) and left para-aortic nodal disease (red arrows). This patient was deemed unsuitable for 177 Lu-PSMA therapy. (B) A patient with intensely 68 Ga-PSMA-avid disease and only weak or no FDG avidity. This patient showed a highly favorable response after four cycles (post 4) of 177 Lu-PSMA therapy with just one residual tracer-avid bone metastasis (arrow) and marked prostate-specific antigen reduction. 18 Figure 4 and in the published literature). 66 For example, in their study using combined SRI/ 18 F-FDG-PET, Zidan and coworkers demonstrated that 50% of patients who had carcinoids were unsuitable for subsequent therapy with a radiotheranostic drug despite having target-positive lesions. 66 The basis for interlesion heterogeneity to radiotheranostic drugs is incompletely understood; however, in NETs, heterogeneous expression of the SSTR2 cell-surface target is thought to be largely driven by epigenetic modifications. 67 67 ). (B) A woman aged 34 years with a high-grade (grade 3; Ki67, 30%) biliary tree NET, which is FDG-avid but SSR-negative (PETNET score, P5): maximum intensity projection, axial-fused, and axial PET imaging. 68 Ga indicates gallium-68; −ve, negative; +ve, positive; 18 F-FDG, fluorine-18 fluorodeoxyglucose; NET, neuroendocrine tumor; SRI, somatostatin receptor imaging; SSR, somatostatin receptor.

RADIOTHERANOSTICS IN ONCOLOGY
investigating epigenetic modification to re-sensitize tumors to SSTR2-targeting radiotheranostic drugs: Lutathera and ASTX727 in Neuroendocrine Tumors (LANTana; Clinicaltrials.gov identifier NCT05178693). The outcome of this trial is eagerly awaited. It has also led to the development and application of a dual SRI/FDG grading scheme: the NETPET scheme. 68 In the study by Chan and coworkers, 68 the NETPET score (with scores from P0 [representing SRI-negative/FDG-negative] to P5 [representing SRI-negative/FDGpositive]; Figure 4) predicted overall survival in univariate analysis, whereas the World Health Organization grade at the time of diagnosis did not. The second scenario, illustrated in Figure 5, represents heterogeneity in PSMA and SSTR2 expression in a patients with metastatic prostate cancer who had neuroendocrine differentiation on pathology resulting from acquired resistance of existing lesions and/or progression of new lesions. Currently. single-agent molecular radiotherapeutics are used in the practice of radiotheranostics. The case study in Figure 5 challenges this notion and supports the testing of additional radiotheranostic targets before or during treatment so F I G U R E 5 Tumor heterogeneity and indication for the use of multiple radiopharmaceuticals targeting different receptors. A patient who had T3bN1M1b prostate cancer (Gleason 5 + 4) with neuroendocrine differentiation was treated with chemotherapy (zoladex, docetaxel, and carboplatin); no liver disease was seen at baseline (PSA levels in ng/ml). MIP, axial-fused, and axial PET images. (A) The patient had serial 68 Ga-PSMA PET/CT imaging, which showed partial treatment response; however, new non-PSMA-avid liver lesions were detected on CT at 5 months posttherapy. (B) Baseline 68 Ga-DOTATATE showed only low-level activity in some bone metastases. However, repeat 68 Ga-DOTATATE showed progression with more intensely avid bone metastases and new DOTATATE-avid, non-PSMA-avid liver metastases; thus the patient was offered 177 Lu-DOTATATE therapy. 68 Ga indicates gallium-68; 177 Lu, lutetium-177; CT, computed tomography; MIP, maximum intensity projection; PET, positron emission tomography; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen; SUV, standardized uptake value. The above account for using a radiotheranostic diagnostic to assess lesion heterogeneity assumes 100% sensitivity, and this, of course, is not the case; so a careful analysis of the context is necessary for the practitioner of radiotheranostics. For instance, considering the use of PSMA imaging as the radiotheranostic diagnostic pair, like any protein, PSMA expression is expected to vary within lesions, between lesions in the same patient, and between patients. The spatial resolution of most current clinical PET scanners in patients is approximately 3-5 mm, which precludes any useful assessment of intralesion heterogeneity except in large lesions with a necrotic core. What is measured by PET is the lesion intensity heterogeneity, and the key consideration between this measure and true protein expression is size. In general, PET intensity increases with PSMA protein expression; however, although high expression in small nodes <1 cm may be seen, the general expectation is that lesions/ nodes <1 cm may go undetected. 71 This partly explains the poor sensitivity of PSMA-PET for nodal involvement of 0.4 (specificity, 0.95) in phase 3 diagnostic trials of 68 Ga-PSMA although patients who had neuroendocrine prostate cancer were excluded. 72 If this hypothesis is true, then we expect advanced technology-total-body PET-with a step change in detection sensitivity, to improve diagnostic accuracy. 73,74 It should be cautioned, however, that the higher sensitivity could also lead to a higher rate of false positives, and direct comparison of PET signal to target expression levels should be a research objective in future studies. Recent studies support the notion that PSMA expression can decrease by up to 20% after multiple lines of therapy; conversely, it is reported that antiandrogens activate PSMA expression. 27,75,76 Because of these (potentially conflicting) changes in PSMA expression with treatment, we cannot assert that a patient with mCRPC who is being considered for step 1 of ThAT will not have interlesion differences in PSMA expression, particularly given the regulatory role of the androgen-signaling pathway on PSMA expression. In a 177 Lu-PSMA-617 trial, patients with discordant FDG-positive, PSMA-negative disease had very poor overall survival of 2.5 months. 77 It is against this background that we support the use of dual imaging, e.g. 18 FDG-PET and 68 Ga-PSMA ( Figures 3 and 5), analogous to consensus recommendations of SRI-PET/ 18 F-FDG-PET in the selection of patients with neuroendocrine tumors for radiotheranostic drug therapy. 78 The use of dual imaging is also enshrined in PET eligibility criteria for the recent TheraP trial in mCRPC: PSMA-positive disease and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. We also encourage the use of this approach for the aforementioned evolving targets, including FAP ( Figure 6) and α v β 6 ( Figure 7). In the practice of dual imaging, consideration should be accorded to improved lesion delineation with the radiotheranostic diagnostic compared with 18 F-FDG or physiologic uptake of 18 F-FDG precluding optimal tumor delineation, e.g., in the brain (Figure 7). In aggregate, the outcome of the radiotheranostic diagnostic currently remains the gold standard for progression to step 2 of ThAT.
The presence of target alone does not guarantee success with radiotheranostics. Two additional considerations are dosimetry (radiation dose to tumor lesions and to all organs of the body) and resistance to the radiotheranostic drug (radioresistance), in particular, the ability of cancer cells to repair DNA that has been sublethally damaged. Accurate estimation of the true organ-absorbed radiation dose is important in the practice of radiotheranostics-at a minimum during early phase trials-and is considered in ThAT. The dosimetry formalism for radiopharmaceuticals versus EBRT is described elsewhere. 79 The dose-predicted therapeutic index is calculated from dosimetry in tumors versus organs at risk. Lessons learned from radioimmunotherapies suggest that approximately 20 Gy may cause complete responses in patients with sensitive tumors, including lymphomas, whereas solid tumors require 35-100 Gy to be tumoricidal. 80 Bone marrow (>1.5 Gy) as well as kidneys and lungs (15)(16)(17)(18)(19)(20) are often limiting. The optimal dose-predicted therapeutic index is estimated as >10:1 for kidneys and >50:1 for bone marrow. 80 The former was identified as a challenge for several therapeutic radiometals; kidney protection agents, including lysine, arginine, and gelofusine, are explored to improve therapeutic index of these radiotheranostics. However, ThAT does not consider intrinsic radioresistance. Key distinguishing features of radiotheranostics from EBRT are dose level and dose rate. A high dose (e.g., 30 Gy) is delivered to the tumor over hours to days and exponentially decays over time, compared with, e.g., 2-Gy fractions daily over weeks in EBRT (to achieve tumor target dose of up to 100 Gy [although the organs-at-risk dose of about 5-50 Gy limits the ideal target tumor dose]). 81 This perhaps propels DNA repair to the fore as a key radioresistance mechanism. Not only do we not have clinically validated DNA-repair PET/SPECT diagnostics, but it is unknown how many staging procedures will be tolerated as part of ThAT. In view of this, and as indicated above, combinations of radiotheranostics and DNA-repair inhibitors are being explored rather than investigating DNA-repair imaging as part of ThAT.

RADIOTHERANOSTICS IN ONCOLOGY
F I G U R E 7 Dual imaging with 68 Ga-SFITGv6 and FDG. (A) A patient with nonsmall cell lung cancer imaged with FDG at 1 hour postinjection and (B) with an α v β 6 integrin-targeting peptide, 68 Ga-SFITGv6, at 1 hour postinjection. (C) Axial CT, axial fused PET, and axial PET images show the left lung primary, mediastinal nodal disease (green arrows), and a right adrenal metastasis (blue arrows). Note also a brain metastasis (red arrows) in the α v β 6 integrin-targeting peptide PET scan, which is less well visualized on the FDG scan. 18 F-FDG or FDG indicates fluorine-18 fluorodeoxyglucose; 68 Ga, gallium-68; CT, computed tomography; SFITGv6, α v β 6 integrin-binding peptide; PET, positron emission tomography; SUV, standardized uptake value. 68 Ga-FAPI imaging in two cases of peritoneal carcinomatosis. (A) Pancreatic primary and (B) ovarian primary imaged with both 68 Ga-FAPI and FDG. Respective MIP images (A,B) and axial fused images (C) in the ovarian cancer case show widespread peritoneal disease, which is more avid/better delineated on FAPI than on FDG (red arrows). Note also the nodal disease in the mediastinum (blue arrows). 18 F-FDG or FDG indicates fluorine-18 fluorodeoxyglucose; 68 Ga, gallium-68; FAPI, fibroblast activation protein inhibitor; MIP, maximum intensity projection; SUV, standardized uptake value. ABOAGYE ET AL.

F I G U R E 6
-269

OPTIMIZING OUTCOME
Unlike EBRT, the practice of radiotheranostics is largely in its infancy, although some examples of this approach date back decades (Table 2). To discuss the impact of radiotheranostics for those patients eligible for treatment, we need to ask how well the therapeutics stop or reverse tumor growth, whether the side effects are tolerable, and whether and how readily cancer cells acquire resistance to these therapies. To address these questions, we need to have knowledge of the molecular changes induced by therapeutic radioisotopes. However, currently, radiobiologic studies are underrepresented in nuclear medicine. Prognostic/grading scores, developed from accumulating experience, have been established to help the treating physician make treatment decisions. 68,82 For several cancers, it may be a while before the full impact of the practice of radiotheranostics is realized; however, initial data are excellent, particularly considering that the majority of patients enlisted for radiotheranostics have high-burden metastatic disease.
Beyond the above description of 177 Lu-beta and 90 Y-beta particleemitting radiopharmaceuticals, alpha particle-emitting radiopharmaceuticals bring even more excitement. A recent meta-analysis concluded that 225 Ac-PSMA-617 is an effective and well tolerated treatment option for patients who have mCRPC, with a pooled overall survival in 201 patients of 12.5 months. 83 The toxicity profile from alpha radiotheranostics drugs is not inconceivable and includes xerostomia and myelosuppression; nephrotoxicity has been less reported but may indeed have a delayed presentation. It can be expected that nephrotoxicity starts 4-5 years after therapy, a period that is much longer than the life expectancy of patients with mCRPC.
Therefore, nephrotoxicity may be relevant if radiotheranostic drug therapy with radiolabeled PSMA compounds is applied in earlier stages of the disease, when a longer life expectancy can be expected.
Phase 3 randomized trials of alpha particles are anticipated and will be required to judge therapeutic impact more clearly. Regardless of the radioisotope, ways to optimize kidney dose is of relevance in the practice of radiotheranostics. In a deviation from the standard Rot-  84 This demonstrates opportunities for optimizing dose based on consideration of the organs at risk. Dose optimization has also been pursued with pretargeting-an approach in which the targeting motif is injected and allowed to localize in tumor/clear from organs at risk, followed by injection of a hapten/bioorthogonal-binding motif present on the targeting moiety. Because the latter is readily cleared from the body, the idea is to achieve high tumor selectivity and lower organ-at-risk dose. Salaun and coworkers exemplified this concept in medullary thyroid carcinoma patients who were treated with anti-carcinoembryonic antigen and an antidiethylenetriaminepentaacetic acid bispecific antibody at 40 mg/m 2 , followed 4-6 days later by 131 I-di-diethylenetriaminepentaacetic acid-indium bivalent hapten injected at 1.8 GBq/m 2 . 85 The therapy provided a disease control rate of 76.2% and manageable hematologic toxicity (54.7% grade 3-4 hematologic toxicity and myelodysplastic syndrome in two patients, including one who was previously heavily treated; renal toxicity was uncommon). A further iteration of pretargeting involves bioorthogonal chemistry methodology, which was recognized in the 2022 Nobel Prize for Chemistry. In this regard, various nuclear medicine investigators have exploited the inverse electron-demand Diels-Alder click reaction between radiolabeled tetrazines (e.g., 18 F-tetrazine, zirconium-89, and copper-64-tetrazine diagnostics; 177 Lu-tetrazine, 212 Pb-tetrazine, and 225 Ac-tetrazine therapeutics) and transcyclooctene-conjugated targeting motifs for massively increasing the dose to tumor versus the organs at risk. The promise of the approach, although evident in preclinical disease models of cancer, is awaited in patients (for review, see Cheal et al 86 ).
Amidst this excitement, we ask the question: is the infrastructure for the practice of radiotheranostics ready for prime-time? For patients in large cities of most western countries, access to PET scanning for ThAT step 1 assessment might be straightforward. However, this may be challenging for patients who are distant from PET scanning hubs. However, tracers for SPECT exist, at least for SSTR2, PSMA, and FAP, that may be used for the selection of patients who may benefit from therapy using gamma cameras. Alternatively, longer half-life 18 F and copper-64 versions of existing ( 68 G) radioligands have been developed to assure delivery to sites distant from cyclotron manufacturing. [87][88][89] Sourcing of the drug dose, a consideration regarding whether patients are treated as outpatients or inpatients, the cost of the current radiotheranostics, and market growth pressures are all logistic issues to consider. It is anticipated that these logistic challenges will be solved alongside the challenges of finding and engaging experienced nuclear medicine practitioners able to administer these radiotherapeutics and the reimbursement of treatment.
Major registration trials in the field of radiotheranostics have been conducted in combination with standard-of-care treatment.
This aspect is in its infancy; however, opportunities exist to increase efficacy through extension of our understanding of the molecular biochemical properties altered in cancers and are being investigated ( Figure 1A and Table 2). As indicated above, a unique feature of radiotheranostics is that dosimetry can be assessed to provide realtime pharmacokinetics/receptor occupancy information. The use of appropriate formalism permits estimation of efficacy and toxicity from the radiotheranostic drug, and consideration of nonoverlapping toxicities with chemotherapy or targeted therapy enables appropriate combination. 79 A review of combination therapies is perhaps beyond the scope of this report; however, there are two notable

CONCLUSION
In patients with most types of metastatic cancer, the likelihood of cure is near impossible. The practice of radiotheranostics brings closer the day when patients with metastatic cancer and expressing appropriate targets can have significant palliation, improved survival, or even cure. However, even when cure is not achievable, it is possible to see cancer as a chronic disease, which may be treated with target-specific, radiolabeled drugs or their combination, leading to much longer life expectancy with mild side effects and improved quality of life. This review illustrates the opportunities and challenges of achieving that objective.