Radiopharmaceutical Chemistry and Drug Development—What’s Changed?

Abstract

Radiation oncologists and nuclear medicine physicians have seen a resurgence in the clinical use of radiopharmaceuticals for the curative or palliative treatment of cancer. To enable the discovery and the development of new targeted radiopharmaceutical treatments, the United States National Cancer Institute has adapted its clinical trial enterprise to accommodate the requirements of a development program with investigational agents that have a radioactive isotope as part of the studied drug product. One change in perspective has been the consideration of investigational radiopharmaceuticals as drugs, with maximum tolerable doses determined by normal organ toxicity frequency like in drug clinical trials. Other changes include new clinical trial enterprise elements for biospecimen handling, adverse event reporting, regulatory conduct, writing services, drug master files, and reporting of patient outcomes. Arising from this enterprise, the study and clinical use of alpha-particle and beta-particle emitters have emerged as an important approach to cancer treatment. Resources allocated to this enterprise have brought forward biomarkers of molecular pathophysiology now used to select treatment or to evaluate clinical performance of radiopharmaceuticals. The clinical use of diagnostic and therapeutic radionuclide pairs is anticipated to accelerate radiopharmaceutical clinical development.

INTRODUCTION

Oncologists are witnessing a resurgence in radiopharmaceuticals for the curative or the palliative treatment of cancer. Radiopharmaceuticals bring about durable complete remissions in some cancers, like somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, or, provide long-lasting palliative control of others, like bone-metastatic prostate cancer or metastatic pheochromocytoma or paraganglioma.^1–3 The United States National Cancer Institute’s (NCI) support of discovery-phase basic science and of development-phase clinical trials has translated into opportunities for enhanced benefit and reduced morbidity from radiopharmaceuticals. Novel understandings in radiochemistry and cancer radiobiology have repositioned radiopharmaceuticals at the cutting-edge of oncological drug research utilizing a personalized medicine approach to treatment.

Programmatic collaborations and initiatives at the NCI’s Cancer Therapy Evaluation Program (CTEP) aim to markedly step-up clinical development of radiopharmaceuticals in combination with oncological drugs.^4–9 A significant change for the success of this programmatic approach has been the acknowledgment that radiopharmaceuticals are drugs rather than radiotherapy.⁴ Framing clinical development of radiopharmaceuticals at the Federal level with this mindset permits repurposed or new radiopharmaceuticals to build upon established oncological drug approaches that are attractive to patients and seek to expand clinical use.^4–9 In this article, we discuss the aspects of radiochemistry and drug development science that encourage modern radiopharmaceutical clinical trials that test monotherapy or multi-agent combinations. This article begins the discussion with many modern changes to the NCI CTEP clinical trial enterprise that now enable radiopharmaceutical clinical development.

CHANGES IN APPROACH TO RADIOPHARMACEUTICAL CLINICAL DEVELOPMENT

A new National Cancer Institute clinical trial enterprise for radiopharmaceuticals

At present, the NCI CTEP clinical trial enterprise approaches oncological agent development through a stepwise trial strategy. In this strategy and following preclinical Investigational New Drug Application (IND)-enabling experiments, phase I toxicity trials are followed by phase II efficacy trials, and then if justified, phase III randomized trials compare the studied anticancer regimen against standard treatment. NCI CTEP investigational agents studied alone or in combination in this clinical trial enterprise necessitate proper and secure physical storage (with record keeping preferably in an investigational agent pharmacy) to meet regulatory guidances. Radioactive radiopharmaceuticals do not fit well into this guidance, at first thought, because decaying radiopharmaceuticals cannot be stored on shelves in warehouses over protracted time periods, which are then shipped to investigational site pharmacies on demand for clinical use. To permit radiopharmaceutical clinical development through the NCI CTEP clinical trial enterprise, an entirely new infrastructure was needed (Figure 1).

FIGURE 1. National Cancer Institute radiopharmaceutical clinical development.

Modern infrastructure support for radiopharmaceutical monotherapy or combination therapy studies involved creation of new elements of the clinical trial enterprise. The United States National Cancer Institute phase 0, I, or II trial programs build upon carefully crafted cell-free or tumor-cell experiments linked to desired biologic target modulation for in vivo exposures that generate proof-of-concept pharmacodynamic endpoint data, as well as, experiments in two (2) in vitro of interest cancer cell lines and two (2) in vivo cancer xenograft models that establish pharmacodynamic or pharmacokinetic sampling strategies for human trials. The National Cancer Institute has established universal precautions for biospecimen handling (e.g., pharmacokinetic blood samples),⁵ means for radiopharmaceutical adverse event reporting,⁶ regulatory conditions for the conduct of radiopharmaceutical trials,⁷ concepts for single drug master files for radiopharmaceuticals comprised of many components or interchangeable radionuclides,⁸ a centralized protocol writing service for early phase trials,⁹ and a radiopharmaceutical clinical outcomes toolbox.⁹ Overall, these elements support and enrich radiopharmaceutical clinical trials that might be implemented in the early phase Experimental Therapeutics Clinical Trials Network (ETCTN) or late phase National Clinical Trials Network (NCTN).

A broad-minded change in clinical trial infrastructure necessitated NCI CTEP first to reconsider its concepts about the levels of radiochemistry and radiobiology evidence used to support its phase 0, I, or II radiotherapy trial programs. For radiopharmaceuticals, NCI CTEP now considers unique offerings from sensibly conducted cell-free or tumor-cell experiments that interrogate desired in vivo biologic target modulation that generate proof-of-concept pharmacodynamic endpoint data as a primary consideration. Such data might come from phase 0 human trials, where there is no expectation of clinical benefit.¹⁰ NCI CTEP still anticipates that its early phase trial letters of intent (LOIs) for radiopharmaceutical development describe dose-effect studies in two (2) in vitro of interest cancer cell lines and two (2) in vivo cancer xenograft models.

A necessary issue to resolve for early phase trials was biospecimen handling after radiopharmaceutical administration. It was reconciled that conventional patient release parameters (< 5 millisievert) allowed routine biospecimen universal precautions to be implemented for sampling, shipping, and handling of posttherapy samples.⁵

A non-duplicative means for patient encountered radiopharmaceutical adverse event and toxicity reporting needed adaptation to provide safety monitoring for these types of trials.⁶ NCI CTEP, as sponsor of radiopharmaceutical trials, must retain records of authorized user prescription, shipment, receipt, and administration of the radiopharmaceutical under conventional standards for the study of investigational agents utilizing an IND or an Exploratory Investigational New Drug Application (xIND).⁷ The xIND allows for phase 0 trials, and, might take advantage of single drug master files made up of cross-filed individual components of radiopharmaceuticals.⁸ The approach also needs a toolbox that updateS clinical outcomes monitoring, such as a method for digital capture of patient reported toxicities.⁹ Together (Figure 1), these elements support and enrich radiopharmaceutical clinical trials activated in either the NCI CTEP early phase Experimental Therapeutics Clinical Trials Network (ETCTN) or its late phase National Clinical Trials Network (NCTN). What follows summarizes changes in clinical strategy and theranostic use of radiopharmaceuticals.

CHANGES IN ALPHA EMITTER RADIOCHEMISTRY FOR CANCER THERAPY

New considerations of radionuclide emitted particles and impact upon radiobiology

The use of alpha (α)-particle emitters has been recognized as a potentially powerful approach to cancer treatment for decades. Recent, and sometimes remarkable, clinical results, coupled with improved availability of these radionuclides in acceptable quantity and purity, has stimulated a refreshed interest in α-particle radiotherapy.¹¹ The advantage of α-emitters, as contrasted to beta (β)-particle emitters, lies largely in the higher linear-energy transfer (LET) that α-particles deposit along a short path length in tissue (~100 keV μm⁻¹). The approval of radium-223 (²²³RaCl₂; Xofigo) for treatment of metastatic castration-resistant prostate cancer in bone has played a key role in demonstrating α-emitter therapies can be developed (and produced for distribution to medical centers) that safely provide therapeutic benefit to patients.² As a result, receptor-targeted α-therapies for cancer are receiving considerable attention and entering clinical trials that might expand clinical indications. By targeting α-emitters to cell surface proteins that are highly expressed in cancer cells, via ligands such as antibodies (mAbs), antibody fragments (fAbs), peptides, or small molecules, deposition of high LET α-radiation is directed more specifically to tumors for improved tumor-cell-specific killing.

Of the known radionuclides whose decay half-lives are amenable to receptor-targeted α-particle therapy (and that can be produced in clinically-relevant quantities and purity), actinium-225 (²²⁵Ac t_1/2 10 days),¹¹ astatine-211 (²¹¹At t_1/2 7 hours),¹² lead-212 (²¹²Pb t_1/2 11 hours),¹³ and thorium-227 (²²⁷Th t_1/2 18 days)¹⁴ are currently in clinical cancer therapy trials (Figure 2; Table 1). Of these, ²²⁵Ac, ²¹²Pb, and ²²⁷Th, are often referred to as in situ radionuclide generators in that decay of each leads to subsequent decay of radionuclide progeny. Bismuth-213 (²¹³Bi), an α-emitter in the ²²⁵Ac decay chain (Fig. 2B), has been investigated for α-particle therapy, but a relatively short half-life (t_1/2 46 minutes) is a practical impediment to the direct use of this radionuclide. Because the decay energy of α-particle emission is sufficient to break chemical bonds (e.g., radionuclide-chelator coupling), decay progeny of ²²⁵Ac, ²¹¹At, and ²²⁷Th are expected to be ejected from the ligand chemical-coupling upon decay of the parent radionuclide. Because ²¹²Pb is a β-emitting radionuclide that decays to the α-emitters ²¹²Bi and ²¹²Po, this effect may be less pronounced for ²¹²Pb. Previous research suggests that approximately 65 percent of ²¹²Bi arising from ²¹²Pb decay is retained using currently-available chelators.¹⁵ In the branched decay of ²¹¹At, the relatively short half-life of progeny ²¹¹Po (t_1/2 0.5 seconds) and long half-life of decay progeny ²⁰⁷Bi also limit the potential for redistribution of radiation dose due to nuclear recoil effects. This is important because the pharmacokinetics and biodistribution of detached progeny is distinct from the targeting ligand, and can potentially lead to significant-unintended radiation dose to normal organs. Further research is needed to develop a more detailed understanding of the in vivo targets of decay progeny in these decay series once decoupled from the targeting ligand (Figure 2).

FIGURE 2. Radionuclide decay series for α-emitters currently under investigation in clinical trials.

The radionuclides employed for α-particle therapy identified in this study as under investigation in clinical trials are more precisely defined as decay series, whereby a parent radionuclide decays (alpha, beta, electron capture (EC), or beta+ decay) to a series of radionuclide progeny. (B, D) ²²⁵Ac, ²¹¹At, and (C) ²²⁷Th emit α-particles, directly, while (A) ²¹²Pb decays via β-particle emission to α-emitters ²¹²Bi and ²¹²Po.

Table 1.

Current and recent receptor targeted α-particle therapy trials from Clinicaltrials.gov.

Radionuclide	Target	Ligand(s)	NCT Identifiers	Tumor types
225Ac	CD33	mAb	NCT00672165, NCT02998047, NCT02575963, NCT03441048	Acute myeloid leukemia
	PSMA	mAb		Prostate cancer
			NCT03276572, NCT04225910
	IGF-R1	mAb		Solid tumors
			NCT03746431
211At	CD45	mAb	NCT04083183	Non-malignant neoplasms, brain tumors, metastatic cancers, neuroblastoma, leukemias, myelodysplastic syndrome
			NCT03128034
212Pb	HER2	mAb	NCT01384253	Ovarian cancer
	SST2R	peptide	NCT03466216	Neuroendocrine tumors
227Th	PSMA	mAb	NCT03724747	Prostate cancer
	Mesothelin	mAb	NCT03507452	Mesothelioma, serous ovarian cancer, metastatic pancreatic ductal adenocarcinoma
				HER2 positive cancerous tumors
	HER2	mAb	NCT04147819
				CD22 positive non-Hodgkin lymphoma
	CD22	mAb	NCT02581878

Searches of Clinicaltrials.gov reveal trials in various stages of enrollment for ²²⁵Ac, ²¹¹At, ²¹²Pb, and ²²⁷Th receptor-targeted α-particle therapies. Nine trials were identified for ²²⁵Ac, primarily focused on anti-CD33 mAbs for acute myeloid leukemia, while only a single trial of an ²²⁵Ac-labeled mAb selected against the insulin-like growth factor receptor (IGF-1R) was found. Searches revealed four clinical trials involving anti-CD45 mAbs labeled with ²¹¹At, focused on treatments of non-malignant neoplasms, brain tumors, metastatic cancer, neuroblastoma, leukemias, and myelodysplastic syndrome. A completed safety trial of a ²¹²Pb-labeled mAb targeted to the human epidermal growth factor receptor 2 (HER2), has been followed by a phase 1 dose escalation trial of a ²¹²Pb-labeled peptide targeting the somatostatin subtype 2 receptor (SST2R) for therapy of neuroendocrine tumors. Clinical trials of ²²⁷Th were identified for mAbs targeting prostate specific membrane antigen (PSMA) for treatment of metastatic castration-resistant prostate cancer, mesothelin receptor, HER2 receptor, and anti-CD22 for treatment of non-Hodgkin lymphoma. Thus, a growing number of targeting ligands have entered into clinical trials to test the hypothesis that receptor-targeted α-particle cancer therapy can be delivered safely and effectively.

Although β-particle emitting radiopharmaceuticals have been used successfully for more than 80 years, significant challenges to the widespread clinical adoption and optimization of α-particle therapies exist. The fundamental radiation biology of α-emitters differs significantly from that of low-LET β-radiation, and the short range of α-particles in tissue (<100 μm) introduces a need to understand the precise distribution of a radiopharmaceutical within target and non-target tissues.¹⁶ As LET increases, so does efficiency for inducing double-strand DNA breaks (DSBs), normalized to the amount of energy deposited in a tissue. The ionization density caused by α-emitters is optimal for inducing DSBs, given that 100 keV μm⁻¹ roughly translates to two ionization events per DNA diameter (~2 nm). In contrast, double strand breaks from β-radiation are often induced by multiple particle tracks occurring at different points in time. The presence of diatomic oxygen significantly increases the lifespan of single strand breaks (SSBs), due to the “fixation” of the broken deoxyribose. Furthermore, a majority of low-LET DNA damage is mediated by free radicals and other reactive oxygen species that result from the ionization of water molecules.¹⁷ These features mean that the propensity for low-LET radiation to induce cell death depends on (a) the time-course of radiation delivery; (b) the presence of oxygen; and (c) the enzymatic reduction-oxidation characteristics of a cell (Figure 3). As these factors are comparatively less significant with α-radiation induced damage, new dose and fractionation schemes will need to be developed for optimal application of these new radiopharmaceuticals.

FIGURE 3. Comparison of the primary modes of DNA damage for α-radiation (high-LET) and β-radiation (low-LET).

High-LET radiation effects DNA damage primarily through direct induction of DNA double-strand breaks (DSBs). Low-LET radiation primarily effects DNA damage through the indirect formation of free radicals and reactive oxygen species. Low-LET radiation therefore tends to induce single-strand breaks, and numerous particle tracks are needed to form DSBs.

Investigators who have sought to characterize the efficacy of α-radiation for deterministic cell-killing have found a biological effectiveness on the order of 3 – 7 times higher than that of low-LET radiation.¹⁸ This relative biological effectiveness (RBE) suggests that therapeutic responses, and normal tissue toxicities, will be reached at significantly lower mean tissue absorbed doses. In hypoxic tumor tissues, which tend to be quite resistant to low-LET radiation, α-radiation may offer a significant therapeutic advantage due to the comparatively minimal impact of diatomic oxygen on DSB induction. Thus, receptor-targeted α-particle therapy for cancer is entering clinical trials with the potential to improve outcomes for cancer patients. Further research is needed to refine our understanding of the cellular responses to interactions with high LET radiation in the receptor-targeted radiopharmaceutical context, and examples now follow.

²¹¹At physical characteristics motivating use for therapeutic radiopharmaceuticals

²¹¹At-based therapeutic radiopharmaceuticals have attractive features that include (a) a relatively short half-life and a clean 100% alpha-emitting decay scheme and (b) halide chemistry as an iodine analog, making it suitable to labeling both macromolecules and small molecules.¹⁹ The relatively short half-life of ²¹¹At (7.2h) also creates a challenge for its distribution, likely leading to the need for production at regional cyclotrons, somewhat akin to positron emission tomography agents.¹⁹ Indeed, ²¹¹At can be produced in reasonable yield from natural bismuth targets via the ²⁰⁹Bi( α,2n)²¹¹At; however, it requires a cyclotron medium energy α-particle beam (optimal around 28 meV) for its production, often beyond the capabilities of the installed cyclotrons producing ¹⁸F positron emission tomography agents. However, it is likely that success with ²¹¹At-based therapeutic radiopharmaceuticals would drive wider the availability of appropriate cyclotron production facilities and enhance attention to other solvable challenges for bismuth targetry and target extraction of ²¹¹At.¹⁹

An advantage of ²¹¹At is the ability to label a broad range of molecules for uses as therapeutic radiopharmaceuticals, such as ²¹¹At-labeled macromolecules.¹² A preclinical study of [²¹¹At]trastuzumab targeted to HER2-expressing leptomeningeal breast cancer shows promising results.²⁰ Similarly, ²¹¹At-labeled monoclonal antibodies can be targeted to leukemia (CD-45), lymphoma (CD-20), and multiple myeloma (CD38), with active clinical trials in leukemia and promising pre-clinical studies in lymphoma and multiple myeloma.^21–24 Moreover, ²¹¹At radiopharmaceuticals targeted to norepinephrine transport in neuroblastoma, the sigma-2 target in proliferative tumors, or PARP-1 using a labeled PARP inhibitor, all show promising pre-clinical results.^25–27 These early results indicate considerable promise for ²¹¹At-labeled radiopharmaceuticals, with actionable biomarkers integrated in such studies considered next in this article.

CHANGES IN RADIOPHARMACEUTIAL BIOMARKERS FOR CANCER THERAPY

Radiopharmaceutical biomarker concepts

Choosing individualized cancer therapy on the basis of the patient characteristics and tumor biological features–often termed precision oncology–is increasingly the goal for cancer treatment. Therapy choices in precision oncology are guided by cancer biomarkers that provide information on tumor biologic features that can predict clinical behavior as well as to guide and assess therapeutic response (Table 2). Imaging biomarkers, especially cancer imaging biomarkers, play an increasing role in the practice of precision oncology.²⁸

Table 2.

Description of the types of cancer biomarkers used to direct cancer treatment.

Biomarker Type	Description
Prognosis	Predicts likelihood of death or other adverse outcome; related to features of the cancer independent of approach to treatment
Prediction	Predicts likelihood of response to a specific treatment
Response	Assesses whether or not the patient has responded to the treatment, often described in categories of progression, stable disease, partial response, complete response
Surrogate Endpoint	Response measure highly predictive of important downstream patient outcomes such as overall survival or disease-free survival

Radiopharmaceutical diagnostic-therapeutic pairs as biomarkers

In radiopharmaceutical therapy, a special type of imaging biomarker, typically a close analog of a paired therapeutic radiopharmaceutical and often called a companion diagnostic or theranostic pair, identifies the presence or absence of the therapeutic target with high fidelity and can also guide therapeutic dosing.²⁹ Some examples of clinically used and emerging theranostic pairs are listed in Table 3. The prototypical application is the use of Na¹³¹I for thyroid cancer, where the radiopharmaceutical serves both a diagnostic and therapeutic role. Cancer uptake of diagnostic doses of Na¹³¹I are used to select patients likely to respond to therapeutic doses of the agent,³⁰and more detailed imaging and biodistribution studies using Na¹³¹I can generate normal tissue dose estimates to guide therapeutic dosing, especially for more advanced disease. More recently, Na¹²³I is used as a diagnostic agent given its more favorable imaging characteristics and lower radiation exposure when used for diagnostic purposes. A similar approach is taken for therapy of pheochromocytoma and paraganglioma using [¹²³I]mIBG for staging and as a predictive marker for the recently FDA approved [¹³¹I]mIBG therapeutic, and [¹³¹I]mIBG can also be used for dosimetry calculations (Figure 4).^31,32PET imaging may provide improved qualitative and quantitative accuracy, providing both tumor and normal tissue dose estimates, as has been done for Na¹²⁴I positron emission tomography-computed tomography (PET/CT) when applied to thyroid cancer treatment.

Table 3.

Theranostic pairs in radiopharmaceutical clinical development.

Disease/Target	Therapeutic Radiopharmaceutical(s)	Diagnostic Radiopharmaceutical(s)
Thyroid cancer	Na131I	Na123I, Na131I
Blastic bone metastases	223RaCI2, 89SrCI2, [153Srn]EMTDP	[99mTc]MDP, Na18F
Somatostatin receptor-expressing neuroendocrine tumors	[177Lu]DOTATATE	[68Ga]DOTATATE, [111In] pentetreotide
MIBG-avid advanced pheochromocytoma & paraganglioma	[131I]mIBG	[123I]mIBG, [131I]mIBG

FIGURE 4. Case description.

A 57 year-old woman with SDHB (succinate dehydrogenase complex iron-sulfur complex B) positive progressive metastatic paraganglioma presented for high specific activity [¹³¹I]MIBG therapy. (A) Posterior planar images done 1, 24 and 48 hours after administration of a dosimetric dose of radiotracer (~185 MBq) are used to calculate the maximum safe therapeutic dose followed by a post therapy scan done 7 days after therapy with ~18.5 GBq of high specific activity [¹³¹I]MIBG. The arrows show radiopharmaceutical accumulation in a site of retroperitoneal metastasis. (B) Axial contrast-enhanced computed tomography image of the abdomen done one day before the dosimetric administration shows a retroperitoneal mass (arrow) that had radiopharmaceutical accumulation in (A). (C) Axial post-contrast T1 magnetic resonance image of the abdomen done 16 months after therapy shows significant shrinkage of the retroperitoneal site of disease (arrow). This shrinkage was accompanied by significant symptomatic improvement.

For other targets, theranostic pairs can employ different radionuclide elements that use common methods for linkage to the targeting molecule, providing similar approaches to labeling and biodistribution for the diagnostic and therapeutic agent. An important example includes paired diagnostics for neuroendocrine tumors that express somatostatin receptors (SSTRs) and thus are amenable to peptide receptor radionuclide therapy (PRRT). In this case, the diagnostic agent uses the positron emitter, ⁶⁸Ga, and therapeutic agent uses the beta-emitter, ¹⁷⁷Lu, both linked through common chelators to DOTATATE, a somatostatin analog with rapid clearance and high affinity for SSTR.¹ In this case, a positron emission tomography agent has largely replaced prior usage of the single-photon emission computerized tomography (SPECT) agent [¹¹¹In] pentetreotide. A similar approach followed in prostate cancer, where there are now prostate membrane-specific antigen (PMSA)-targeted agents. Finally, in some cases imaging agents that are biochemically distinct can target a similar biologic process and serve as a companion diagnostic to therapeutic radiopharmaceuticals targeting the same process. This is the case for bone metastasis-targeted agents such as ²²³RaCl₂ and the bone imaging agent [^99mTc]-methylene diphosphonate (MDP).² In this case both agents bind in sites of new bone formation, targeting two components of bone mineralization—phosphate ([^99mTc]MDP) and calcium (²²³RaCl₂), both deposited into the bone matrix by osteoblasts.

Radiopharmaceutical molecular images as biomarkers

Beyond theranostic pairs, molecular imaging has also been used for other biomarker applications to identify potential factors that may mediate resistance to radiopharmaceutical therapy and help assess therapeutic response. For endocrine-related tumors—a group of tumors often treated by radiopharmaceutical therapy (thyroid cancer, neuroendocrine tumors)—some markers have shown promise as markers of therapeutic resistance. For example, studies of [¹⁸F]-fluorodeoxyglucose (FDG) PET/CT applied to thyroid cancer and neuroendocrine tumors suggest that higher FDG uptake is indicative of a more aggressive tumor phenotype that then may be resistant to beta-emitter radiopharmaceutical therapy due to lower target expression, increased radiation resistance, or a combination of both.³³ Diagnostic imaging agents have also been used to assess response to radiopharmaceutical therapy. This is often done with the companion diagnostic agent, which can be helpful in assessing response.³⁴ However, results may be misleading when the diagnostic imaging agent has the same target as the therapeutic agent in that imaging may fail to identify residual (or even progressive/non-responsive) tumor with reduced or absent expression of the target. In this case, an imaging agent targeted to facets of cancer biology other than the therapeutic target may provide a truer indication of treatment response.

Radiopharmaceutical biomarker future directions

As the clinical use of radiopharmaceutical therapy increases, the science of its related radiobiology should also increase. In addition to improved quantification and sophistication in the use of diagnostic-therapeutic pairs, the science of biomarkers for radiopharmaceutical therapy advances in the breadth and depth of both tissue and imaging-based biomarkers. These biomarkers will be used to examine the impact of relevant factors such as the tumor microenvironment, immune activation, DNA repair, and other cancer-relevant biomarkers on the therapeutic success of targeted radiopharmaceuticals. In addition, the ability to label therapeutic companion agents with long-lived positron-emitting isotopes, together with advances in the ability of PET imaging to generate high quality and quantitatively accurate images from low levels of tracer, will lead to improved estimates of dynamic radiopharmaceutical concentration and dosimetry both for the tumor and normal tissues.

CONCLUSION

Radiation oncologists and nuclear medicine physicians are engaged in a resurgence of radiopharmaceuticals for the curative or palliative treatment of cancer. An NCI initiative has reformed its clinical trial enterprise for radiopharmaceuticals that have a radioactive payload. Now the study and the clinical use of alpha-particle and beta-particle emitters are important elements of comprehensive cancer treatments. Biomarkers are critical to select treatment or to evaluate clinical performance of radiopharmaceuticals and need further study. Lastly, diagnostic-theranostic pairs are likely to accelerate radiopharmaceutical clinical development and bring these agents sooner to patients.