Reviews

Radiotheranostics in oncology:
current challenges and emerging
opportunities
SPECT
= Single-photon Lisa Bodei 1,2, Ken Herrmann3,4, Heiko Schöder1,2, Andrew M. Scott5,6,7,8
emission and Jason S. Lewis 1,2,9,10 ✉
computed
tomography Abstract | Structural imaging remains an essential component of diagnosis, staging and response
assessment in patients with cancer; however, as clinicians increasingly seek to noninvasively
investigate tumour phenotypes and evaluate functional and molecular responses to therapy,
theranostics — the combination of diagnostic imaging with targeted therapy — is becoming
more widely implemented. The field of radiotheranostics, which is the focus of this Review, com-
bines molecular imaging (primarily PET and SPECT) with targeted radionuclide therapy, which
involves the use of small molecules, peptides and/or antibodies as carriers for therapeutic radio-
nuclides, typically those emitting α-, β- or auger-radiation. The exponential, global expansion of
radiotheranostics in oncology stems from its potential to target and eliminate tumour cells with
minimal adverse effects, owing to a mechanism of action that differs distinctly from that of most
other systemic therapies. Currently, an enormous opportunity exists to expand the number of
patients who can benefit from this technology, to address the urgent needs of many thousands
of patients across the world. In this Review, we describe the clinical experience with established
radiotheranostics as well as novel areas of research and various barriers to progress.

Tc = technetium Radiotheranostics1,2 differs from the vast majority of technologies, radiotheranostic approaches involve the
F = Fluorine other cancer therapies in its capacity for simultane- administration of radiolabelled diagnostic forms of tar-
Ga = Gallium ous imaging and therapy. This unique capacity can geted compounds (using isotopes such as 99mTc, 18F and
Lu = Lutetium be exploited clinically in various ways, including by 68
Ga), enabling expression of the therapeutic target to be
Y = Yttrium visually assessing the biodistribution of the targeted visualized in vivo with a companion imaging method
drug, selecting patients to receive targeted therapies before switching to the radiolabelled therapeutic coun-
(which can be described as ‘seeing what you treat’) terpart. Radiotheranostics can also enable visualization
and reducing the high risks of failure associated with of tumour burden, thus allowing clinicians to ‘treat what
drug development by visualizing and quantifying both you see’. Moreover, repeat imaging enables clinicians to
the presence and engagement of the target, thus offer- assess the effects of therapy on target expression (Fig. 1).
ing feedback on pharmacodynamics while also testing Certain radiotheranostics involve radionuclides that, in
candidate radionuclides. In this Review, we describe addition to their therapeutic component (as emitters of
the clinical successes achieved thus far with radiother- either auger-, α- or β-radiation) (Tables 1 and 2), can
anostic approaches, including differences from other visualize the agent in real time (owing to emission of
forms of therapy, the current challenges associated either γ or positron radiation) (Fig. 2). For example, the
with the effective and widespread deployment of radio- therapeutic effects of 177Lu-conjugated radiotheranostics
theranostic agents, their future potential and emerging are primarily mediated by the emission of β-radiation,
opportunities. while the γ-emissions can be used for imaging, including
to confirm the successful localization of the agents and to
What is radiotheranostics? quantify the radiation dose delivered to both the target
The selection of patients for targeted therapies is usu- lesions and normal organs5,6. The dosimetric potential
ally based on clinical parameters (such as disease of personalized radiotheranostics is an underexplored
✉e-mail: lewisj2@mskcc.org stage), often incorporating information from molec- aspect that holds tremendous potential for further opti-
https://doi.org/10.1038/ ular biomarkers in tissue (such as PD-L1 (ref. 3) or mization of the therapeutic index by informing decisions
s41571-022-00652-y HER2 expression4). By contrast, and unlike preceding on the balance between the efficacy and toxicity of these

534 | August 2022 | volume 19 www.nature.com/nrclinonc

0123456789();:
 Reviews

Key points target-negative tumour cells when radioisotopes with

longer path length (such as those emitting β-radiation)
• Radiotheranostics combines molecular imaging (primarily PET and SPECT) with are used. This effect, which is limited to high-energy
targeted radionuclide therapy, typically with radionuclides that emit α-, β- or β-particles (emitted by 90Y and 177Lu, among others),
auger-radiation. might offer a distinct advantage against tumours with
• The exponential, global expansion of radiotheranostics in oncology stems from the microscopic variations in target expression, and an
potential to target and eliminate tumour cells with minimal adverse effects owing absence of this form of radiation might limit the effi-
to a mechanism of action that is distinctly different from that of most other systemic
cacy of α-emitting and auger-emitting radioisotopes of
therapies.
short path length. As a result of this effective combi-
• Approvals of new radiotheranostic agents such as 177Lu-DOTATATE and 177Lu-PSMA-617
nation of diagnosis and therapy, the delineation of tar-
alongside the availability of companion diagnostic agents (such as 68Ga-DOTATATE
and 68Ga-PSMA-11, respectively) have driven a resurgence of interest in the field that is
gets with limited or non-uniform expression does not
driving numerous clinical trials testing novel radiotheranostics. necessarily limit their utility as targets for radio­nuclide
• Novel and potentially clinically important radiotheranostic approaches are expanding
therapy. Heterogeneous target expression is one of
the range of targets to include those present in the tumour microenvironment, such the main limitations of the effectiveness of traditional
as blood vessels, cancer-associated fibroblasts, the stromal matrix and immune cells. cancer therapies11; therefore, the ability to deposit lethal
• Although access to radiotheranostics is expanding, challenges such as lack of isotope ionization below the required target saturation levels of
availability, shortages of trained personnel, regulatory burdens and costs might all even the lowest-availability antigens is a major advan-
limit the extent of global dissemination. tage of radionuclide therapies12. Moreover, drug devel-
opment, especially in the field of oncology, is associated
with failure rates of around 90%, earning the transition
therapies on an individual basis. Unlocking this poten- from preclinical research to clinical implementation the
tial and demonstrating the true utility of dosimetry, moniker ‘the valley of death’13. Nevertheless, the devel-
however, will require more prospective data from ongo- opment processes for targeted imaging agents enables
ing and future studies with larger groups of patients in early assessment of the biodistribution of both the
clinically relevant settings. Data from prospective trials intended target (across a range of patients and tumour
that demonstrate the utility of dosimetry over the stand- sites) and the radioactively labelled ligand — ameliorat-
ard approach are finally becoming available7. Efforts to ing the risk of failure, as the development of a potential
simplify organ dosimetry approaches by involving fewer lead ligand could be quickly halted, adapted or accel-
data points are also underway. In addition, opportuni- erated on the basis of data from early biodistribution
ties to combine radiotheranostic approaches with other studies, thereby increasing the success rates of radio­
forms of radiotherapy, such as external-beam radiother- nuclide therapies over those of conventional oncological
apy (EBRT) in patients with prostate cancer, will also therapies. The potential for conjugation of a radioisotope
require dosimetry studies to optimize both dose delivery onto a ligand with established pharmacokinetic and tar-
and therapeutic outcomes. geting properties, as seen with 177Lu-PSMA-617, offers
Radiotheranostic agents that specifically direct another method of minimizing the risk of failed clinical
a lethal payload of α-, β- or to a lesser extent, translation.
auger-emitting radioisotopes8–10 — such as 223Ra, 177Lu
or 111In — have proved very effective as anticancer Established radiotheranostics
treatments (Table 2) . Importantly, radiotheranostic The long history of using radiotheranostics to target the
approaches address the common challenges posed by same structure for both diagnostic imaging and radi-
heterogeneous target expression in two important ways. onuclide therapy dates back to the 1930s, when Hertz
First, the diagnostic aspect allows clinicians to evaluate et al.14 first presented the concept, followed by the use of
the extent of heterogeneous target expression between radioactive iodine in patients with hyperthyroidism14,15.
different lesions before therapy. Second, the thera- The successful clinical application of radioactive iodine
peutic aspect offers the potential for ‘crossfire’ radia- in a patient with thyroid cancer was initially reported
tion with cytotoxic bystander effects on the adjacent, by Seidlin et al. in 1946 (ref.16). Diagnostic imaging and
treatment of both benign (for example, Graves’ disease
and goitre) and malignant (differentiated thyroid can-
Author addresses cer) thyroid diseases is based on selective uptake via
1
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. the sodium–iodine symporter, which is predominantly
2
Department of Radiology, Weill Cornell Medical School, New York, NY, USA. expressed in thyroid tissue. Accordingly, radioactivity —
3
German Cancer Consortium, University Hospital Essen, Essen, Germany. especially during treatment — is selectively deposited
4
Department of Nuclear Medicine, University of Duisburg-Essen, University Hospital in tissues that express the sodium–iodine symporter,
Essen, Essen, Germany. largely sparing other organs and tissues11. Despite these
5
Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, distant origins, radioactive iodine remains an important
Melbourne, Victoria, Australia. treatment for patients with either benign or malignant
6
Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Victoria,
thyroid diseases (Table 1).
Australia.
7
School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
8
Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia. Anti-CD20 radioimmunotherapies
9
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, Several decades after the global expansion in the use
NY, USA. of radioactive iodine, the completely new concept of
10
Department of Pharmacology, Weill Cornell Medical School, New York, NY, USA. radiotheranostics slowly found its way into the clinic.

NAtuRe RevIeWs | ClINIcAl ONcology volume 19 | August 2022 | 535

0123456789();:
 Reviews

Diagnostic phase Therapeutic phase Follow-up

Cycle 1 Cycle x

PET or SPECT isotope α-, β- or auger-emitters

Fig. 1 | Overview of the concept of radiotheranostics. Radiopharmaceuticals are paired with targeted ligands to ‘see
with precision’ and then ‘treat with targeting’.
In most PET
scans a The beginning of the twenty-first century saw the rapid (OS) and time to skeletal complications of men with
development of radioimmunotherapy for patients with castration-resistant prostate cancer (CRPC) and bone
radiotracer
lymphoma. Radioactively labelled mouse monoclo- metastases24. The reported median OS benefit of more
called
nal antibodies targeting the CD20 antigen expressed than 3 months and the corresponding hazard ratio
fluorodeoxyglu
on the surface of all B cells were explored using two (HR) of 0.70, both relative to placebo, were perceived
cose (FDG) is
separate approaches17 and, accordingly, provided a as practice-changing, leading to FDA approval in 2013
used, which is
novel therapy for patients with B cell lymphomas. (Table 2). Before the introduction of 223Ra-dichloride,
similar to In 2002, the FDA approved 90Y-ibritumomab tiuxe- bone-seeking radiopharmaceuticals used for the treat-
naturally tan, the first radioimmunotherapy, for patients with ment of bone metastases were typically β-emitters, such
occurring relapsed and/or refractory, low-grade or follicular B cell as 89Sr-chloride and 153Sm-ethylenediamine tetramethyl-
glucose (a type non-Hodgkin lymphoma (NHL)18 (Table 2). Another ene phosphonate (EDTMP). These agents were usually
of sugar) so anti-CD20-binding mouse antibody, 131I-tositumomab, administered as a single infusion, leading to palliation of
your body received FDA approval in 2003 for the treatment pain symptoms and an improved quality of life (QOL);
treats it in a of patients with relapsed and/or refractory NHL 19 nonetheless, concerns regarding the risks of haemato-
similar way. (Table 2). Regrettably, despite very good clinical per- logical toxicities precluded repeat administration25–27.
formance and a limited toxicity profile in several clin- The success of 223Ra-dichloride led to a rapid decline
ical trials of conventional radioimmunotherapies plus in the use of 89Sr-chloride and 153Sm-EDTMP in the USA,
high-dose myeloablative conditioning chemotherapy, although both are still used clinically in many countries
both drugs were commercially unsuccessful, leading in which 223Ra-dichloride is not routinely available. The
to the discontinuation of 131I-tositumomab in 2014 mechanism of action of 223Ra-dichloride differs from
(refs17,20–22) (Table 2). This commercial failure has been that of other radiotheranostic agents that directly tar-
attributed to various factors, including physicians’ get tumour cells: taking advantage of the similarity of
reluctance to refer patients owing to the availability of radium to calcium, 223Ra predominantly localizes to
alternative non-radioactive therapies, the scarcity areas of increased bone turnover, which is a charac-
of plans for logistical co-operation between nuclear teristic feature of bone metastases, with the α-emitting
medicine and oncology clinics, educational issues and, 223
Ra-dichloride then irradiating the surrounding cells,
in the USA, medical reimbursement concerns23. The including tumour cells. Despite this apparent effective-
market’s rejection of these two radioimmunothera- ness, the widespread clinical use of 223Ra-dichloride had
pies temporarily caused a setback to the field and cur- to be modified when a life cycle management phase III
tailed further investments in the development of other study (ERA 223) combining 223Ra-dichloride with the
radiotheranostic agents. novel androgen-receptor signalling inhibitor (ARSI)
abiraterone revealed an increased rate of symptomatic
Ra-dichloride
223
skeletal events, leading to premature unblinding 28.
The next major milestone was the publication of data 223
Ra-dichloride is currently still considered to be a
from the ALSYMPCA trial, a prospective randomized potent bone-metastasis-directed treatment, although
phase III study, which demonstrated for the first time this agent is now typically administered alongside
that 223Ra-dichloride, delivered over several cycles, sig- bone-protective agents such as zoledronic acid and/or
nificantly prolongs both the median overall survival denosumab.

536 | August 2022 | volume 19 www.nature.com/nrclinonc

0123456789();:
 Reviews

Table 1 | Selected isotopes for use in radiotheranostics

Nuclide Use Half-life (t½) Common production methods Notes
Imaging isotopes
18
F PET 110 min Cyclotron: 18O(p,n)18F Routinely available
43
Sc PET 3.89 h Cyclotron: Ti(p,α) Sc; Ca(d,n) Sc;
46 43 42 43
Paired with 47Sc; can be expensive and production is
Ca(p,n)43Sc
43
challenging
44g
Sc PET 3.97 h Cyclotron: 44Ca(p,n)44m/gSc Paired with 47Sc; high γ-emission can negatively affect
Generator: Ti/ Sc
44 44 dosimetry and make handling more challenging;
cyclotron produces isomer 44mSc, requires in vivo
generator or contaminant
55
Co PET 17.53 h Cyclotron: 54Fe(d,n)55Co; 58Ni(p,α)55Co Paired with 58mCo; production can be challenging
61
Cu PET 3.34 h Cyclotron: 61Ni(p,n)61Cu; natNi(d,x)61Cu Paired with 67Cu; requires local cyclotron access
68
Ga PET 67.71 min Cyclotron: 68Zn(p,n)68Ga Paired with 177Lu
Generator: 68Ge/68Ga
71
As, As, As
72 74
PET 65.30 h, 26.0 h, Cyclotron: 70Ge(d,n)71As Paired with 77As; can be expensive and production is
17.77 days challenging
Cyclotron: 72Ge(p,n)72As
Generator: 72Se/72As
Cyclotron: 74Ge(p,n)74As
76
Br PET 16.2 h Cyclotron: 76Se(p,n)76Br Paired with 77Br and potentially 211At; production can
be challenging
86
Y PET 14.74 h Cyclotron: 86Sr(p,n)86Y Paired with 90Y
89
Zr PET 78.41 h Cyclotron: Y(p,n) Zr
89 89
Readily available; often the optimal isotope for
radiolabelling macromolecules with longer in vivo
pharmacokinetics
99m
Tc SPECT 6.01 h Generator: 99Mo/99mTc Readily available; paired with 153Sm, 186Re and
188
Re; accelerator-driven fast neutron routes under
Cyclotron: 100
Mo(p,2n) Tc
99m
development
124
I PET 4.18 days Cyclotron: 124Te(p,n)124I Paired with 131I; commercially available but can be
expensive; co-emitted high-energy γ-radiation limits
handling and clinical use
132
La, 133La, 134La PET 4.8 h, 3.9 h, Cyclotron: natBa(p,x)132La Availability is currently limited and production can be
6.45 min challenging, paired with 225Ac or 227Th
Cyclotron: natBa(p,x)132La
Generator (in vivo): 134Ce/134La
152
Tb PET 17.5 h Accelerator: tantalum spallation Can be paired with 161Tb; 155Tb (t½ 5.32 days)
(proton/heavy ion) can be used for SPECT; availability is currently
limited
203
Pb SPECT (from 203Tl 51.92 h Cyclotron: 205Tl(p,3n)203Pb Paired with 212Pb; availability is currently limited
daughter)
Imaging/therapeutic isotopes
47
Sc β-Therapy, SPECT 3.35 days Generator: 47Ca/47Sc Availability currently limited
Reactor: Ti(n,p) Sc
47 47

64
Cu PET, β-therapy 12.7 h Cyclotron: 64Ni(p,n)64Cu Readily available
Reactor: 64Zn(n,p)64Cu
67
Cu β-Therapy, SPECT 61.83 h Accelerator: 68Zn(p,2p)67Cu Has the advantages of lower γ-energies
Reactor: 67Zn(n,p)67Cu being co-emitted; availability currently limited
— concerted global efforts to increase supply are
ongoing
67
Ga SPECT, auger 3.26 h Cyclotron: 68Zn(p,2n)67Ga Readily available; mainly used for diagnostic purposes
therapy
77
As β-Therapy 38.83 h Generator: 77Ge/77As Paired with 72As
111
In SPECT, auger 2.81 days Cyclotron: 111Cd(p,n)111In Readily available; mainly used for diagnostic purposes
therapy
117m
Sn SPECT, auger 13.6 days Cyclotron 114Cd(α,n)117mSn Limited availability
therapy
123
I SPECT, auger 13.22 h Cyclotron: 124Xe(p,2n)123I Readily available; mainly used for diagnostic purposes
therapy

NAtuRe RevIeWs | ClINIcAl ONcology volume 19 | August 2022 | 537

0123456789();:
Reviews

Table 1 (cont.) | Selected isotopes for use in radiotheranostics

Nuclide Use Half-life (t½) Common production methods Notes
Imaging/therapeutic isotopes (cont.)
131
I β-Therapy, SPECT 8.03 days Reactor: 130Te(n,γ)131I Readily available; often used as a standalone imaging
isotope for thyroid imaging or as 131I-MIBG. Can be
paired with 124I
153
Sm β-Therapy, SPECT 46.28 h Reactor: 152Sm(n,γ)153Sm Readily available
161
Tb β-Therapy, SPECT 6.89 days Reactor: Gd(n,γ) Gd → Tb
160 161 161
Paired with 152Tb but can also be paired with 68Ga;
availability currently limited — concerted global
efforts to increase supply are ongoing
177
Lu β-Therapy, SPECT 6.65 days Reactor: 176Lu(n,γ)177Lu Readily available; paired with 68Ga
Reactor: Yb(n,γ) Yb → Lu
176 177 177

186
Re β-Therapy, SPECT 3.72 days Reactor: Re(n,γ)186Re
185
Availability currently limited
188
Re β-Therapy, SPECT 17.00 h Generator: 188W/188Re Availability currently limited
Therapeutic isotopes
58m
Co Auger therapy 9.10 h Cyclotron: 58Fe(p,n)58mCo; Paired with 55Co; production can be challenging
Fe(d,n)58mCo; 61Ni(p,α)58mCo
57

Br
77
Auger therapy 57.04 h Cyclotron: 77Se(p,n)77Br Paired with 76Br
Y
90
β-Therapy 64.05 h Reactor: 90Zr(n,p)90Y Readily available, paired with 86Y
149
Tb α-Therapy 4.12 h Accelerator: tantalum spallation Emits γ-, positron- and α-radiation — enabling PET/
(proton/heavy ion) SPECT/α-therapy; availability currently limited
Accelerator: 151Eu(3He,5n)149Tb
211
At α-Therapy 7.21 h Cyclotron: 209Bi(α,2n)211At Availability currently limited — concerted global
efforts to increase supply are ongoing; can be paired
with diagnostic radioiodine and potentially 76Br
213
Bi α-Therapy 45.61 min Generator: 225Ac Availability currently limited
212
Pb/ Bi212
α/β-Therapy 10.6 h/60 min Generator: Ra
224
Availability currently limited
223
Ra α-Therapy 11.43 days Generator: 227Th Readily available
227
Th α-Therapy 18.69 days Generator: Ac
227
Availability currently limited
225
Ac α-Therapy 9.92 days Accelerator: 232Th proton spallation Availability currently limited — concerted global
efforts to increase supply are ongoing; direct
Cyclotron: 226Ra(p,2n)225Ac
accelerator production is limited owing to
Generator: 229Th generator contamination with 227Ac
Light source: 226Ra(γ,2n)225Ra → 225Ac;
226
Ra(γ,p)225Fr → 225Ra → 225Ra
Reactor: 226Ra(n,2n)225Ra → 225Ac;
226
Ra(n,p)225Fr → 225Ra → 225Ra
MIBG, meta-iodobenzylguanidine.

Somatostatin analogues targeting molecule by macrocyclic chelators, such as

The next major step in the field of radiotheranostics began DOTA (instead of DTPA). Several non-controlled, retro­
with the development of somatostatin-receptor-targeting spective studies and a few prospective trials initially
agents for patients with neuroendocrine tumours demonstrated excellent responses (objective response
(NETs). In parallel with development of the imaging rate (ORR) 18–60% for 177Lu-DOTATATE with median
agent 111In-pentetreotide, which was approved for clini- progression-free survival (PFS) of 20–36 months)
cal use by the FDA in 1994, the internalizing properties and mild to moderate toxicities (mainly involving
of somatostatin analogue peptides that specifically tar- the bone marrow and kidneys) in patients with NETs
get somatostatin receptor 2 enable targeted delivery of receiving these therapies34. Among the various ligands
111
In to NET cells29. This treatment was named peptide (DOTATOC, DOTATATE, DOTANOC), 177Lu-labelled
receptor radionuclide therapy (PRRT). Despite involving compounds quickly gained widespread use owing to the
the administration of high levels of radioactivity (up to high response rates and advantages over 90Y peptides
18.5 GBq of 111In per cycle and, cumulatively, 160 GBq), including the possibility of γ-imaging and reduced tox-
111
In-pentetreotide had only modest levels of efficacy icities. The year 2012 saw the launch of the prospective,
(partial response rate of 8%, related to the lack of inter- randomized phase III NETTER-1 trial, which in 2017
calation of the electrons in the DNA helix30,31), with high revealed a significant improvement in PFS in patients
costs. This limited efficacy led to the progressive aban- with somatostatin-receptor-positive midgut carcinoid
donment of auger-emitters in favour of β-emitters32,33 tumours who received four cycles of 177Lu-DOTATATE,
(initially 90Y and, more recently, 177Lu) linked to the compared with non-reactive high-dose octreotide35. The

538 | August 2022 | volume 19 www.nature.com/nrclinonc

0123456789();:
 Reviews

corresponding HR of 0.21 reflected an almost five times significant improvement in median PFS and the excel-
greater risk of disease progression for patients who did lent tolerability seen at earlier time points37. Importantly,
not receive 177Lu-DOTATATE. Given the potential risks the FDA also approved 68Ga-DOTATATE (Table 2), a
of haematological toxicities associated with radiothera- one-pot, simple kit-based preparation, for PET-based
nostics, in addition to the mild to moderate severity of imaging of tumours in both adult and paediatric patients
most toxicities, QOL evaluations have provided addi- with somatostatin-receptor-positive NETs. The radio-
tional evidence of the tolerability and efficacy of this theranostic partnering of 68Ga-DOTATATE (USA) or
therapeutic approach — which are important criteria 68
Ga-DOTATOC (DOTA-(d-Phe1, Tyr3)-octreotide)
for regulatory authorities. Indeed, the NETTER-1 trial (EU) and 177Lu-DOTATATE has made the ‘treat what
demonstrated significantly improved health-related you see’ paradigm into a reality.
QOL in patients receiving 177Lu-DOTATATE compared The design of the ALSYMPCA24 and NETTER-1
with the control group (including a mean time to dete- (ref.35) trials provides a model for the development of
rioration of overall health status of 28.8 months versus new radiotheranostic agents and for expanding the use
6.1 months)36. These ground-breaking results led to the of existing radionuclide therapies. Current phase III tri-
FDA approval of 177Lu-DOTATATE and an improvement als testing the efficacy of somatostatin-based radiother-
in the standard of care for patients with locally advanced anostics in patients with GEP-NETs include COMPETE
and/or inoperable somatostatin-receptor-positive gas- (NCT03049189), COMPOSE (NCT04919226) and
troenteropancreatic NETs (GEP-NETs) almost 25 years NETTER-2 (NCT03972488), all of which are designed to
after the introduction of PRRT; they also attracted expand the application of somatostatin-receptor-directed
the attention of major pharmaceutical companies. radiotheranostics to patients with more aggressive
Long-term follow-up data from NETTER-1 confirm the tumours. Additional studies are currently exploring the

Table 2 | Radiopharmaceuticals approved for radionuclide therapy in oncology indications

Agent Approval Companion Indication Efficacy data
(FDA, EMA) diagnostics
[131I]sodium 1971a,118 [131I]sodium iodide Treatment of selected patients with Enables complete thyroid ablation in 92% of
iodide differentiated thyroid carcinoma patients with low-risk thyroid cancer; 98% were
free of disease at 5 years146; uptake observed
in 59% of patients with metastatic thyroid
cancer147,148
153
Sm-EDTMP 1997, 1998 99m
Tc-bisphosphonates, Palliation of bone pain in patients 62–72% had pain relief at 4 weeks following a
including with multiple painful skeletal single dose of 153Sm-EDTMP, including complete
99m
Tc-medronate; metastases pain relief in 31%; pain relief persisted for up to
99m
Tc-oxidronate; 16 weeks in 43% of patients149; improvements in
99m
Tc-pyrophosphate 4-week pain scores and opioid use vs controls26,149
90
Y-ibritumomab 2002, 2004 111
In-ibritumomab R/R low-grade or follicular B cell ORR 80% vs 56%, P = 0.02 for rituximab alone
tiuxetanb NHL; previously untreated patients (CR in 30% vs 16%); median DOR 14.2 vs 12.1 months
with follicular NHL who achieve (P = 0.64), durable responses ≥6 months. in 64% vs
a partial or complete response to 47% (P = 0.03)17; clinical benefit was also seen in
first-line chemotherapy various combination settings150–154
131
I-tositumomabc 2003, 2003 131
I-tositumomab CD20+ R/R low-grade, follicular ORR 49–64%; median DOR 6.5–16 months in
or transformed NHL following single-arm studies155,156
disease progression during or after
rituximab
I-iobenguane
131
2018a,157 123
I-iobenguane Noradrenaline-positive ORR 25%, DCR 92%; 53% of responders had
(or MIBG) pheochromocytomas or tumour responses lasting ≥6 months, median OS
paragangliomas 36.7 months158
223
Ra-dichloride 2013, 2013 – CRPC with symptomatic bone Median OS 14.9 vs 11.3 months with placebo,
metastases and no known visceral HR 0.70, 95% CI 0.58–0.83, P < 0.001; time to
metastases first SSE 15.6 vs 9.8 months, HR 0.66, 95% CI
0.52–0.83, P < 0.001; increase in FACT-P QOL score
≥10 points in 25% vs 16% of patients, P = 0.02
(refs24,159,160)
177
Lu-DOTATATE 2018, 2017 68
Ga-DOTATATE (USA); Somatostatin receptor-positive Median OS 48.0 vs 36.3 monthsd, HR 0.84, 95% CI
64
Cu-DOTATATE (USA); gastroenteropancreatic 0.60–1.17, P = 0.30; increase in QOL37
68
Ga-DOTATOC (EU) neuroendocrine tumours
177
Lu-PSMA-617 2022, Ga-PSMA-11, FDA
68
Treatment of metastatic CRPC Median PFS 8.7 vs 3.4 months; median OS 15.3 vs
pending approved in 2021 and following disease progression on 11.3 months in the 177Lu-PSMA-617 and control
2022 AR inhibitors and taxane-based groups; time to first SSE 11.5 vs 6.8 months HR
chemotherapy 0.50, 95% CI 0.40–0.62, P < 0.001 (ref.43)
a
EMA nationally authorized medicinal product. bDiscontinued in the USA in 2021. cApproval withdrawn and discontinued in 2014. dImprovement in median
overall survival (OS) likely underestimated owing to 36% crossover from control arm. AR, androgen receptor; CI, confidence interval; CR, complete response;
CRPC, castration-resistant prostate cancer; DCR, disease control rate; DOR, duration of response; DOTATATE, DOTA0, Tyr3-octreotate; EDTMP, ethylenediamine
tetramethylene phosphonate; HR, hazard ratio; MIBG, meta-iodobenzylguanidine; NHL, non-Hodgkin lymphoma; OR, objective response; ORR, objective response
rate; PFS, progression-free survival; PSMA, prostate-specific membrane antigen; QOL, quality of life; R/R, relapsed and/or refractory; SSE, symptomatic skeletal event.

NAtuRe RevIeWs | ClINIcAl ONcology volume 19 | August 2022 | 539

0123456789();:
Reviews

possibility of using 177Lu-DOTATATE for the treatment therapy (typically ARSIs with or without GNrH agonists
of other somatostatin-receptor-expressing tumours or glucocorticoids) compared with standard-of-care
beyond NETs, such as small-cell lung cancer and therapy43 (Table 2). In March 2022, the FDA approved
meningioma (NCT05142696, NCT03971461). 177
Lu-PSMA-617 for men with PSMA-positive met-
astatic CRPC as determined by 68Ga-PSMA-11 PET
PSMA-based agents imaging. Data from the VISION trial also indicate that
NETs are rare tumours that affect a limited number of 177
Lu-PSMA-617 plus standard-of-care therapy delays
patients, who often receive treatment at a few specialized the time to worsening of health-related QOL, the onset
centres, although the expansion of radiotheranostics to of pain and the time to first symptomatic skeletal event
relatively common malignancies such as prostate, breast versus standard-of-care therapy alone43 (Table 2). The
or lung cancer is transforming both the field and its case for FDA and EMA approval of 177Lu-PSMA-617 in
perception. Accordingly, advocates of radiotheranostic 2022 was supported by additional data from the TheraP
approaches have responded quickly to the introduction trial, a randomized phase II study that compared the
of a highly specific peptide ligand capable of binding efficacy of 177Lu-PSMA-617 with that of cabazitaxel in
to the prostate-specific membrane antigen (PSMA)38, men with metastatic CRPC with disease progression
which is overexpressed in most prostate cancers. Initial on docetaxel (12-month PFS 19% versus 3%), thus
reports on imaging39 and radionuclide therapy40 with indicating the superiority of 177Lu-PSMA-617 over
PSMA-targeted radiotheranostics have resulted in second-line chemotherapy44. Patient-reported outcomes
the development of multiple PSMA binding ligands. The (PROs) were also improved with 177Lu-PSMA-617 in the
past few years have seen the FDA approval of two PSMA TheraP trial44. Prospective trials are increasingly incor-
PET agents, 18F-DCFPyL and 68Ga-PSMA-11 (Table 2) porating PRO-based QOL assessments in an attempt
for patients with prostate cancer with suspected metas- to provide a more holistic evaluation of the effects of
tases who are candidates for initial definitive therapy radiotheranostics. Building on data from the TheraP
and for those with suspected disease recurrence based and VISION trials, several ongoing phase III trials are
on an elevated serum prostate-specific antigen (PSA) expected to provide data on the efficacy of PSMA-based
level. PSMA PET is now also included in clinical prac- radiotheranostics earlier in the course of metastatic
tice guidelines41, the 2022 NCCN guidelines42 for pri- CRPC, including PSMAfore (NCT04689828) and
mary disease staging, for the detection and localization PSMAddition (NCT04720157); on the performance
of disease recurrence or persistence in patients with of alternative peptide ligands, including in SPLASH
sustained high serum PSA levels after radical pros- (NCT04647526) and ECLIPSE (NCT05204927); and
tatectomy or radiotherapy, for documenting disease on antibody-based PSMA-targeted radiotheranos-
progression, and in the selection of patients for appli- tics in PROSTACT (NCT04876651). Other trials are
cation of 177Lu-PSMA-617 as in the phase III VISION exploring the efficacy of α-emitters such as 225Ac-PSMA
study. Data from this trial were published in 2021 and (NCT05219500, NCT04597411). New additional diag-
indicate a statistically significant improvement in OS nostic agents that could be combined with approved
for patients with metastatic CRPC who received up therapeutic agents are also currently in development,
to six cycles of 177Lu-PSMA-617 plus standard-of-care such as 64Cu-SAR-bisPSMA 45, which contains two

a b c e g h i j

d f

Fig. 2 | Responses to approved theranostics, as demonstrated using radical prostatectomy, androgen-deprivation therapy and abiraterone.
their imaging counterpart. a | Coronal PET 68 Ga-DOTATATE e | After five cycles of 177Lu-PSMA-617 , the adenopathy is markedly
maximum-intensity projection (MIP) depicting a patient with an atypical decreased in size. f | Fused axial PET–CT images provide a more detailed
bronchial carcinoma, with disease progression on everolimus with view of the pelvic nodal metastases after 177Lu-PSMA, with several nodes
extensive osseous (blue solid arrows) and hepatic (dashed arrows) that are visible in panel d no longer present in panel f. g,h | Anterior (panel g)
metastases. b | After four cycles of 177Lu-DOTATATE, a marked reduction in and posterior (panel h) coronal PET 99mTc-MDP MIPs depicting a patient
both the number and extent of bone and liver lesions can be observed. with de novo metastatic Gleason grade 9 prostate cancer with metastatic
c,d | Coronal PET 68Ga-PSMA-11 MIP (panel c) and fused axial PET–CT lesions located in the spine, ribs, pelvis and femur. i,j | After six cycles of
images (panel d) depicting a patient with Gleason grade 9 prostate cancer 223
Ra-dichloride, a decreased intensity of uptake can be observed at all
with extensive retroperitoneal and pelvic nodal metastases following metastatic sites.

540 | August 2022 | volume 19 www.nature.com/nrclinonc

0123456789();:
 Reviews

PSMA binding motifs, thus offering a ‘dual-targeting’ an editorial published in September 2019, the number
approach that can be adapted according to availability of US patients eligible each year for novel radiothera-
and logistics, and is currently being tested in the phase I nostic agents52 includes 20,000 with NETs for diagnostic
PROPELLER study (NCT04839367). SAR-bisPSMA 68
Ga-DOTATATE or 64Cu-DOTATATE PET imaging,
could potentially also be deployed with the therapeutic and 7,500 for 177Lu-DOTATATE therapy, as well as
67
Cu isotope. 160,000 patients with prostate cancer who are eligible for
diagnostic PSMA imaging and 40,000 for therapy with
Other agents 177
Lu-PSMA. The accuracy of these estimates remains
Another important therapeutic concept fitting beneath to be established, although these numbers suggest that
the umbrella of radiotheranostics is the use of radioac- radiotheranostic procedures are becoming a relevant
tive microspheres (small, injectable 25–32 µm diameter option for an increasing number of patients. Additional
particles typically made from glass, resin or poly-lactic factors driving the expansion of radiotheranostic appli-
acid)46 for the delivery of selective intra-arterial radio­ cations include: first, the availability of data from sev-
therapy (SIRT), which is often referred to as transar- eral pivotal clinical trials that demonstrate the clinical
terial radioembolization (TARE). Three distinct types benefits of novel diagnostic and therapeutic radiophar-
of microsphere are currently available, including glass maceuticals such as NETTER-1 (refs35,36), OSPREY53,
or resin microspheres bound to 90Y and a poly-lactic 68
Ga-PSMA-11 (ref.54), VISION43 and TheraP44; second,
acid labelled with 166Ho (ref.47). All three types of micro- the 2022 FDA approval of 177Lu-PSMA-617 for the treat-
sphere can be used to treat patients with primary liver ment of metastatic prostate cancer; third, the adoption
cancers or liver metastases, for example, from primary of new technologies for early cancer detection 55–58
colorectal cancer, NETs or breast cancer47–49. Despite and the availability of better therapies that improve both
initially encouraging clinical results, data from a suc- the response rates and OS of patients with cancer59–62;
cessful phase III study involving TARE were only fourth, the rising prevalence of cancer worldwide
reported in December 2021 (ref.48). The EPOCH study (19.3 million new cases were registered worldwide in
(NCT01483027) demonstrated a significant improve- 2020, and this number is expected to increase to
ment in both median PFS (8.0 months versus 7.2 months; 28.4 million in 2040, with the largest increase occurring
HR 0.69, 95% CI 0.54–0.88; P = 0.0013) and hepatic PFS in developing countries by 2040)63; fifth, the increas-
(9.1 months versus 7.2 months; HR 0.59, 95% CI 0.46–0.77; ing global life expectancy60–62,64; and sixth, techno-
P < 0.0001) in patients who received radioembolization logical advances, such as expected improvements in
with 90Y-glass microspheres plus chemotherapy com- small-molecule, peptide and antibody technologies, the
pared with those who received chemotherapy only; identification of new targets and delivery mechanisms
however, median OS was not significantly different48. for radionuclide-based imaging and therapy (such
Personalized dosing seems to improve the response rates as cell-surface molecules and targets located in the
to this approach, although these promising phase II data tumour microenvironment), and the emergence of novel
need to be confirmed in a randomized phase III study7,50. light-based probes and combination therapies, such as
those involving antibody–drug conjugates (ADCs).
Promises and challenges for radiotheranostics
Promises Market valuation. A general consensus exists that radi-
Rapid growth and future demand. Radiotheranostic otheranostics has a promising future, although estimates
applications are gaining prominence in both cancer of market value and predictions of growth vary. In part,
imaging and cancer therapy51. This increase in interest this variation relates to how the market is defined: for
largely relates to the advent of diagnostic and therapeutic example, narrowly as the market for radiopharmaceuti-
compounds that have fundamentally changed the way cals; more broadly as the market for nuclear medicine;
we manage cancer. Some of these procedures are now or, as the overall theranostics market that also includes
widely available clinically, and others will likely soon fol- optical probes and in vitro testing and the range of radio­
low. For example, although the NETTER-1 and VISION pharmaceuticals considered relevant to theranostic
trials both used standard doses for therapy, the therapeu- approaches. Accordingly, estimated market valuations
tic index can potentially be improved by optimizing the for 2021 range from $1.7 billion to ~$6.0 billion65–67,
amount of injected radioactivity, optimizing treatment with estimated compound annual growth rates (CAGRs)
regimens including their time intervals and the num- ranging from 4.7–10.7% to as high as 19.6% between
ber of treatment cycles, and by personalizing treatment 2022 and 2029–2031 (Fig. 3). In an attempt to increase
based on dosimetry and early imaging-based response both efficiency and profitability, the radiopharmaceu-
assessments. tical industry has seen several mergers and acquisitions
The number of new clinical trials exploring radio- over the past years. Nevertheless, start-up companies
theranostic approaches continues to increase substan- continue to enter this growing market in an attempt to
tially. This development is driven by several factors, address previously unmet needs, such as the poor prog-
including the growing availability of novel hybrid noses of patients with certain cancers (despite consid-
imaging technologies for better cancer detection and erable general progress with non-radiolabelled targeted
monitoring and the increasing application of nuclear therapies), and to develop novel methods of killing
medicine in oncology, including the approvals of sev- cancer cells using targeted radiation.
eral new radiotheranostic agents for cancer diagnosis North America will remain the dominant region
and therapy. For example, according to estimates from for radiotheranostic applications, with ~45% of market

NAtuRe RevIeWs | ClINIcAl ONcology volume 19 | August 2022 | 541

0123456789();:
Reviews

12

FDA approval of
10 177
Lu-PSMA-617
FDA approval of for PSMA-positive
177
Lu-DOTATATE mCRPC
8

US$ (billions)
FDA approval of for NETs
223
Ra-dichloride for
bone-metastatic CRPC
6

0
2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026

99m
Tc FDG-PET Other diagnostics Radiotherapeutics

Fig. 3 | The predicted global nuclear medicine market 2013–2026. This projected market growth likely reflects the
availability of a greater number of agents, implementation at an increasing number of centres and projected increases in
the numbers of patients with cancer globally. ©MEDraysintell Nuclear Medicine Report & Directory, Edition 2021. CRPC,
castration-resistant prostate cancer; mCRPC, metastatic CRPC; NET, neuroendocrine tumour; PSMA, prostate-specific
membrane antigen.

value, followed by Europe (led by Germany, the UK and adjusted to compensate for the much shorter shelf-lives
France) and the Asia Pacific region (led by China, Japan of radiotheranostic agents and the resulting limitations
and India). Substantial growth is also expected both in the number of patients who can receive treatment per
in South America and in parts of Asia over the com- production cycle. However, as previously mentioned,
ing decade. A substantial unmet need for radiothera- such challenges have already been successfully addressed
nostics also exists in low and middle income countries for radioiodine, 90Y radioembolization and even for rel-
(LMICs)51,65–67. atively short-lived diagnostic radioisotopes such as 18F
Assuming that the current promise of radiotheranos- and 68Ga. The limited global supply of rare earth radioi-
tics holds up, justifying the continued large investments sotopes, which are frequently used for radiotheranostic
in research and development (R&D) and the clinical applications, also poses challenges.
introduction of new agents that improve patient out-
comes, the greatest improvements in outcomes are likely Workforce and equipment. A Lancet Oncology
to be achieved in cancers with the highest incidence and Commission report in 2021 (ref.68) revealed a serious
mortality rates (such as lung cancer, with 235,760 new international shortage of physicians specializing in
cases and 131,880 deaths in the USA in 2021) as well as nuclear medicine and the use of the advanced imaging
in certain malignancies with a generally lower incidence equipment (such as PET–CT or SPECT–CT) needed for
that also have very high mortality rates, such as pancre- therapy planning, dosimetry and response assessment.
atic, ovarian, small-cell lung and hepatobiliary cancers. The current number of nuclear medicine physicians
However, the expansion of radiotheranostics also faces and treatment facilities might suffice in some western
numerous challenges. countries, although the commission noted significant
shortages of both staff and equipment in many other
Challenges countries across the globe, especially in LMICs.
Production, distribution and storage. Both within and
across countries, wide variations exist in the availabil- Access to radiotheranostics. To bring the benefits of radio­
ity of medical cyclotrons, good manufacturing practice theranostics to patients worldwide and also overcome
(GMP)-compliant production facilities (which can lead inequities in access to health care, these agents must
to substantial differences in costs between commercial be made accessible in all countries with appropriate
suppliers and ‘in-house’ producers) for radiotheranos- nuclear medicine facilities. For example, an analysis by
tic agents, and dedicated theranostic treatment centres the Society of Nuclear Medicine and Molecular Imaging
that meet the relevant radiation safety standards. Thus, Global Initiative published in September 2020 (ref.69)
reliable distribution networks capable of ensuring both showed that agents that were introduced clinically many
the safe and timely delivery of these agents must be years ago, such as 131I for the treatment of hyperthyroid-
established to meet the rapid increase in demand. All ism, were available in 94% of the 35 queried countries
radiotheranostic agents have a limited shelf-life, mainly (including several LMICs), whereas other agents (which
owing to the radioactive half-lives of the radionuclides are used widely in routine clinical practice in the USA
(Table 1). In contrast to conventional cancer therapies, and parts of western Europe) such as 153Sm-EDTMP
both manufacturing (central versus local) and logistics were only used in 51% of countries. 177Lu-DOTATATE
(delivery, application and waste management) must be and 177Lu-PSMA were rarely available, likely reflecting

542 | August 2022 | volume 19 www.nature.com/nrclinonc

0123456789();:
 Reviews

the fact that several of these agents were only approved explain why 177Lu-DOTATATE received FDA approval
by the FDA in the past few years and have not been in February 2018, approximately 4 months after EMA
approved in many countries outside of Europe and approval. Conversely, other national regulatory agencies
the USA. might not necessarily make the same decisions as the
FDA, owing to the application of different thresholds for
Training of expert personnel. The size of the existing clinical benefit and/or cost effectiveness73.
workforce and the number of sites capable of preparing
and administering radiotheranostic agents in both the Clinical trials and the real world. To date, the devel-
USA and many other countries is currently simply not opment of radionuclide therapies has been largely
sufficient to meet the growing demand — hence the need enabled by compassionate use provision available at
for training programmes (at all levels) and site upgrades academic centres and single-centre trials. However,
and/or the establishment of truly multidisciplinary care robust data from multicentre trials are required for
centres capable of providing adequate medical physics marketing approval of new drugs, including radiop-
and clinical and nursing care in the same location. A cru- harmaceuticals. These trials are generally conducted
cial need exists for a new generation of radiochemists and under very specific conditions (including in carefully
radiopharmacists to safely design, manufacture and pro- selected patient populations with highly specific inclu-
duce diagnostic and therapeutic radiopharmaceuticals sion and exclusion criteria and timings of procedures);
on an industrial scale. data from such trials might not always accurately reflect
Radionuclide-based therapies must be adminis- outcomes in ‘real-world’ conditions when these treat-
tered by properly trained physicians, generally nuclear ments are administered less selectively to patients with
medicine specialists, and in certain scenarios by radi- differing disease burdens, comorbidities, ages and/or
ologists with additional training in nuclear medicine. ethnicities74–76. Interest in investigating how promising
Historically, many nuclear medicine training pro- clinical trial data can be reproduced in the real world
grammes have placed less of an emphasis on thera- has therefore increased. The collection of real-world evi-
peutics than on diagnostic procedures. This emphasis dence (RWE) is one option, and this approach is increas-
largely reflects the distribution of procedural volumes ingly being used by the FDA77. However, obtaining a
(roughly 90% diagnostic versus 10% therapeutic in statistically robust amount of RWE often takes several
many larger institutions) and, increasingly since 2001, years, is associated with additional costs and remains far
the widespread use of hybrid imaging techniques, from perfect as a confirmatory tool78.
necessitating additional training in structural imaging
techniques. However, with the increasing availability Managing the expectations of physicians and patients.
of radiotheranostic agents, training programmes must The VISION and TheraP trials have provided evidence
now place a greater emphasis on the administration of to support the utility of 177Lu-PSMA-617 in patients with
radionuclide-based therapies with adequate training metastatic CRPC, providing a justification for approval,
in the principles of internal medicine. Beyond techni- which was announced in March 2022. However, compre-
cal expertise in the safe handling of these agents, along hensive data on the utility of 177Lu-PSMA-617 in patients
with expertise in dosimetry and radiation safety, this with early-stage prostate cancer, or in those with other
training also requires greater engagement with patient malignancies, are still being generated. Moreover, the
management, including a deep understanding of disease gap between the development of new radiotheranostic
processes, pathology, pharmacology and treatment algo- probes and their successful clinical translation and reg-
rithms, to enable physicians to apply radiotheranostics ulatory approval is growing. Nevertheless, anecdotally,
in the overall context of the patient’s disease manage- patients are already enquiring about this therapy for
ment. Such training will probably require dedicated non-approved conditions, reflecting sometimes unreal-
subspecialty or fellowship training pathways70–72. istic expectations, in part related to press releases and
based on opinions expressed by various online media79.
Regulation. Before marketing approval, national or Although unrealistic expectations must be tempered,
international regulatory bodies (such as the FDA in the unfounded fears must also be addressed. Referring phy-
USA or EMA for the EU) must review the safety and sicians, patients, their families and the general public
efficacy of any proposed new drugs or imaging agents. might harbour misgivings about the safe use of radio­
Novel agents can be administered to patients before pharmaceuticals. Such ‘radiophobia’ is a real effect80, and it
marketing approval under the auspices of a clinical is for health-care providers, hospitals, treating physicians
trial; however, full regulatory approval generally forms and patient support groups to fully educate the public on
the basis for the initiation of widespread clinical use both the advantages and limitations of radiotheranostics.
and the initiation of reimbursement systems by both
government agencies and private insurers. A lack of Financial viability. The development and clinical appli-
co-ordination of approval processes between various cation of radiotheranostics is associated with high costs.
regulatory agencies can delay drug availability: for exam- The reimbursement processes for radiotheranostics
ple, the FDA does not recognize the approval decisions are often complex and vary across different national
of other national agencies or the EMA, and independ- health-care systems according to whether reimburse-
ent FDA review is required before marketing approval ment is government funded or insurance based, the
in the USA, sometimes leading to delays and/or addi- mechanisms by which reimbursement costs are calcu-
tional administrative costs. These considerations might lated and the availability of radiotheranostics. Owing to

NAtuRe RevIeWs | ClINIcAl ONcology volume 19 | August 2022 | 543

0123456789();:
Reviews

these various aspects, reimbursement might not always that provide employer-sponsored health insurance
fully cover the true costs of delivery of this therapy. This and investment into education and infrastructure by
could introduce barriers to both access and availability, the federal government88. Although radiotheranostics
particularly in LMICs. The high costs of newly approved is currently only a very small fraction of health-care
therapeutic radiopharmaceuticals mirrors that seen with expenditure, this situation could change rapidly with
other newly approved cancer drugs81, whose cost effec- the advent of new agents marketed at similar prices to
tiveness and sometimes marginal benefits have been 177
Lu-DOTATATE and 223Ra-dichloride. Despite these
criticized73,76. agents often becoming available at lower market prices in
The high costs of novel radiotheranostic agents partly LMICs, their costs relative to GDP renders these agents
reflect the R&D costs of radiotheranostics. In 2019, the essentially unaffordable in many of these countries. Thus,
pharmaceutical industry overall spent $83 billion on even when accounting for the fact that the market prices
R&D. This was ten times more than in the 1980s when of most drugs and radiopharmaceuticals are generally
adjusted for inflation, increasing from historic rates of lower outside the USA, costs are a major challenge to the
around 12–15% to up to 25% of net revenues. A simi­ worldwide89 adoption of radiotheranostics and will need
lar level of investment in R&D of around 15% can to be addressed in the coming years.
only be observed in certain other innovation-driven
industries such as software development and the Biological challenges. Currently, therapeutic strategies
manufacture of semiconductors82. Novartis, the pro- involving radiotheranostics lead to objective responses
vider of 177Lu-DOTATATE and 177Lu-PSMA-617, spent in only 30–60% of patients. Moreover, median PFS is
US$8.98 billion (18.4% of net revenue) on R&D in only in the region of 28–36 months for patients with
2020 (ref.83). Nevertheless, high R&D expenditure is at indolent NETs5 and ~9 months for those with aggressive
best only one contributing factor to high drug prices. metastatic CRPCs43.
Although pricing in the UK and other countries may be The reasons for the lack of consistent tumour con-
based on health technology assessments of the expected trol include suboptimal drug delivery owing to insuf-
benefit and willingness to pay for such benefit, in the ficient tumour perfusion, heterogeneous expression
USA and in many other countries with multiple private of receptors and/or target antigens on the tumour cell
insurance providers, the pricing of novel drugs is based surface, and the type of radiation delivered. Most cur-
on market considerations and closely linked to the price rent radiopharmaceutical therapies use radionuclides
point of other drugs that are approved for the same or that emit β-radiation, which confers the advantage of
similar indications. Thus, drug pricing is somewhat a greater radiation coverage area; however, β-emitters
arbitrary and not necessarily linked either to R&D costs mainly induce single-strand breaks in DNA, as opposed
or to the extent of clinical benefit. Moreover, owing to to α-emitters, which mainly induce double-strand DNA
differences in the approach to medical reimbursement, breaks90. A lack of retention of radiopharmaceuticals at
market prices often vary substantially from country to the target site (owing to rapid dissociation of the targeted
country. In the USA, drug prices are currently not regu­ probe) might also limit efficacy. Finally, some tumours
lated or negotiated by government agencies, such as are inherently radioresistant or might acquire radiore-
the Center for Medicare and Medicaid services (CMS), sistance following irradiation. This resistance arises
which contributes to higher health-care costs compared from the diverse range of genomic alterations present in
with those seen in many other countries84–86. The domi­ cancer cells and their microenvironment, which, under
nant positions of a few pharmaceutical companies are the selective pressures of toxic radiation, can become
another factor that contributes to high prices. For example, radioresistant via cellular senescence, hypoxia, meta-
Novartis, the manufacturer of 177Lu-DOTATATE and bolic alterations and/or an increased capacity for DNA
177
Lu-PSMA-617 currently dominates the market damage repair91.
for theranostic agents, although this situation might Tumour dedifferentiation, which is associated with
change as other companies begin to develop alternative the loss of specific cell-surface receptors or antigens,
PSMA-targeted theranostics. is an important aspect of radioresistance, particularly
The high and rising costs of modern anticancer drugs when applied to targeted radiotheranostics. Relevant
and (now increasingly) radiopharmaceuticals poses examples of tumour dedifferentiation include the loss of
considerable challenges to both health-care systems sodium–iodine symporter expression in dedifferentiated
and patients worldwide. High drug prices are particu- thyroid cancer and of somatostatin receptor expression
larly problematic in the USA: US health-care spending in high-grade NETs92,93. The relative paucity of specific
currently accounts for 17.7% of gross domestic product targets for clinically aggressive cancers, which confer a
(GDP) and has continued to increase (in 2019 by 4.6%, particularly poor prognosis, is an additional challenge.
reaching US$11.6 trillion). During the next decade,
national health-care expenditure is projected to increase Balancing efficacy and toxicity. Therapeutic efficacy
by 5.4% annually, to 19.7%, a growth rate that is 1.1% requires the delivery of a certain target dose of radiation
faster than projected GDP growth87. Economically devel- to tumour cells. This consideration is particularly rele-
oped countries generally tend to spend a larger propor- vant for β-emitters, which induce mainly single-strand
tion of GDP on health care; nonetheless, the trajectory breaks and scattered double-strand breaks, which can
of US health-care spending might not be sustainable be less cytotoxic than α-radiation11,94. Unfortunately,
and is beginning to constrain investment in other sec- improving efficacy by augmenting the amount of radi-
tors of society, such as R&D investments by companies ation administered also increases the risks of toxicity

544 | August 2022 | volume 19 www.nature.com/nrclinonc

0123456789();:
 Reviews

to nonmalignant tissues95. This trade-off between effi- in whom concerns of possible myelodysplasia were
cacy and toxicity is a crucial determinant of the amount tempered by the expected improvements in survival
of radioactivity that can be safely administered and duration. Of note, clinical characteristics and prior
needs to be studied specifically for each therapeutic treatments received are both only partially predictive of
radiopharmaceutical. adverse events in a given individual. This lack of any
Most contemporary therapeutic radiopharmaceuti- notable correlation has led to the concept of individual,
cals administered at predefined tolerated doses confer possibly genomics-based, susceptibility94.
mild to moderate toxicities according to NCI criteria96. To address these safety issues, several strategies have
Such events are broadly characterized as either acute, been proposed101, such as the use of α-emitter ther-
subacute or chronic, but require better biological char- anostics (which seem to be effective even in patients
acterization. Transient subacute bone marrow compro- with cancers that are refractory to 177Lu-PSMA-617 or
mise (transient anaemia and decreased white cell and 177
Lu-DOTATATE102,103), development of innovative
platelet counts) is an adverse event that is common agents for current targets, targeting of alternative recep-
to many radiotheranostic agents97. Chronic adverse tors and/or antigens, use of combination therapies and/or
events are clinically most concerning and are typically sensitization techniques, locoregional administration of
permanent. Most of these events can be ascribed to therapy, use of free-radical scavenging therapies36,104–106
two mechanisms: inflammation and/or fibrosis, result- and individualization of therapy8,107,108. Further assess-
ing in reduced organ function; and radiation-induced ments regarding how variances in host genomic pro-
clonal selection, leading to uninhibited proliferation94. files influence a patient’s response to various cancer
Xerostomia, the chronic salivary gland toxicity drugs might prove crucial for the development of novel
resulting from exposure to high-dose radioiodine individualized treatment strategies109.
or PSMA-targeted radiotheranostic agents involv-
ing 177Lu, is an example of a chronic fibrotic adverse Future developments
effect. This effect can lead to mild xerostomia in 8% Most multicentre clinical trials of radiotheranostics
of patients, and this risk increases to 89% with use of involve patients with metastatic NETs or prostate cancer.
225
Ac-PSMA, becoming severe in 10% of patients treated However, an increasing number of novel targeted radio-
with α-emitters92–94,98 Another example is the chronic theranostic agents are being explored in patients with a
renal damage associated with 90Y-labelled PRRT, which range of advanced-stage and/or metastatic cancer types
occurs in 2.8% of patients94. Long-term bone marrow (Supplementary Table 1). Radiotheranostic approaches
toxicities might also be seen in patients receiving radio­ have shown efficacy in many cancers, nonetheless, com-
nuclide therapies, such as the rare but almost invari­ bination therapies hold the potential to further improve
ably fatal therapy-related myeloproliferative syndrome. clinical outcomes and are currently being evaluated
The lifetime incidence of therapy-related myeloprolif- in clinical trials.
erative syndrome in patients with metastatic thyroid
cancers or those with NETs who receive repeated high Combination therapies
doses of radioiodine or 90Y-PRRT is around 1.5–2.3%97. Combination with established systemic therapies is
Some of the established chronic adverse events (such an emerging, exciting approach with the potential to
as renal failure or salivary gland impairment) are dose improve the outcomes of patients receiving radiother-
dependent, while others (such as therapy-related myelo­ anostic agents (Fig. 4). Approaches involving targeted
proliferative syndrome) are stochastic and have an radionuclides currently under evaluation, either in
indeterminate relationship with the extent of radiation preclinical studies or in early-phase trials, include com-
exposure. By definition, a stochastic event is random binations with chemotherapy, radiosensitizers, EBRT
and not directly related to the administered dose; how- and immunotherapies (NCT04343885, NCT04419402,
ever, the probability of such events increases at higher NCT05146973, NCT03874884, NCT05109728,
doses. The current interpretation is that these events NCT03805594 and NCT03658447)110–125.
have a very high threshold and are related to individual The antitumour activity of targeted radionuclide
susceptibility97. Classical risk factors (such as previous therapy is based on the induction of DNA damage, sug-
treatment with myelotoxic chemotherapy or extensive gesting the potential for synergistic therapeutic effects
bone marrow irradiation) and broad clinical characteris- through combination with conventional chemother-
tics (such as thrombocytopenia) explain only a minority apies, including the antimetabolite capecitabine, the
of the adverse effects of radiotheranostics94. alkylating agent temozolamide or the topoisomerase
inhibitor topotecan (NCT02358356, NCT02736500).
Bone marrow. Bone marrow is a crucial dose-limiting Enhanced effects have been demonstrated in several
organ for most systemic therapies, such as radioio- preclinical models and have been explored in early-phase
dine, radioligand therapy (such as 177Lu-DOTATATE clinical trials of radiolabelled peptides and antibodies in
or 177Lu-PSMA-617) and radioimmunotherapy. In the patients across several cancers including NETs, colorec-
case of PRRT, cumulative doses of 177Lu-DOTATATE of tal cancer and neuroblastoma126–129. For example, the
around 30 GBq can be safely administered to most indi- randomized phase II CONTROL NET study, in which
viduals, even in the absence of dosimetric assessments. patients with pancreatic or midgut NETs (pNETs and
Data on re-treatment, resulting in lifetime exposures of mNETs, respectively) received 177Lu-octreotate plus
up to 60 GBq of 177Lu or higher has been reported from capecitabine and temozolamide versus 177Lu-octreotate
a few individuals with very advanced-stage disease99,100, monotherapy met the target landmark PFS in patients

NAtuRe RevIeWs | ClINIcAl ONcology volume 19 | August 2022 | 545

0123456789();:
Reviews

Immune cell

Direct cytotoxic
effects on Androgen
stromal cells deprivation
therapies
Block immune
CAF PD-1 CTLA4 checkpoints
Androgen anti-PD-1/PD-L1
receptor antibodies, anti-CTLA4
antibodies
PD-L1 CD80/
CD86
Inhibit MAPK
MEK and BRAFV600E
inhibitors

DNA damage Ionizing

radiation MAPK Sodium–iodine
External beam
radiotherapy symporter

Increase DNA damage AKT PI3K

• Alkylating agents,
topoisomerase inhibitors DNA damage
• Anti-metabolites Inhibit cellular growth
mTOR and proliferation
mTOR inhibitors
Inhibit DNA repair
PARP inhibitors, DDR and repair
topoisomerase inhibitors
and DDR inhibitors
Disrupt microtubules
Taxanes

Microtubule

Cell death

Fig. 4 | Therapeutic approaches involving radiotheranostics. Therapeutic (such as cancer-associated fibroblasts (CAFs)) and kill stromal cells, which
effects on cancer cells caused by DNA damage induced by either α-, β- or can indirectly lead to tumour regression. Bystander effects, owing to use of
auger-emitting radionuclides can be enhanced via combination with drugs β-emitters, on the DNA of cancer cells that do not express radiotheranostic
that either cause direct damage to DNA (such as chemotherapies) or inhibit target proteins can nonetheless lead to tumour cell death. Targeted
DNA damage repair directly (such as PARP inhibitors) or through modulation radionuclide therapies might also induce antigen presentation following
of the associated signalling pathways (such as novel androgen-deprivation cancer cell death and, when combined with immune-checkpoint inhibitors,
therapies). Radiotheranostics can also target the tumour microenvironment lead to enhanced antitumour activity. DDR, DNA damage response.

who received combination therapy (12-month PFS study demonstrate tolerability and clinical responses in
76% for patients with pNETs, 15-month PFS 90% for patents with GEP-NETs who received 177Lu-DOTATATE
patients with mNETs). Numerically greater ORRs were and everolimus126,133.
also observed in patients with either mNETs or pNETs DNA damage induced by radionuclide therapy might
who receiving combination therapy (ORR 31% versus also be enhanced by combination therapy with agents
15% and 68% versus 33%, respectively), albeit with a that inhibit DNA repair. PARP proteins, for example,
greater incidence of grade 3 (mostly haematological) are involved in the repair of both single-strand and
adverse events in patients with mNETs (at least one double-strand DNA breaks, and PARP inhibitors have
event in 75% versus 28%). Long-term follow-up will been shown to sensitize various preclinical models to
be required to determine any significant differences in radionuclide therapy112,113. This approach is currently
PFS129. Further studies involving combination therapies, being investigated in academic clinical trials testing
such as a phase I study demonstrating that 177Lu-J591 olaparib in combination with 177Lu-DOTATATE in
plus docetaxel is feasible and safe in patients with met- patients with GEP-NETs (NCT04086485) and with
astatic CRPC130 and an ongoing phase II study compar- 177
Lu-PSMA-617 in patients with metastatic CRPC
ing 177Lu-PSMA-617 plus docetaxel against docetaxel (NCT03874884).
in patients with newly diagnosed metastatic CPRC The DNA damage response (DDR) pathway
(NCT04343885), have either been completed or are also includes ataxia telangiectasia mutated (ATM),
currently ongoing. ataxia telangiectasia and Rad3-related (ATR) and
Activation of the mTOR and PI3K signalling DNA-dependent protein kinase catalytic subunit
pathways has been shown to induce radioresistance. (DNA-PKcs); inhibitors of these proteins have therefore
Therefore, mTOR inhibitors might have a role in enhanc- been explored as radiosensitizers114. Most clinical studies
ing responsiveness to radionuclide therapy. Data from investigating combinations of these agents with radio-
preclinical studies provide contrasting results110,131,132; therapy have focused on EBRT, while combinations with
nonetheless, data from the single-arm, phase I NETTLE radionuclide therapy have so far been explored mainly

546 | August 2022 | volume 19 www.nature.com/nrclinonc

0123456789();:
 Reviews

in preclinical models, with improvements in antitu- Novel targets and approaches

mour activity observed with each modality relative to The development of radiotheranostics has focused prin-
monotherapy116,117. Similarly, inhibitors of other mole- cipally on targeting emitters of either α- or β-radiation
cules that might modulate the function of DDR proteins to the surfaces of tumour cells followed by intracellular
(such as EGFR or HSP90) have been shown to enhance trafficking and retention, resulting in DNA damage2.
the efficacy of radiolabelled antibodies and peptides in Novel and potentially clinically important radiother-
preclinical models115. Synergy between radionuclide anostic approaches are expanding the range of targets
therapy and the DDR pathway is an important area of to include those present in the tumour microenviron-
potential exploration in future clinical trials (for example, ment, such as blood vessels, cancer-associated fibroblasts
NCT04750954). (CAFs), the stromal matrix and immune cells136,137. The
The ability of EBRT to enhance antitumour immu­ stromal cells located in the tumour microenvironment
nity has been established mechanistically, and clini­cal are generally more genetically stable than tumour cells,
trials combining radiotherapy with immune-checkpoint which might downregulate or entirely lose expression
inhibitors have provided some encouraging of certain targets; stromal cells might also contribute to
results118,119,134,135. In contrast to focal EBRT, radio­ the development of an immunosuppressive microenvi-
nuclide therapies are administered systemically and can ronment and to drug resistance138. Prolyl endopeptidase
therefore target more-widespread disease. Nonetheless, FAP (FAP), expressed on CAFs, has emerged as a tar-
simi­lar to EBRT, enhancement of therapeutic efficacy get of novel radiotheranostics that is broadly expressed
has been observed when these agents are combined with by the fibroblasts present in most adenocarcinomas
immune-checkpoint inhibitors in preclinical studies120,121. and is being evaluated in several clinical trials sup-
Clinical trials combining 177Lu-PSMA-617 with the ported by both industry and academia (NCT04571086,
anti-PD-1 antibody pembrolizumab in patients with NCT04621435, NCT04849247 and NCT04939610;
metastatic CRPC are ongoing (NCT03658447, Supplementary information)101,139,140. The current gen-
NCT03805594). This approach appears to be well tol- eration of FAP-targeted theranostic agents includes var-
erated, with response rates suggesting that radioligand ious ligands with biological half-lives that range from
therapy leads to improved antitumour immunity (ORR short (FAPI-46) to substantially longer (FAP-2286)139.
44–78%)122,123. Radionuclide therapy might also have Identifying the optimal combination of FAP ligand and
synergistic effects when combined with EBRT. An exam- radionuclide will be an important stage in the devel-
ple of this effect is provided by the administration of the opment of these agents that will likely depend on the
LAT-1-targeting radionuclide [131I]iodo-l-phenylalanine intended clinical use, for example, diagnosis versus ther-
(131I-IPA) in a rat model of glioma124; this combination apy, including use as monotherapy versus combination
is currently being evaluated in IPAX-1, a phase I/II clin- therapy.
ical trial involving patients with recurrent glioblastoma Pairing α- and β-emitting radiotheranostic agents
(NCT03849105). might provide another potentially fruitful approach,
Combination therapy might also have a role in taking advantage of the different radiation path lengths
promoting the upregulation of the targets of radio­ and cell-kill mechanisms. In addition, damage to cells
nuclide therapy. For example, in patients with that are not directly targeted can arise from irradiation
radioiodine-refractory thyroid cancer, expression of the of nearby target-null cells (crossfire effects) or the release of
sodium–iodine symporter can be upregulated by treat- biologically active factors (bystander effects), such as free
ment with MAP kinase inhibitors such as selumetinib, radicals or immune system factors, resulting in cytotox-
thereby restoring radioiodine avidity and therapeutic icity far away from the irradiated cells141. Finally, pretar-
responsiveness62. Several multicentre trials are cur- geting approaches can potentially enhance the uptake of
rently exploring the use of tyrosine kinase inhibitors radiolabelled proteins and peptides by tumour cells and
that target MEK or BRAFV600E in patients with NRAS thus reduce the risk of haematological toxicities142–145.
or BRAFV600E-mutant radioiodine-refractory thyroid
cancer (IRAS 183600, MERAIODE, NCT03244956). Conclusions
Conversely, in one study, blockade of the andro- The careful deployment of radiotheranostics in patients
gen receptor (AR) has been shown to upregulate with cancer has the potential to considerably improve
PSMA expression in patients with CRPC, although treatment outcomes. However, several major challenges
downregulation of PSMA expression was also remain to be addressed. Generating evidence to enable a
observed after androgen deprivation in patients with wider range of radiotheranostic agents to receive regula-
hormone-sensitive disease in the same study125. In tory approval and rapidly reach the market is imperative.
addition to effects on PSMA expression, AR blockade Moreover, strategies are needed to improve the availa-
has been demonstrated to delay the repair of DNA bility of radiotheranostics globally. The current success
damage and sensitize cells to radiation, which further of radiotheranostics will likely attract increasing inter-
supports the rationale for its use in combination with est from both academia and industry in identifying and
177
Lu-PSMA-617. The efficacy of 177Lu-PSMA-617 developing novel targeted agents, which is expected to
plus enzalutamide versus enzalutamide alone is cur- generate earlier and better methods of cancer detection,
rently being investigated in patients with metastatic individualized treatments and improved outcomes for
CRPC who have progressed on docetaxel but have patients.
not received prior novel anti-androgen therapy in the
phase II Enza-P study (NCT04419402). Published online 20 June 2022

NAtuRe RevIeWs | ClINIcAl ONcology volume 19 | August 2022 | 547

0123456789();:
Reviews

1. Jadvar, H., Chen, X., Cai, W. & Mahmood, U. and radiation oncologists. J. Nucl. Med. 52, 830–838 47. Weber, M. et al. EANM procedure guideline for the
Radiotheranostics in cancer diagnosis and (2011). treatment of liver cancer and liver metastases with
management. Radiology 286, 388–400 (2018). 24. Parker, C. et al. Alpha emitter radium-223 and intra-arterial radioactive compounds. Eur. J. Nucl.
2. Herrmann, K. et al. Radiotheranostics: a roadmap for survival in metastatic prostate cancer. N. Engl. J. Med. Med. Mol. Imaging 49, 1682–1699 (2022).
future development. Lancet Oncol. 21, e146–e156 369, 213–223 (2013). 48. Mulcahy, M. F. et al. Radioembolization with
(2020). 25. Porter, A. T. & McEwan, A. J. Strontium-89 as an chemotherapy for colorectal liver metastases:
3. FDA. VENTANA PD-L1 (SP142) assay - P160002/ adjuvant to external beam radiation improves pain a randomized, open-label, international, multicenter,
S009, https://www.fda.gov/medical-devices/ relief and delays disease progression in advanced phase III trial. J. Clin. Oncol. 39, 3897–3907 (2021).
recently-approved-devices/ventana-pd-l1-sp142- prostate cancer: results of a randomized controlled 49. Braat, A. J. A. et al. Additional holmium-166
assay-p160002s009 (2020) trial. Semin. Oncol. 20, 38–43 (1993). radioembolisation after lutetium-177-dotatate in
4. FDA. HERCEPTIN (trastuzumab) label, https:// 26. Sartor, O., Quadramet 424Sm10/11 Study Group. patients with neuroendocrine tumour liver metastases
www.accessdata.fda.gov/drugsatfda_docs/ Samarium-153-Lexidronam complex for treatment (HEPAR PLuS): a single-centre, single-arm, open-label,
label/2010/103792s5250lbl.pdf (2010) of painful bone metastases in hormone-refractory phase 2 study. Lancet Oncol. 21, 561–570 (2020).
5. Park, S. et al. Somatostatin receptor imaging and prostate cancer. Urology 63, 940–945 (2004). 50. Garin, E., Tselikas, L., Guiu, B. & Campillo-Gimenez, B.
theranostics: current practice and future prospects. 27. Handkiewicz-Junak, D. et al. EANM guidelines Personalised dosimetry for SIRT: new standard or
J. Nucl. Med. 62, 1323–1329 (2021). for radionuclide therapy of bone metastases with bridge to surgical resection? - Authors’ reply. Lancet
6. NCCN. NCCN Guidelines, https://www.nccn.org/ beta-emitting radionuclides. Eur. J. Nucl. Med. Mol. Gastroenterol. Hepatol. 6, 162 (2021).
guidelines/guidelines-detail?category=1&id=1448 Imaging 45, 846–859 (2018). 51. Arnold, C. Theranostics could be big business in
(2021). 28. Smith, M. et al. Addition of radium-223 to abiraterone precision oncology. Nat. Med. 28, 606–608 (2022).
7. Garin, E. et al. Personalised versus standard acetate and prednisone or prednisolone in patients 52. Czernin, J., Sonni, I., Razmaria, A. & Calais, J.
dosimetry approach of selective internal radiation with castration-resistant prostate cancer and bone The future of nuclear medicine as an independent
therapy in patients with locally advanced metastases (ERA 223): a randomised, double-blind, specialty. J. Nucl. Med. 60, 3S–12S (2019).
hepatocellular carcinoma (DOSISPHERE-01): placebo-controlled, phase 3 trial. Lancet Oncol. 20, 53. Pienta, K. J. et al. A phase 2/3 prospective multicenter
a randomised, multicentre, open-label phase 2 408–419 (2019). study of the diagnostic accuracy of prostate specific
trial. Lancet Gastroenterol. Hepatol. 6, 17–29 29. de Herder, W. W. et al. Neuroendocrine tumors and membrane antigen PET/CT with 18F-DCFPyL in
(2021). somatostatin: imaging techniques. J. Endocrinol. prostate cancer patients (OSPREY). J. Urol. 206,
8. Sgouros, G., Bodei, L., McDevitt, M. R. & Invest. 28, 132–136 (2005). 52–61 (2021).
Nedrow, J. R. Radiopharmaceutical therapy in cancer: 30. De Jong, M. et al. Somatostatin receptor-targeted 54. Fendler, W. P. et al. Assessment of 68Ga-PSMA-11
clinical advances and challenges. Nat. Rev. Drug radionuclide therapy of tumors: preclinical and clinical PET accuracy in localizing recurrent prostate cancer:
Discov. 19, 589–608 (2020). findings. Semin. Nucl. Med. 32, 133–140 (2002). a prospective single-arm clinical trial. JAMA Oncol. 5,
9. Ku, A., Facca, V. J., Cai, Z. & Reilly, R. M. Auger 31. Bodei, L., Kassi, A., Adelstein, S. J. & Mariani, G. 856–863 (2019).
electrons for cancer therapy - a review. EJNMMI Radionuclide therapy with iodine-125 and other 55. Phallen, J. et al. Direct detection of early-stage
Radiopharm. Chem. 4, 27 (2019). auger-electron-emitting radionuclides: experimental cancers using circulating tumor DNA. Sci. Transl. Med.
10. Poty, S., Francesconi, L. C., McDevitt, M. R., models and clinical applications. Cancer Biother. 9, eaan2415 (2017).
Morris, M. J. & Lewis, J. S. Alpha-emitters for Radiopharm. 18, 861–877 (2003). 56. Klein, E. A. et al. Clinical validation of a targeted
radiotherapy: from basic radiochemistry to clinical 32. Anthony, L. B. et al. Indium-111-pentetreotide methylation-based multi-cancer early detection test
studies-part 1. J. Nucl. Med. 59, 878–884 (2018). prolongs survival in gastroenteropancreatic using an independent validation set. Ann. Oncol. 32,
11. Pouget, J. P., Catherine, L., Deshayes, E., Boudousq, V. malignancies. Semin. Nucl. Med. 32, 123–132 1167–1177 (2021).
& Navarro-Teulon, I. Introduction to radiobiology (2002). 57. Bredno, J., Lipson, J., Venn, O., Aravanis, A. M. &
of targeted radionuclide therapy. Front. Med. 2, 12 33. Smit Duijzentkunst, D. A., Kwekkeboom, D. J. & Jamshidi, A. Clinical correlates of circulating
(2015). Bodei, L. Somatostatin receptor 2-targeting cell-free DNA tumor fraction. PLoS ONE 16, 0256436
12. Pouget, J. P. et al. From the target cell theory to a compounds. J. Nucl. Med. 58, 54S–60S (2017). (2021).
more integrated view of radiobiology in targeted 34. Bodei, L., Kwekkeboom, D. J., Kidd, M., Modlin, I. M. 58. Chabon, J. J. et al. Integrating genomic features for
radionuclide therapy: the Montpellier group’s & Krenning, E. P. Radiolabeled somatostatin analogue non-invasive early lung cancer detection. Nature 580,
experience. Nucl. Med/ Biol. 104–105, 53–64 therapy of gastroenteropancreatic cancer. Semin. 245–251 (2020).
(2022). Nucl. Med. 46, 225–238 (2016). 59. Markham, M. J. et al. Clinical cancer advances 2020:
13. Adams, D. J. The valley of death in anticancer drug 35. Strosberg, J. et al. Phase 3 trial of 177Lu-Dotatate for annual report on progress against cancer from the
development: a reassessment. Trends Pharmacol. Sci. midgut neuroendocrine tumors. N. Engl. J. Med. 376, American Society of Clinical Oncology. J. Clin. Oncol.
33, 173–180 (2012). 125–135 (2017). 38, 1081 (2020).
14. Hertz, S., Roberts, A. & Evans, R. D. Radioactive 36. Strosberg, J. et al. Health-related quality of life in 60. Allemani, C. et al. Global surveillance of trends in
iodine as an indicator in the study of thyroid patients with progressive midgut neuroendocrine cancer survival 2000-14 (CONCORD-3): analysis of
physiology. Proc. Soc. Exp. Biol. Med. 38, 510–513 tumors treated with 177Lu-Dotatate in the phase III individual records for 37 513 025 patients diagnosed
(1938). NETTER-1 trial. J. Clin. Oncol. 36, 2578–2584 (2018). with one of 18 cancers from 322 population-based
15. Chapman, E. M. & Evans, R. D. The treatment of 37. Strosberg, J. R. et al. NETTER-1 investigators. registries in 71 countries. Lancet 391, 1023–1075
hyperthyroidism with radioactive iodine. J. Am. Med. 177Lu-Dotatate plus long-acting octreotide versus (2018).
Assoc. 131, 86–91 (1946). high‑dose long-acting octreotide in patients with 61. Hashim, D. et al. The global decrease in cancer
16. Seidlin, S. M., Marinelli, L. D. & Oshry, E. Radioactive midgut neuroendocrine tumours (NETTER-1): mortality: trends and disparities. Ann. Oncol. 27,
iodine therapy; effect on functioning metastases of final overall survival and long-term safety results from 926–933 (2016).
adenocarcinoma of the thyroid. J. Am. Med. Assoc. an open-label, randomised, controlled, phase 3 trial. 62. Howlader, N. et al. The effect of advances in
132, 838–847 (1946). Lancet Oncol. 22, 1752–1763 (2021). lung-cancer treatment on population mortality.
17. Witzig, T. E. et al. Randomized controlled trial of 38. Eder, M. et al. 68Ga-complex lipophilicity and the N. Engl. J. Med. 383, 640–649 (2020).
yttrium-90-labeled ibritumomab tiuxetan targeting property of a urea-based PSMA inhibitor for 63. Sung, H. et al. Global cancer statistics 2020:
radioimmunotherapy versus rituximab PET imaging. Bioconjug. Chem. 23, 688–697 (2012). GLOBOCAN estimates of incidence and mortality
immunotherapy for patients with relapsed or 39. Afshar-Oromieh, A., Haberkorn, U., Eder, M., worldwide for 36 cancers in 185 countries. CA Cancer
refractory low-grade, follicular, or transformed Eisenhut, M. & Zechmann, C. M. [68Ga]Gallium- J. Clin. 71, 209–249 (2021).
B-cell non-Hodgkin’s lymphoma. J. Clin. Oncol. 15, labelled PSMA ligand as superior PET tracer for 64. Tamura, R. et al. Alterations of the tumor
2453–2463 (2002). the diagnosis of prostate cancer: comparison with microenvironment in glioblastoma following
18. Grillo-Lopez, A. J. Zevalin: the first radioimmunotherapy 18F-FECH. Eur. J. Nucl. Med. Mol. Imaging 39, radiation and temozolomide with or without
approved for the treatment of lymphoma. Expert. Rev. 1085–1086 (2012). bevacizumab. Ann. Transl. Med. 8, 297 (2020).
Anticancer. Ther. 2, 485–493 (2002). 40. Kratochwil, C. et al. [177Lu]Lutetium-labelled PSMA 65. Future Market Insights. Radiopharmaceuticals Market
19. Friedberg, J. W. & Fisher, R. I. Iodine-131 ligand-induced remission in a patient with metastatic By Radioisotope Type (Technetium-99, Fluorine-18,
tositumomab (Bexxar): radioimmunoconjugate prostate cancer. Eur. J. Nucl. Med. Mol. Imaging 42, Iodine-131, Leutetium-177), Application (Oncology,
therapy for indolent and transformed B-cell 987–988 (2015). Cardiology, Gastroenterology, Neuroendocrinology,
non-Hodgkin’s lymphoma. Expert. Rev. Anticancer. 41. Mottet N., et al. EAU Guidelines: Prostate Cancer, Neurology, Nephrology), Source (Cyclotrons,
Ther. 4, 18–26 (2004). https://uroweb.org/guideline/prostate-cancer/ (2001). Nuclear Reactors) & Region – Forecast 2021–2031.
20. Leahy, M. F., Seymour, J. F., Hicks, R. J. & Rurner, J. H. 42. NCCN. Recently Updated Guidelines, https://www. https://www.futuremarketinsights.com/reports/
Multicenter phase II clinical study of iodine-131- nccn.org/guidelines/recently-published-guidelines radiopharmaceuticals-market (2021).
rituximab radioimmunotherapy in relapsed or (2022). 66. Fortune Business Insights. Nuclear Medicine Market
refractory indolent non-Hodgkin’s lymphoma. J. Clin. 43. Sartor, O., VISION Investigators. Lutetium-177- Size, Share & COVID-19 Impact Analysis, By Type
Oncol. 20, 4418–4425 (2006). PSMA-617 for metastatic castration-resistant prostate (Diagnostic Radiopharmaceuticals and Therapeutic
21. Ferrucci, P. F. et al. High activity 90Y-ibritumomab cancer. N. Engl. J. Med. 16, 1091–1103 (2021). Radiopharmaceticals), By Application (Neurology,
tiuxetan (Zevalin) with peripheral blood progenitor 44. Hofman, M. S. et al. [(177)Lu]Lu-PSMA-617 versus Cardiology, Oncology, and Others), By End-user
cells support in patients with refractory/resistant cabazitaxel in patients with metastatic castration- (Hopsitals & Clinics, Diagnostic Centers, and Others),
B-cell non-Hodgkin lymphomas. Br. J. Haematol. 139, resistant prostate cancer (TheraP): a randomised, and Regional Forecast, 2021–2028. Market Research
590–599 (2007). open-label, phase 2 trial. Lancet 397, 797–804 Report. https://www.fortunebusinessinsights.com/
22. Timmerman, L. Why Good Drugs Sometimes Fail: The (2021). industry-reports/nuclear-medicine-radiopharmaceuticals-
Bexxar Story, https://xconomy.com/national/2013/ 45. McInnes, L. E. et al. Therapeutic efficacy of a bivalent market-101812 (2022).
08/26/why-good-drugs-sometimes-fail-in-the-market- inhibitor of prostate-specific membrane antigen 67. DataM Intelligence. Global Theranostics Market:
the-bexxar-story/ (2013). labeled with 67Cu. J. Nucl. Med. 1, 8290832 (2021). Market Size, Share and Forecast; Market Outlook,
23. Schaefer, N. G., Huang, P., Buchanan, J. W. & 46. d’Abadie, P. et al. Microspheres used in liver Opportunity and Data Analysis 2022–2029. https://
Wahl, R. L. Radioimmunotherapy in non-Hodgkin radioembolization: from conception to clinical effects. www.datamintelligence.com/research-report/
lymphoma: opinions of nuclear medicine physicians Molecules 26, 3966 (2021). theranostics-market (2021).

548 | August 2022 | volume 19 www.nature.com/nrclinonc

0123456789();:
 Reviews

68. Hricak, H. et al. Medical imaging and nuclear 94. Bodei, L. et al. Long-term tolerability of PRRT in 807 115. Kelly, M. P. et al. Therapeutic efficacy of 177Lu-CHX-
medicine: a Lancet Oncology Commission. Lancet patients with neuroendocrine tumours: the value and A″-DTPA-hu3S193 radioimmunotherapy in prostate
Oncol. 22, e136–e172 (2021). limitations of clinical factors. Eur. J. Nucl. Med. Mol. cancer is enhanced by EGFR inhibition or docetaxel
69. Cutler, C. S. et al. Global issues of Imaging 42, 5–19 (2015). chemotherapy. Prostate 1, 92–104 (2009).
radiopharmaceutical access and availability: a Nuclear 95. Sarnelli, A. et al. Therapeutic schemes in 177Lu and 116. Wickstroem, K. et al. Synergistic effect of a
Medicine Global Initiative project. J. Nucl. Med. 62, 90
Y-PRRT: radiobiological considerations. Q. J. Nucl. mesothelin-targeted 227Th conjugate in combination
422–430 (2021). Med. Mol. Imaging 61, 216–231 (2017). with DNA damage response inhibitors in ovarian
70. Bodei, L., Chiti, A., Modlin, I. M., Scott, A. M. & 96. National Cancer Institute, Division of Cancer cancer xenograft models. J. Nucl. Med. 60,
Schoder, H. The path to the future: education Treatment & Diagnosis. Common Terminology Criteria 1293–1300 (2019).
of nuclear medicine therapeutic specialists as for Adverse Events (CTCAE). Last Updated: 09/21/20, 117. Lundsten, S., Spiegelberg, D., Raval, N. R. &
responsible physicians. J. Nucl. Med. 60, 1663–1664 https://ctep.cancer.gov/protocoldevelopment/ Nestor, M. The radiosensitizer Onalespib increases
(2019). electronic_applications/ctc.htm (2022). complete remission in 177Lu-DOTATATE-treated mice
71. Herrmann, K. et al. Joint EANM, SNMMI and IAEA 97. Bodei, L. et al. Myeloid neoplasms after bearing neuroendocrine tumor xenografts. Eur. J.
enabling guide: how to set up a theranostics centre. chemotherapy and PRRT: myth and reality. Nucl. Med. Mol. Imaging 47, 980–990 (2020).
J. Nucl. Med. https://doi.org/10.2967/jnumed.122. Endocr. Relat. Cancer 23, C1–C7 (2016). 118. Weichselbaum, R. R., Liang, H., Deng, L. & Fu, Y.-X.
264321 (2022). 98. Ma, J., Li, L., Liao, T., Gong, W. & Zhang, C. Efficacy Radiotherapy and immunotherapy: a beneficial
72. Lee, S. T. et al. The importance of training, and safety of 225Ac-PSMA-617-targeted alpha therapy liaison? Nat. Rev. Clin. Oncol. 14, 365–379 (2017).
accreditation and guidelines for the practice of in metastatic castration-resistant prostate cancer: 119. Parikh, A. R. et al. Radiation therapy enhances
theranostics: the australian perspective. J. Nucl. Med. a systematic review and meta-analysis. Front. Oncol. immunotherapy response in microsatellite stable
https://doi.org/10.2967/jnumed.122.263996 (2022). 12, 796657 (2022). colorectal and pancreatic adenocarcinoma in a
73. Cherla, A., Naci, H., Kesselheim, A. S., Gyawali, B. 99. Yordanova, A. et al. Safety of multiple repeated phase II trial. Nat. Cancer 2, 1124–1135 (2021).
& Mossialos, E. Assessment of coverage in england cycles of 177Lu-octreotate in patients with recurrent 120. Chen, H. et al. Integrin αvβ3-targeted radionuclide
of cancer drugs qualifying for US food and drug neuroendocrine tumour. Eur. J. Nucl. Med. Mol. therapy combined with immune checkpoint blockade
administration accelerated approval. JAMA Intern. Med. Imaging 44, 1207–1214 (2017). immunotherapy synergistically enhances anti-tumor
181, 490–498 (2021). 100. van der Zwan, W. A. et al. Salvage peptide receptor efficacy. Theranostics 9, 7948–7960 (2019).
74. Elimova, E. et al. Updating reports of phase 3 clinical radionuclide therapy with [(177)Lu-DOTA,Tyr(3)] 121. Czernin, J. et al. Immune-checkpoint blockade
trials for cancer. JAMA Oncol. 7, 593–596 (2021). octreotate in patients with bronchial and enhances 225Ac-PSMA617 efficacy in a mouse model
75. Ebrahim, S. et al. Reanalyses of randomized clinical gastroenteropancreatic neuroendocrine tumours. of prostate cancer. J. Nucl. Med. 62, 228–231
trial data. JAMA 312, 1024–1032 (2014). Eur. J. Nucl. Med. Mol. Imaging 46, 704–717 (2019). (2021).
76. Schnog, J. B., Samson, M. J., Gans, R. O. B. & 101. Kratochwil, C. et al. Targeted α-therapy of metastatic 122. Aggarwal, R. S. et al. Immunogenic priming with
Duits, A. J. An urgent call to raise the bar in oncology. castration-resistant prostate cancer with 177
Lu-PSMA-617 plus pembrolizumab in metastatic
Br. J. Cancer 125, 1477–1485 (2021). 225Ac-PSMA-617: swimmer-plot analysis suggests castration resistant prostate cancer (mCRPC): a phase
77. Ahn, H. J. et al. Radiation-induced CXCL12 efficacy regarding duration of tumor control. J. Nucl. 1b study. J. Clin. Oncol. 39, 5053 (2021).
upregulation via histone modification at the promoter Med. 59, 795–802 (2018). 123. Sandu, S. K. et al. PRINCE: Interim analysis of the
in the tumor microenvironment of hepatocellular 102. Kratochwil, C., Haberkorn, U. & Giesel, F. L. phase Ib study of 177Lu-PSMA-617 in combination
carcinoma. Mol. Cell 42, 530–545 (2019). (225)Ac-PSMA-617 for therapy of prostate cancer. with pembrolizumab for metastatic castration
78. US Food and Drug Administration. Real-World Semin. Nucl. Med. 50, 133–140 (2020). resistant prostate cancer (mCRPC). Ann. Oncol. 32,
Evidence, https://www.fda.gov/science-research/ 103. Ballal, S., Yadav, M. P., Bal, C., Sahoo, R. K. & S626–S677 (2021).
science-and-research-special-topics/real-world- Tripathi, M. Broadening horizons with (225) 124. Samnick, S. et al. Efficacy of systemic radionuclide
evidence (2020). Ac-DOTATATE targeted alpha therapy for therapy with p-131I-iodo-L-phenylalanine combined
79. Johnson, S. B. et al. Cancer misinformation and gastroenteropancreatic neuroendocrine tumour with external beam photon irradiation in treating
harmful information on facebook and other social patients stable or refractory to (177)Lu-DOTATATE malignant gliomas. J. Nucl. Med. 50, 2025–2032
media: a brief report. J. Natl Cancer Inst. https:// PRRT: first clinical experience on the efficacy and (2009).
doi.org/10.1093/jnci/djab141 (2021). safety. Eur. J. Nucl. Med. Mol. Imaging 47, 934–946 125. Emmett, L. et al. Rapid modulation of PSMA
80. Lindberg, J. C. H. ‘J’accuse.!’: the continuous failure (2020). expression by androgen deprivation: serial 68
to address radiophobia and placing radiation in 104. Kristiansson, A. et al. Kidney protection with the Ga-PSMA-11 PET in men with hormone-sensitive
perspective. J. Radiol. Prot. 41, 459 (2021). radical scavenger α1-microglobulin (A1M) during and castrate-resistant prostate cancer commencing
81. Rajkumar, S. V. The high cost of insulin in the United peptide receptor radionuclide and radioligand androgen blockade. J. Nucl. Med. 60, 950–954
States: an urgent call to action. Mayo Clin. Proc. 95, therapy. Antioxidants 10, 1271 (2021). (2019).
22–28 (2020). 105. Bohuslavizki, K. H. et al. Salivary gland protection 126. Claringbold, P. G., Brayshaw, P. A., Price, R. A.
82. Takakusagi, Y. et al. Multimodal molecular imaging by amifostine in high-dose radioiodine therapy of & Turner, J. H. Phase II study of radiopeptide
study evaluates pharmacological alteration of the differentiated thyroid cancer. Strahlenther. Onkol. 177Lu-octreotate and capecitabine therapy of
tumor microenvironment to improve radiation 175, 57–61 (1999). progressive disseminated neuroendocrine tumours.
response. Cancer Res. 78, 6828–6837 (2018). 106. Crumbaker, M. et al. Phase I/II trial of the combination Eur. J. Nucl. Med. Mol. Imaging 38, 302–311 (2011).
83. Congressional Budget Office. Research and of 177Lutetium prostate specific membrane antigen 127. Herbertson, R. A. et al. Targeted chemoradiation
Development in the Pharmaceutical Industry, 617 and idronoxil (NOX66) in men with end-stage in metastatic colorectal cancer: a phase I trial
https://www.cbo.gov/publication/57126 (2021) . metastatic castration-resistant prostate cancer of 131I-huA33 with concurrent capecitabine.
84. Vokinger, K. N. et al. Price changes and within-class (LuPIN). Eur. Urol. Oncol. 4, 963–970 (2021). J. Nucl. Med. 55, 534–539 (2014).
competition of cancer drugs in the USA and Europe: 107. Bodei, L. et al. Molecular profiling of neuroendocrine 128. Genolla, J. et al. high-activity therapy with
a comparative analysis. Lancet Oncol. 23, 514–520 tumours to predict response and toxicity to peptide 131I-metaiodobenzylguanidine (131I-mIBG) and
(2022). receptor radionuclide therapy. Lancet Oncol. 21, topotecan for the treatment of high-risk refractory
85. Himmelstein, D. U., Campbell, T. & Woolhandler, S. e431–e443 (2020). neuroblastoma. Eur. J. Nucl. Med. Mol. Imaging 46,
Health care administrative costs in the United States 108. De Giorgi, U. et al. Circulating androgen receptor gene 1567–1575 (2019).
and Canada. Ann. Intern. Med. 21, 134–142 (2020). amplification and resistance to 177Lu-PSMA-617 in 129. Pavlakis, N. et al. Australasian Gastrointestinal Trials
86. Pozen, A. & Cutler, D. M. Medical spending metastatic castration-resistant prostate cancer: results Group (AGITG) CONTROL NET Study: Phase II study
differences in the United States and Canada: the role of a phase 2 trial. Br. J. Cancer 125, 1226–1232 evaluating the activity of 177Lu-Octreotate peptide
of prices, procedures, and administrative expenses. (2021). receptor radionuclide therapy (LuTate PRRT) and
Inquiry 47, 124–134 (2010). 109. Scott, A. M. & Bodei, L. Pharmacogenomics in capecitabine, temozolomide CAPTEM) — First results
87. CMS.gov: Centers for Medicare and Medicaid radionuclide therapy: impact on response to for pancreas and updated midgut neuroendocrine
Services. NHE Fact Sheet, https://www.cms.gov/ theranostics. J. Nucl. Med. 1, 884–885 (2021). tumors (pNETS, mNETS). J. Clin. Oncol. 38, Abstr.
Research-Statistics-Data-and-Systems/Statistics- 110. Chan, T. G., O’Neill, E., Habjan, C. & Cornelissen, B. 4608 (2020).
Trends-and-Reports/NationalHealthExpendData/ Combination strategies to improve targeted 130. Batra, J. S. et al. Phase I trial of docetaxel plus
NHE-Fact-Sheet (2021). radionuclide therapy. J. Nucl. Med. 61, 1544–1552 lutetium-177-labeled anti-prostate-specific membrane
88. Institute of Medicine. Delivering Affordable Cancer (2020). antigen monoclonal antibody J591 (177Lu-J591)
Care in the 21st Century: Workshop Summary 111. Satapathy, S. et al. 177Lu-DOTATATE plus for metastatic castration-resistant prostate cancer.
(National Academies Press, 2013). radiosensitizing capecitabine versus octreotide Urol. Oncol. 38, 848.e9–848.e16 (2020).
89. Dusetzia, S. B. Your money or your life - the high long-acting release as first-line systemic therapy 131. Pool, S. E. et al. mTOR inhibitor RAD001
cost of cancer drugs under medicare part D. N. Engl. in advanced grade 1 or 2 gastroenteropancreatic promotes metastasis in a rat model of pancreatic
J. Med. https://doi.org/10.1056/NEJMp2202726. neuroendocrine tumors: a single-institution neuroendocrine cancer. Cancer Res. 73, 12–18
(2022). experience. JCO Glob. Oncol. 7, 1167–1175 (2013).
90. Pouget, J.-P. & Constanzo, J. Revisiting the (2021). 132. Johnbeck, C. B., Nielsen, C. K., Knigge, U. & Kjaer, A.
radiobiology of targeted alpha therapy. Front. Med. 8, 112. Nonnekens, J. et al. Potentiation of peptide receptor Synergistic effect of combined treatment with
692436 (2021). radionuclide therapy by the PARP inhibitor olaparib. 177Lu-DOTATATE and Everolimus in neuroendocrine
91. Tang, L. et al. Role of metabolism in cancer cell Theranostics 18, 1821–1832 (2016). tumors as monitored by 18F-FDG-PET: studies
radioresistance and radiosensitization methods. 113. Cullinane, C. et al. Enhancing the anti-tumour activity in human neuroendocrine xenografts [abstract].
J. Exp. Clin. Cancer Res. 37, 87 (2018). of 177Lu-DOTA-octreotate radionuclide therapy in J. Nucl. Med. 53, 57 (2012).
92. De la Vieja, A. & Riesco-Eizaguirre, G. Radio-iodide somatostatin receptor-2 expressing tumour models by 133. Claringbold, P. G. & Turner, J. H. NeuroEndocrine
treatment: from molecular aspects to the clinical view. targeting PARP. Sci. Rep. 10, 10196 (2020). tumor therapy with Lutetium-177-octreotate and
Cancers 13, 995 (2021). 114. Huang, R.-X. & Zhou, P.-K. DNA damage response everolimus (NETTLE): a phase I study. Cancer Biother.
93. Waseem, N., Aparici, C. M. & Kunz, P. L. Evaluating signaling pathways and targets for radiotherapy Radiopharm. 30, 261–269 (2015).
the role of theranostics in grade 3 neuroendocrine sensitization in cancer. Signal. Transduct. Target Ther. 134. Schoenfeld, J. D. et al. Durvalumab plus
neoplasms. J. Nucl. Med. 60, 882–891 (2019). 1, 60 (2020). tremelimumab alone or in combination with low-dose

NAtuRe RevIeWs | ClINIcAl ONcology volume 19 | August 2022 | 549

0123456789();:
Reviews

or hypofractionated radiotherapy in metastatic 149. Serafini, A. N. et al. Palliation of pain associated 160. Nilsson, S. et al. Patient-reported quality-of-life
non-small-cell lung cancer refractory to previous with metastatic bone cancer using samarium-153 analysis of radium-223 dichloride from the
PD(L)-1 therapy: an open-label, multicentre, randomised, lexidronam: a double-blind placebo-controlled clinical phase III ALSYMPCA study. Ann. Oncol. 27, 868–874
phase 2 trial. Lancet Oncol. 23, 279–291 (2022). trial. J. Clin. Oncol. 16, 1574–1581 (1998). (2016).
135. Theelen, W. S. M. E. et al. Pembrolizumab with or 150. Gopal, A. K. et al. 90Y-Ibritumomab tiuxetan,
without radiotherapy for metastatic non-small-cell fludarabine, and TBI-based nonmyeloablative Acknowledgements
lung cancer: a pooled analysis of two randomised allogeneic transplantation conditioning for patients The authors thank G. Scott for the careful editing of this man-
trials. Lancet Respir. Med. 9, 467–475 (2021). with persistent high-risk B-cell lymphoma. Blood 28, uscript and S. Lapi (University of Alabama) and J. Engle
136. Scott, A. M., Wolchok, J. D. & Old, L. J. Antibody 1132–1139 (2011). (University of Wisconsin-Madison) for help with Table 1. This
therapy of cancer. Nat. Rev. Cancer 12, 278–287 151. Smith, M. R. et al. Phase II study of rituximab plus work was supported in part by NIH grants R35 CA232130
(2012). cyclophosphamide, doxorubicin, vincristine, and (J.S.L.) and P30 CA008748 (J.S.L., L.B., H.S.), and NHMRC
137. Lee, S. T., Buarvenich, I. & Scott, A. M. Novel target prednisone immunochemotherapy followed by Investigator grant 1177837 (A.M.S.).
selection for nuclear medicine studies. Semin. Nucl. yttrium-90-ibritumomab tiuxetan in untreated
Med. 49, 357–368 (2019). mantle-cell lymphoma: Eastern Cooperative Oncology Author contributions
138. Valkenburg, K. C., De Groot, A. E. & Pienta, K. J. Group Study E1499. J. Clin. Oncol. 30, 3119–3126 All authors made an equal contribution to all aspects of the
Targeting the tumour stroma to improve cancer (2012). preparation and writing of this manuscript.
therapy. Nat. Rev. Clin. Oncol. 15, 366–381 (2018). 152. Morschhauser, F. et al. 90Yttrium-ibritumomab
139. Baum, R. P. et al. Feasibility, biodistribution tiuxetan consolidation of first remission in advanced- Competing interests
and preliminary dosimetry in peptide-targeted stage follicular non-Hodgkin lymphoma: updated L.B. has acted as a consultant and/or speaker for
radionuclide therapy (PTRT) of diverse results after a median follow-up of 7.3 years from the AAA-Novartis, Clovis Oncology, Iba, ITM and MTTI and
adenocarcinomas using 177Lu-FAP-2286: first-in- International, Randomized, Phase III First-LineIndolent received research funding from AAA-Novartis. K.H. has
Human Results. J. Nucl. Med 63, 415–423 (2022). trial. J. Clin. Oncol. 1, 1977–1983 (2013). received personal fees from Adacap, Aktis Oncology, Amgen,
140. Lindner, T. et al. Development of quinoline-based 153. Lugtenburg, P. J. et al. Rituximab-PECC induction Bayer, BTG, Curium, Endocyte, GE Healthcare, IPSEN,
theranostic ligands for the targeting of fibroblast followed by 90 Y-ibritumomab tiuxetan consolidation Pharma15, Novartis, Siemens Healthineers, SIRTEX,
activation protein. J. Nucl. Med. 59, 1415–1422 in relapsed or refractory DLBCL patients who are Theragnostics and YMabs; has received non-financial support
(2018). ineligible for or have failed ASCT: results from a from ABX and Sofie Biosciences and has received research
141. Widel, M. Radionuclides in radiation-induced phase II HOVON study. Br. J. Haematol. 187, funding from BTG. A.M.S. has acted as a consultant of
bystander effect; may it share in radionuclide therapy? 347–355 (2019). Imagion Bio and ImmunOs; has received research funding
Neoplasma 64, 641–654 (2017). 154. Shimoni, A. et al. A randomized study comparing from AbbVie, AVID, Cyclotek, Curis; has recevied research
142. Altai, M., Membreno, R., Cook, B., Tolmachev, V. yttrium-90 ibritumomab tiuxetan (Zevalin) and funding from AVID, Adalta, EMD Serono, Fusion, Humanigen,
& Zeglis, B. M. Pretargeted imaging and therapy. high-dose BEAM chemotherapy versus BEAM alone ITM, Merck, Medimmune, Telix Pharmaceuticals and
J. Nucl. Med. 58, 1553–1559 (2017). as the conditioning regimen before autologous stem Theramyc, and is a co-founder of Certis Therapeutics
143. Cheal, S. M. et al. Curative multicycle cell transplantation in patients with aggressive and Paracrine Therapeutics. J.S.L. has acted as an adviser of
radioimmunotherapy monitored by quantitative lymphoma. Cancer 1, 4706–4714 (2012). Boxer, Clarity Pharmaceuticals, Curie Therapeutics, Earli,
SPECT/CT-based theranostics, using bispecific 155. Davies, A. J. et al. Tositumomab and iodine I 131 Evergreen Theragnostics, Telix Pharmaceuticals, TPG Capital
antibody pretargeting strategy in colorectal cancer. tositumomab for recurrent indolent and transformed and Varian Medical Systems; is a co-inventor on technologies
J. Nucl. Med. 58, 1735–1742 (2017). B-cell non-Hodgkin’s lymphoma. J. Clin. Oncol. 15, licensed to Diaprost, Daiichi Sankyo, Elucida Oncology,
144. Keinänen, O. et al. Harnessing 64Cu/67Cu 1469–1479 (2004). Macrocyclics and Samus Therapeutics; and is the co-founder
for a theranostic approach to pretargeted 156. Kaminski, M. S. et al. Pivotal study of iodine I 131 of, and holds equity in, pHLIP and Sharp RTx. H.S. declares
radioimmunotherapy. Proc. Natl Acad. Sci. USA 10, tositumomab for chemotherapy-refractory low-grade no competing interests.
28316–28327 (2020). or transformed low-grade B-cell non-Hodgkin’s
145. Zeglis, B. M. et al. A pretargeted PET imaging strategy lymphomas. J. Clin. Oncol. 1, 3918–3928 (2001). Peer review information
based on bioorthogonal Diels-Alder click chemistry. 157. EMA. European Medicines Agency: Science Medicines Nature Reviews Clinical Oncology thanks Jeremie Calais,
J. Nucl. Med. 54, 1389–1396 (2013). Health. List of nationally authorised medicinal products, Jacek Capala, Kazuma Ogawa, Rodney Hicks and the other,
146. Schlumberger, M. et al. Outcome after ablation in https://www.ema.europa.eu/en/documents/psusa/iodine- anonymous, reviewer(s) for their contribution to the peer
patients with low-risk thyroid cancer (ESTIMABL1): 131i-iobenguane-list-nationally-authorised-medicinal- review of this work.
5-year follow-up results of a randomised, phase 3, products-psusa/00001764/201505_en.pdf (2016).
equivalence trial. Lancet Diabetes Endocrinol. 6, 158. Pryma, D. A. et al. Efficacy and safety of high-specific- Publisher’s note
618–626 (2018). activity 131I-MIBG therapy in patients with advanced Springer Nature remains neutral with regard to jurisdictional
147. Ho, A. L. et al. Selumetinib-enhanced radioiodine pheochromocytoma or paraganglioma. J. Nucl. Med. claims in published maps and institutional affiliations.
uptake in advanced thyroid cancer. N. Engl. J. Med. 60, 623–630 (2019).
14, 623–632 (2013). 159. Sartor, O. et al. Effect of radium-223 dichloride on Supplementary information
148. de Keizer, B. et al. Efficacy of high therapeutic doses symptomatic skeletal events in patients with The online version contains supplementary material available
of iodine-131 in patients with differentiated thyroid castration-resistant prostate cancer and bone at https://doi.org/10.1038/s41571-022-00652-y.
cancer and detectable serum thyroglobulin. Eur. J. metastases: results from a phase 3, double-blind,
Nucl. Med. Mol. Imaging 28, 198–202 (2001). randomised trial. Lancet Oncol. 15, 738–746 (2014). © Springer Nature Limited 2022

550 | August 2022 | volume 19 www.nature.com/nrclinonc

0123456789();: