Molecular imaging in oncology: Current impact and future directions

Abstract

The authors define molecular imaging, according to the Society of Nuclear Medicine and Molecular Imaging, as the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems. Although practiced for many years clinically in nuclear medicine, expansion to other imaging modalities began roughly 25 years ago and has accelerated since. That acceleration derives from the continual appearance of new and highly relevant animal models of human disease, increasingly sensitive imaging devices, high‐throughput methods to discover and optimize affinity agents to key cellular targets, new ways to manipulate genetic material, and expanded use of cloud computing. Greater interest by scientists in allied fields, such as chemistry, biomedical engineering, and immunology, as well as increased attention by the pharmaceutical industry, have likewise contributed to the boom in activity in recent years. Whereas researchers and clinicians have applied molecular imaging to a variety of physiologic processes and disease states, here, the authors focus on oncology, arguably where it has made its greatest impact. The main purpose of imaging in oncology is early detection to enable interception if not prevention of full‐blown disease, such as the appearance of metastases. Because biochemical changes occur before changes in anatomy, molecular imaging—particularly when combined with liquid biopsy for screening purposes—promises especially early localization of disease for optimum management. Here, the authors introduce the ways and indications in which molecular imaging can be undertaken, the tools used and under development, and near‐term challenges and opportunities in oncology.

Full text

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Abstract: The authors define molecular imaging, according to the Society of Nuclear
Medicine and Molecular Imaging, as the visualization, characterization, and measure-
ment of biological processes at the molecular and cellular levels in humans and other
living systems. Although practiced for many years clinically in nuclear medicine, ex-
pansion to other imaging modalities began roughly 25 years ago and has accelerated
since. That acceleration derives from the continual appearance of new and highly
relevant animal models of human disease, increasingly sensitive imaging devices,
high- throughput methods to discover and optimize affinity agents to key cellular tar-
gets, new ways to manipulate genetic material, and expanded use of cloud com-
puting. Greater interest by scientists in allied fields, such as chemistry, biomedical
engineering, and immunology, as well as increased attention by the pharmaceutical
industry, have likewise contributed to the boom in activity in recent years. Whereas
researchers and clinicians have applied molecular imaging to a variety of physiologic
processes and disease states, here, the authors focus on oncology, arguably where
it has made its greatest impact. The main purpose of imaging in oncology is early
detection to enable interception if not prevention of full- blown disease, such as the
appearance of metastases. Because biochemical changes occur before changes
in anatomy, molecular imaging— particularly when combined with liquid biopsy for
screening purposes— promises especially early localization of disease for optimum
management. Here, the authors introduce the ways and indications in which molecu-
lar imaging can be undertaken, the tools used and under development, and near- term
challenges and opportunities in oncology.
Keywords: magnetic resonance imaging (MRI), nuclear medicine, optical imaging,
positron emission tomography (PET), single- photon emission computed tomography
(SPECT), theranostics
Introduction
On its website, the Society of Nuclear Medicine and Molecular Imaging defines
molecular imaging as a type of medical imaging that provides detailed pictures at the
molecular and cellular levels of what is occurring inside the body.1 This accurate, but
staid, definition belies the immense progress researchers and clinicians have made
over the past 2 decades in applying the principles of molecular imaging across sev-
eral fields, from basic and translational science through state- of- the- art patient di-
agnosis and therapy. Fundamentally, molecular imaging allows for the visualization
of biochemical processes and patterns of target localization that are invisible at the
anatomic imaging level.
Although endogenous image contrast can be leveraged or induced within tis-
sues,2,3 much of molecular imaging requires administration of an imaging agent,
usually intravenously, which interacts with a targeted environment to uncover
biological pathways. Because a hallmark of molecular imaging is lack of pertur-
bation of the cell, environment, or process under study, the imaging agents often
serve as tracers, with no effect on the entity they are designed to measure. Tracers
can be molecules or analogs of molecules that participate in metabolic pathways
or they can be targeted to serve as substrates for or bind to specific enzymes,
Molecular imaging in oncology: Current impact and future
directions
Steven P. Rowe, MD, PhD; Martin G. Pomper, MD, PhD
The Russell H. Morgan Department
of Radiology and Radiological
Science, Johns Hopkins University
School of Medicine, Baltimore,
Maryland.
Corresponding Authors: Steven P.
Rowe, MD, PhD, The Russell H. Morgan
Department of Radiology and Radiological
Science, Johns Hopkins University
School of Medicine, 600 N. Wolfe Street,
Baltimore, MD 21287 (srowe8@jhmi.edu);
Martin G. Pomper, MD, PhD, The Russell
H. Morgan Department of Radiology and
Radiological Science, Johns Hopkins
University School of Medicine, 600
N. Wolfe Street, Baltimore, MD 21287
(mpomper@jhmi.edu).
DISCLOSURES: This study was supported
by grants from the National Institutes
of Health (CA134675, CA184228, and
EB024495). Steven P. Rowe is a consultant
to Progenics Pharmaceuticals, the licensee
of 18F- DCFPyL, and receives research
funding from the company; in addition, he
reports contracts with D&D Pharmatech,
Lantheus Pharmaceuticals, and FutureChem
USA; grants from the US Department
of Defense; personal and institutional
royalties from D&D Pharmatech; personal
fees from D&D Pharmatech and Precision
Molecular, Inc; honoraria from Lantheus
Pharmaceuticals; has filed approximately
5 patents; participates in a data safety
monitoring board or advisory board at
Lantheus Pharmaceuticals; and owns
stock or stock options in D&D Pharmatech
outside the submitted work. Martin G.
Pomper is coinventor on a US patent
covering 18F- DCFPyL and, as such, is
entitled to a portion of any licensing fees
and royalties generated by this technology
(this arrangement has been reviewed and
approved by the Johns Hopkins University
in accordance with its conflict- of- interest
policies); in addition, he reports research
funding from Progenics Pharmaceuticals;
grants or contracts from D&D Pharmatech,
Neximmune, Sanofi, and 511 Pharma;
personal and institutional royalties
from Lantheus- Holdings/Progenics
Pharmaceuticals, Intuitive Surgical, and
D&D Pharmatech; licenses with Novartis,
Cyclotek, and Blue Earth Diagnostics;
personal fees from D&D Pharmatech and
Precision Molecular, Inc; has filed more
than 60 patients; participates in data safety
monitoring boards or advisory boards at
Jubilant, RefleXion, Hoffman- LaRoche,
Sinotau, and the Cancer Prevention and
Research Institute of Texas; owns stock
or stock options in D&D Pharmatech and
FutureChem USA; is a founder of Precision
Molecular, Inc; and is former president of
the World Molecular Imaging Society (2018-
2019) outside the submitted work.
doi: 10.3322/caac.21713. Available online
at cacancerjournal.com

Molecular imaging
334 CA: A Cancer Journal for Clinicians
receptors, antigens, or transporters. In many scenarios,
the tracer will be radiolabeled, ie, with a radionuclide,
although, as discussed below, this is not always the case.
A second component necessary for molecular imaging is
appropriate hardware— a sensor or scanner that can de-
tect the tracer and translate that detection into spatial in-
formation. Optimized molecular imaging approaches will
have a high- affinity tracer for a pathway or target that is
near- uniquely present in the process of interest, as well as
a scanner with high sensitivity and high spatial, contrast,
and temporal resolution.
In the current review, we focus on selected, common imag-
ing modalities and examples that highlight molecular imaging
in oncology. Specifically, we detail techniques in optical and
near- infrared (NIR) imaging, magnetic resonance imaging
(MRI), and nuclear medicine techniques, including single-
photon emission computed tomography (SPECT) and pos-
itron emission tomography (PET) (Table 1).4- 119 We also
provide specific examples from translational science and cancer
clinical care of the utilization of molecular imaging, with a par-
ticular focus on the use of these methods to guide and improve
patient management. Finally, we delineate the challenges faced
by the field and the potential benefits of overcoming them.
Modalities
A comprehensive description of all molecular imaging
modalities is beyond the scope of this review, with sev-
eral valuable reviews having recently appeared.120- 122
Accordingly, we endeavored to highlight a subset of the
most commonly used modalities and their relative advan-
tages and disadvantages. Key aspects of these modalities
are listed in Table 1.
Optical Techniques
Optical imaging is primarily a preclinical tool, although its
extensive use in molecular imaging in small animal models
of cancer merits discussion here. In many modern early
phase clinical trials, aspects of the biological justifica-
tions for many of the agents being investigated have been
preclinically evaluated with optical imaging techniques.
Optical imaging subsumes multiple submodalities, in-
cluding bioluminescence imaging (BLI), fluorescence, and
chemiluminescence.4 BLI, first reported by Contag and
colleagues, enabled the ability to follow cellular activity,
including gene expression, in living animals.123 BLI makes
use of the reaction between luciferase enzymes and their
substrates, eg, firefly luciferase and luciferin, which pro-
duces light.4 Clever applications of chemical techniques
have allowed bioluminescence to be used to understand
several fundamental mechanistic aspects of cancer biol-
ogy, 124 and it is routinely used to monitor the effects of
cancer therapy.125,126
Fluorescence, the process of light emission after excitation
of a fluorophore with a different wavelength of light, relies
on genetically encoded fluorescent proteins or on synthetic
or naturally fluorescent molecules, which may be targeted
to a cell or protein of interest.4 Preclinically, it has found
application in the study of protein- protein interactions, cell
tracking, and tumor targeting in vivo.5- 7 The rapidly growing
areas of photoacoustic imaging, photodynamic therapy, and
photoimmunotherapy all leverage an aspect of fluorescence
by detecting sound generated by the thermoelastic expansion
of tissues induced by fluorescent light (photoacoustic imag-
ing) or by creating an environment conducive to tumor cell
kill (photodynamic therapy and photoimmunotherapy).17,18
A significant disadvantage of fluorescence imaging is the in-
trinsic fluorescence present in normal proteins within tissues,
leading to a decrease in signal- to- noise, although this can be
addressed through the design of red- shifted fluorescent pro-
teins.8 Fluorescent agents that emit in the NIR region (see
below) enable sufficient depth of light penetration to allow
for real- time surgical guidance, including in clinical trials.9
NIR has multiple advantages for intraoperative imaging,
including low absorption in blood and other tissues, low
scatter, and invisibility to the human eye without the aid of
instrumentation.10 NIR- guided surgery offers opportunities
for better discrimination of diseased tissue from normal tis-
sue, decreased margin positivity rates, and minimization of
anesthesia times.11 For these reasons, NIR has been exten-
sively explored for guiding cancer surgeries (Fig. 1),127 and a
specific example is discussed below.
Surface- enhanced Raman scattering (SERS) is another
type of optical imaging with high sensitivity and speci-
ficity for the delineation of surgical margins. This tech-
nique may be an important part of surgical guidance in
the future. Jermyn and colleagues studied SERS for in-
traoperative brain cancer detection.128 Those authors re-
ported a sensitivity of 93% and specificity of 91% for the
differentiation of normal brain from dense cancer and ad-
jacent brain invaded by cancer cells,128 suggesting utility
in a class of tumors that is often extensively infiltrative.
Li et al used a high- affinity, small- molecule Raman probe
targeted against the prostate- specific membrane antigen
(PSMA) to selectively identify prostate cancer (PCa)
cells,129 an important step toward the use of SERS in in-
traoperative guidance for PCa.
Although optical techniques remain largely in the pre-
clinical domain, advancements in tracer development for
CA Cancer J Clin 2022;72:334-352 © 2021 The Authors. CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer
Society. This is an open access article under the terms of the Creative Commons Attribution- NonCommercial- NoDerivs License, which permits use and distribution
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TABLE 1. Selected Modalities for Molecular Imaging in Oncology and Relative Advantages and Disadvantages
MODALITY USES IN ONCOLOGY ADVANTAGES/DISADVANTAGES (AVAILABILITY) SELECTED REFERENCES
Optical
Fluorescence Surgical guidance Nonionizing radiation; photodynamic and photoimmunother-
apy/moderate penetration depth (research, translational)
Serkova 2021,4 Rowe &Mapp 2008,5 Rabut & Ellenberg 2004,6 Gao 2010,7
Shaner 2004,8 Hernot 2019,9 Hyun 2016,10 Vahrmeijer 2013,11 Lu 2018,12
Ishizawa 2009,13 Xu 2020,14 Asanuma 2015,15 Hernot 201916
Photoacoustic Tissue characterization; surgical guidance Nonionizing radiation; high optical specificity; real- time/
moderate penetration depth (research)
Attia 2019,17 Mitsunaga 201118
Ultrasound Targeted drug delivery; blood- brain barrier disrup-
tion; tumor characterization
Nonionizing radiation; readily available scanners; low cost
(translational, clinical)
Xu 2020,14 Endo- Takahashi 2020,19 Airan 2017,20 Hult 2020,21
Farhadi 201922
Magnetic resonance
Spectroscopy Brain tumors, prostate cancer Endogenous contrast; widely available/low sensitivity; limited
metabolites (translational, clinical)
Koutcher & Burt 1984,23 Pillai 2009,24 Barker 2009,25 Negendank 1996,26
Brindle 2017,27 Brat 2015,28 Choi 2012,29 Li 2015,30 Chan 2019,31
Edden 2007,32 Ma 2013,33 Claudino 2007,34 Qi 201935
CEST Brain tumors, obstructive uropathy Endogenous contrast; new chemical signatures/technically
complex; sensitivity unknown (translational)
Wu 2016,36 Ward 2000,37 Xu 201538,39
USPIO Cell tracking; phagocyte detection; lymph node
metastases
Endogenous contrast; new chemical signatures/technically
complex; sensitivity unknown (translational)
Zimmer 1995,40 Wu 2019,41 Ngen 2021,42 Glover 2020,43 Mathiasen 2019,44
Schilham 2021,45 Toth 2017,46 Barajas 201947
Hyperpolarization Characterization of tumor metabolism High signal; potential to investigate a wide array of metabolic
pathways; expensive; pathways under study may be
perturbed by high concentration of hyperpolarized agents
(research)
van Zijl 2021,48 Wang 2019,49 Woitek 202050
Radionucleotide
SPECT Bone scans; brain tumors; sentinel node mapping;
radiation dosimetry for theranostics
Widely available/low sensitivity; low resolution; diminishing
use in oncology (clinical)
Anger 1952,51 Kelly 2020,52 Rowe 2015,53 Gorin 2016,54 Rowe 2017,55
Wilson 202056
PET Specific molecular targets; metabolism
(glucose/glutamine)
High sensitivity and potential for high specificity/complex
infrastructure; costly agents (translational, clinical)
Wahl 2008,57 Sanchez- Crespo 2013,58 Verhagen 2021,59 Cherry 201760 and
2018,61 Zhang 2020,62 Sanli 2017,63 Wahl 1994,64 Newman 1994,65 Lu
2012,66 Shreve 1999,67 Cheson 2014,68 Hicks 2021,69 Johnson 2016,70
Hope 2019,71 Jadvar 2016,72 Fanti 2016,73 Savir- Baruch 2017,74 Rowe
2019,75 Barratto 2018,76 Eiber 2017,77 Werner 2020,78 Perera 2020,79
Kiess 2015,80 Maurer 2016,81,82 Gorin 2018,83 Pienta 2021,84 van Leeuwen
2019,85 Cookson 2007,86 Roach 2006,87 Fendler 2019,88 Markowski 2020,89
Morris 2021,90 Joice 2017,91 Phillips 2020,92 Sharma 2021,93 Rohrich
2021,94 Serfling 2021,95 Giesel 2021,96 Lindner 2021,97 Kessler 2021,98
Wu 2021,99 Friedman 2020,100 Van Acker 2001,101 Stumpe 2004,102
Familiari 2011,103 Kagna 2012,104 Cho 2020,105 Mutch 2018,106
Ordonez 2021,107 Foss 2018,108 Petrik 2012109 and 2014,110 Davies 2017111
Theranostic Thyroid cancer, neuroendocrine tumors, prostate
cancer
High specificity through image guidance/complex
infrastructure; costly agents (translational, clinical)
van der Heil 2003,112 Strosberg 2017,113 Buatti 2021,114 Burkett 2021,115
Yadav 2019,116 Hofman 2018117 and 2021,118 Novartis AG 2021119
Abbreviations: CEST, chemical exchange saturation transfer; PET, positron emission tomography; SPECT, single- photon emission computed tomography; USPIO, ultrasmall superparamagnetic iron oxide nanoparticles.

Molecular imaging
336 CA: A Cancer Journal for Clinicians
other molecular imaging modalities may help to drive the
translation of NIR probes into human clinical practice.9
Challenges to implementing NIR probes in clinical routine
include the need for optimized tracers that have rapid up-
take in the tissue of interest but clear quickly from back-
ground tissues as well as the intrinsic need for development
of highly sensitive instruments and bright fluorescent dyes.9
As with many molecular imaging modalities that depend on
exogenously administered agents, there are significant barri-
ers to clinical translation, such as expensive biodistribution
and toxicology studies that need to be carried out for any
new composition of matter.
Magnetic Resonance Imaging
Often classified as an anatomic imaging modality, recent
advances with MRI demonstrate the ability of this modal-
ity to image molecular processes. All MRI techniques are
based on the principle that some atomic nuclei are able to
align like small magnets within a magnetic field because
of their spin properties.23 Fundamentally, MRI involves a
high magnetic field and the generation of images through
the selective application of radiofrequency pulses, which
lead to different patterns of signal in different tissues based
on tissue composition, ie, based on the nature and concen-
tration of the nuclei present in those tissues. Traditionally,
MRI has been used to create high- resolution anatomic im-
ages of soft tissue structures, such as the brain and muscu-
loskeletal system, for which computed tomography (CT)
has lacked the contrast resolution to provide useful diag-
nostic information.
However, MRI uses the same principles as nuclear mag-
netic resonance spectroscopy (MRS), meaning that it can
identify the individual resonances of protons (and other
paramagnetic atomic nuclei) and specific compounds if
those entities are present in sufficient concentrations. As
such, many clinical and investigational MRI techniques fall
under the aegis of molecular imaging. For example, MRS
can detect compounds that are present at high (millimolar)
concentrations and that have a proton signal resolvable from
water. As suggested above, MRS uses the same principles of
signal acquisition as other MRI techniques. However, the
data are analyzed in a different way so that, instead of an-
atomic images being created, the concentrations of differ-
ent paramagnetic atoms are displayed as a function of their
chemical shift resonances.24 As with other MRI techniques,
the massive amount of hydrogen present in biological mol-
ecules makes it the paramagnetic atom of choice for MRS,
although examining hydrogen atoms in metabolites requires
suppression of the signal from hydrogen atoms in surround-
ing bulk water.
For compounds at lower (micromolar) concentrations,
chemical exchange saturation transfer (CEST) can be used,
provided the compound of interest has a proton that can be
exchanged with surrounding water protons.36 CEST agents
were first introduced in 2000 and offer an alternative to
traditional MRI contrast materials that increase signal by
enhancing water proton relaxivity.37 Although it is able to
visualize the presence of substrates at lower concentrations
than MRS, CEST still lacks the sensitivity of PET and also
can suffer from some of the same specificity issues, includ-
ing hyperemic effects that may lead to higher signal from
exogenously administered agents in inflammation and other
conditions. Examples of the uses of MRS and CEST in mo-
lecular imaging of cancer are presented below.
An early, preclinical molecular imaging technique that is
finding its way into the clinic is the use of ultrasmall iron
oxide nanoparticles and other metallic nanoparticles to
image phagocytic cells by MRI and, by extension, tumors
and metastases with which they become associated.40 A fur-
ther advance of this technology has been the recent devel-
opment of instrumentation specifically for magnetic particle
imaging.41 Targeted magnetic nanoparticles can serve as a
platform to define the depth of penetration of nanoparti-
cles within solid tumors using MRI.42 Leveraging the high
FIGURE 1. The Use of Indocyanine Green for Surgical Guidance During a
Lung Segmentectomy. (A) The intersegmental plane was difficult to identify
with traditional techniques but (B) was visualized much more clearly with
the use of indocyanine green (red arrows in B). Reproduced from: Liu Z,
Yang R, Cao H. Near- infrared intraoperative imaging with indocyanine green
is beneficial in video- assisted thoracoscopic segmentectomy for patients
with chronic lung diseases: a retrospective single- center propensity- score
matched analysis. J Cardiothorac Surg. 2020;15:303.127

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337VOLUME 72 | NUMBER 4 | JULY/AUGUST 2022
signal generated from metallic susceptibility, a key indication
for this technology is for cell tracking, including the tracking
of transplanted cardiac and other stem cells.43,44 In a tech-
nique referred to as magnetic resonance (MR) lymphogra-
phy, ferumoxytol and its analogs have been used to detect
lymph nodes involved in PCa, in one clinical instance ri-
valing PSMA- targeted PET in sensitivity.45 Ultrasmall iron
oxide nanoparticles have also found substantial application
to neuroinflammation46 and in tracking pseudoprogression
of glioblastoma.47
Lastly among the techniques that we will discuss in this
section is hyperpolarized MRI, which makes use of a com-
plex process to align the nuclei of 13C- labeled agents to mas-
sively increase the signal that is available.48,49 Hyperpolarized
MRI can be used to investigate a variety of physiologic and
pathologic processes, including metabolic pathways in can-
cer.48 A recent example from Woitek et al showed that a re-
duction in the 13C- labeled lactate– to– 13C- labeled pyruvate
ratio was predictive of response to therapy in patients with
breast cancer undergoing neoadjuvant chemotherapy.50
As with many imaging agents, placing them within a
specific environment or changing the isotope if radioactive
(see below) can convert them to therapeutics. An imaging
agent that, with minimal alteration, can also effect therapy
is referred to as a theranostic.130 For example, placing me-
tallic nanoparticles within an alternating magnetic field
creates a heating effect that has proved therapeutic in
cancer.131
Single- Photon Emission Computed Tomography
Although other modalities can provide higher spatial resolu-
tion, SPECT remains an important methodology across the
gamut of imaging- evaluable pathology. SPECT, like MRI
but unlike PET, is clinically ubiquitous. SPECT relies on
radiotracers that emit single photons from nuclear decay
processes followed by the detection of these photons with
a gamma camera. Traditionally, gamma cameras have been
composed of a scintillation crystal that converts the emitted
photons into visible light,51 a series of backing photomulti-
plier tubes that increase the signal from the visible light, and
a collimator between the patient and the scintillation crys-
tal that allows the emitted photons to be spatially localized.
Gamma cameras can be used for planar imaging; however,
in many modern molecular imaging applications, they are
spun around the patient to create tomographic images, ie,
SPECT.
The limited spatial resolution of SPECT is still adequate
for many clinical applications. The fundamental strengths
of SPECT derive from the large number of single- photon–
emitting radionuclides that are readily available, including
technetium- 99m (99mTc), iodine- 123 (123I), and indium- 111
(111I). These radionuclides produce emitted photons of dif-
ferent energies, which can be distinguished by the gamma
camera, permitting the simultaneous acquisition of multiple
radiotracers. Furthermore, the availability of radionuclides
with a long physical half- life (T1/2), eg, 111In (T1/2 = 67
hours), allows for both delayed imaging for diagnostic pur-
poses and the determination of dosimetry for selected ther-
apeutic radiopharmaceuticals.52
Although single- photon– emitting radiotracers lack the
high spatial resolution and routine quantifiability of PET
radiotracers, the intrinsic advantages of having radionuclides
that decay with different energies and the wide array of ra-
diotracers that are available will keep SPECT relevant for
routine clinical applications for the foreseeable future.
Positron Emission Tomography
PET is the gold standard for sensitivity in clinical molecu-
lar imaging. The basic principle of PET is that proton- rich
radionuclides decay by emitting positrons (β+), which sub-
sequently travel a short distance and annihilate with an elec-
tron (β−) to create two 511- kiloelectron volt photons that
arise almost exactly 180 degrees apart.57 Rings of detectors
can be used to take advantage of coincidence detection to
identify the locations of the annihilation events. Common
radionuclides used for PET imaging include organic/
organic- like isotopes (eg, carbon- 11 [11C], nitrogen- 13, and
fluorine- 18 [18F]) and radiometals (eg, gallium- 68 [68Ga],
copper- 64 [64Cu], and zirconium- 89 [89Zr]). For many
clinical and research applications, 18F provides an ideal com-
bination of medicinal chemistry properties, radionuclide
half- life (T1/2 = 110 minutes), positron yield and energy.58
As noted above, radionuclide- based imaging techniques
such as PET play important roles in theranostics, namely,
in selecting patients for the corresponding therapy. An ad-
vantage of radionuclide- based theranostic pairs is that, by
merely changing the radionuclide within the chelator, (eg,
68Ga to 177Lu) or changing the isotope of the halogen (eg,
123I to I24I), one may move from an imaging to a therapeutic
agent within the same molecular scaffold.
Intrinsic advantages of PET include high- contrast res-
olution and quantifiable imaging parameters. In modern
practice, coregistered CT is used to create attenuation
maps that allow highly accurate attenuation correction.
With advanced techniques, such as resolution recovery,
motion correction, and point- spread function recon-
struction, PET is continuing to evolve as a cornerstone
of modern clinical molecular imaging. Furthermore, PET
is increasingly being combined with MRI (ie, PET/MR),
potentially allowing for powerful combinations of the mo-
lecular imaging features of each of the individual modal-
ities while also saving radiation dose to patients.59 Along
those lines, the sensitivity of total- body PET allows for
the administration of radiopharmaceutical doses at a frac-
tion of the dose of current clinical studies.60- 62 That en-
ables expanded use of PET in pediatric populations or for

Molecular imaging
338 CA: A Cancer Journal for Clinicians
patients who require frequent studies in whom radiation
dosimetry must be carefully taken into account.
Ultrasound
The advantages of ultrasound imaging include real- time
dynamic imaging, small physical footprint of the (portable)
scanning device, lack of radioactivity, and relatively low cost.
Although primarily used clinically for anatomic delineation
and for studying flow- based phenomena (Doppler), ultra-
sound molecular imaging with microbubbles for the targeted
delivery of drugs, including genetic material, is proliferat-
ing.19 It is also used for focal disruption of the blood- brain
barrier to enable access to the brain for hydrophilic diag-
nostic and therapeutic agents.20 Photoacoustic imaging may
provide highly specific cancer signatures not available from
other techniques.21 Through modification of what was orig-
inally a bacterial gene, Shapiro and coworkers have used ul-
trasound and an acoustic reporter to image gene expression
in mammalian cells.22 The delivery of sound pulses to tissue
is now being studied and implemented in analogy to using
MR pulse sequences.12 As more is learned in this area, ul-
trasound may increase in versatility for biomedical research
and medicine through further extension into the molecular
realm.
Examples of Molecular Imaging Utilization
The breadth of the impact of modern molecular imaging on
medicine and the biomedical sciences is difficult to encapsu-
late in any brief review. As opposed to a comprehensive list-
ing of current applications of molecular imaging, we present
a series of examples that demonstrate how the principles of
molecular imaging can affect the care of patients with cancer.
Near- Infrared Imaging for Surgical Guidance
The major limitation of applying optical imaging tech-
niques to human subjects is the limited depth of pene-
tration achievable with the detectors for optical probes.
However, this limitation is nearly moot in the context of
intraoperative imaging, in which there is exposure of the
tissues under study. As such, optical imaging techniques
have been studied extensively for the purposes of surgi-
cal guidance. NIR probes have been suggested to improve
clinical workflow and to have advantages in speed, patient
outcomes, and cost relative to traditional, unguided surgi-
cal methods.11
The first application of NIR agents to intraoperative
guidance made use of indocyanine green, a dye that is ap-
proved by the US Food and Drug Administration.20 In
an initial study, Ishizawa and coworkers found that hepa-
tobiliary excretion of indocyanine green allowed for the
clear delineation of superficial colorectal liver metastases
and primary hepatocellular carcinomas.13 The tumors were
demarcated by surrounding rims of fluorescence, with little
background uptake in the normal liver.
Since that first study, the number of available NIR
probes has rapidly expanded to include specific tumor-
targeting small molecules, peptides, antibodies, and
aptamers.14 Asanuma and coworkers leveraged the over-
expression of β- galactosidase in ovarian cancer so that
hydroxymethyl rhodol fluorescence dyes containing β-
galactoside could be used to identify peritoneal metastases
intraoperatively.15 Although preclinical, that study is an
elegant example of the use of altered patterns of protein
expression in cancer to drive specific imaging of subtle
sites of cancer dissemination.
NIR surgical guidance is being pursued in a variety of
organ systems16; however, it has been most extensively used
to date in the brain. Maximal resection of aggressive gliomas
offers advantages in survival, yet it is also important to min-
imize the impact on surrounding brain to avoid neurologi-
cal deficits. For these reasons, Butte and coworkers explored
the use of the peptide agent Tumor Paint BLZ 100 (Blaze
Bioscience, Inc) in mice with implanted human glioma
cells.132 Those authors reported high signal- to- background
in the removed brains from dead mice and believed that the
approach was feasible for surgical guidance.132 Although a
great deal of research remains to be done to have specific,
tumor- targeted NIR surgical guidance as part of routine
clinical work, the promising preclinical results suggest that
this line of inquiry should be broadly pursued. For example,
a phase 1 study for the fluorescent identification of positive
primary tumor margins and disease- involved lymph nodes in
men with PCa is currently accruing patients (ClinicalTrials.
gov identifier NCT04574401). In future years, we are likely
to see several additional clinical trials for similar indications
as new compounds for NIR imaging of novel cancer- relevant
targets are developed.
Brain Tumor Imaging with Magnetic Resonance
Spectroscopy
The most common metabolites visualized by MRS25 are
N- acetyl aspartate (NAA), choline (Cho), creatine/phos-
phocreatine (Cr), and lactate.24 The normal relative concen-
trations of these compounds in brain are well understood,
as are the perturbations in those concentrations in different
types of brain tumors. Under normal conditions, NAA, a pu-
tative neuronal marker, comprises the highest peak on the
spectrum, with lower concentrations of Cr and Cho. Tumors
generally demonstrate abnormally decreased NAA/Cr and
increased Cho/Cr ratios compared with normal brain, sug-
gesting internal loss of normal neural tissue but also higher
rates of cellular turnover; however, intrinsic heterogeneity
among tumor grades can make it difficult to derive tumor
aggressiveness from MRS data.26

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Nonetheless, the clever application of MRS methods to
the evaluation of brain tumors has led to the noninvasive
determination of important tumor characteristics.27 For ex-
ample, the discovery of mutant isocitrate dehydrogenase in
low- grade gliomas and some glioblastomas that was asso-
ciated with improved outcomes28 spurred the identification
of the oncometabolite 2- hydroxyglutarate by MRS.29 This
suggests that noninvasive characterization and prognostica-
tion of gliomas may be possible and that tumor heterogene-
ity that might limit pathological analysis can be overcome
with imaging.
Future developments may increase the relevance of
MRS. The introduction of ultrahigh- field 7- Tesla scanners
into the clinic,30 spectral editing (ie, the targeting of a nu-
cleus or functional group on one species while removing
an overlapping resonance due to another species from the
spectrum),31,32 and the advent of new techniques like MR
fingerprinting33 may overcome some limitations, such as low
sensitivity. The complementary field of metabolomics con-
tinues to evolve, with potential applications in selection of
cancer therapy and response assessment.34 As new patterns
of metabolites are identified, MRS is an adaptable modality
that can potentially noninvasively identify those patterns.
Furthermore, as with other modalities discussed in this re-
view, MRS is likely to benefit from the burgeoning role of
artificial intelligence (AI) in radiology. There are already
hints that MRS that is leveled- up with machine learning (a
type of AI) may overcome the limitations of individual fea-
tures for noninvasively predicting glioma tumor grade.35 Qi
and coworkers found that a machine learning- driven model
generated an area under the curve of 0.820 for a validation
set, which was better than the individual performance of tra-
ditional metabolic features.35
However, these emerging technologies and applications
must mature before MRS techniques are likely to be part of
routine clinical MR acquisitions in oncology. Nonetheless,
noninvasive means of molecular characterization of brain tu-
mors carry considerable promise, and preclinical and transla-
tional efforts will continue.
Brian Tumor Imaging With Chemical Exchange
Saturation Transfer MRI
In a key preclinical study, Xu and coworkers inoculated
mice with a human glioma cell line and then used glucose
as a dynamic contrast medium to visualize the tumors.38
By using a frequency offset that could detect the water-
exchangeable hydroxyl protons in glucose (glucoCEST),
areas of the blood- brain barrier became apparent on the
images. Termed dynamic glucose- enhanced (DGE) MRI,
this method has significant appeal in that the infused con-
trast agent is also an endogenous metabolite, and there is
no administration of potentially toxic gadolinium metal
chelates.
Given promising preclinical results, DGE MRI has
been explored in human subjects.32 In an initial study with
4 healthy volunteers and 3 patients who had glioma, DGE
glucoCEST demonstrated spatially variable enhancement
within the tumors (Fig. 2).39 Interestingly, the enhancement
both varied with time and was not strictly concordant with
regions of gadolinium- based enhancement.39 These findings
suggest that there may be additional information available
from DGE MRI that may include the relative permeabil-
ity of the blood- brain barrier39 and the degree of inherent
glycolytic metabolism within different parts of the tumor.
Given the apparent spatially and temporally complex pro-
cesses governing uptake of glucose and gadolinium- based
contrast agents, it is highly likely that insights from AI will
be needed to derive detailed prognostic information from
those patterns.
Renal Mass Characterization
Multiple modalities, including MRI, SPECT, and PET,
have all played a role in bringing molecular imaging to the
forefront of indeterminate renal mass characterization. Until
recently, renal masses were typically imaged with multiphase,
contrast- enhanced anatomic imaging protocols using CT or
MRI, and limited information on the nature of the masses
could be gleaned from their enhancement patterns.133,134
Although renal mass biopsy is a safe and effective means of
risk stratification,135 the negative predictive value for ruling
FIGURE 2. A 25- Year- Old Man With Anaplastic Astrocytoma. These are
axial dynamic glucose- enhanced difference images at 5.3- second temporal
resolution. Note the differential and heterogeneous enhancement centered
in the region of the right insula and extending into the right frontal and
temporal lobes. Although the contrast between the abnormal right side
and the normal left side is less than might be encountered with some other
molecular imaging modalities, it is nonetheless impressive that tumor
visualization can take place through the exogenous application of glucose.
Reprinted from: Xu X, Yadav NN, Knutsson L, et al. Dynamic glucose-
enhanced (DGE) MRI: translation to human scanning and first results in
glioma patients. Tomography. 2015;1: 105- 114.39

Molecular imaging
340 CA: A Cancer Journal for Clinicians
out cancer is low, and there is a relatively high nondiagnostic
rate.136 Because of these limitations, most patients undergo
empiric partial or radical nephrectomy on the assumption
that most indeterminate renal masses will be renal cancer.
This leads to thousands of unnecessary surgeries in the
United States each year.137
Molecular imaging has provided a means by which
indeterminate renal masses may be better evaluated be-
fore surgical resection. Ideally, molecular imaging meth-
ods would allow for the differentiation of benign/indolent
tumors (such as oncocytomas) from aggressive renal cell
carcinoma (RCC) subtypes (such as clear cell RCC
[ccRCC]). For example, multiparametric MRI that in-
cludes functional sequences examining the diffusivity of
water and the dynamic contrast enhancement of tissues
can be used to create a ccRCC likelihood score (ccLS).138
The ccLS tracks with the positive predictive value for a
lesion representing a ccRCC, from 5% for ccLS1 through
93% for ccLS5.138
SPECT and PET have also been used for renal mass char-
acterization. Multiple different targets have been leveraged. An
important example is the development of radiolabeled giren-
tuximab, a monoclonal antibody against carbonic anhydrase
IX that is highly expressed on ccRCC cells. 124I- girentuximab
PET/CT was used in patients with indeterminate renal
masses in the REDECT trial (ClinicalTrials.gov identifier
NCT00606632) and was found to have better sensitivity and
specificity than CT for the identification of ccRCC.139
Recently, a commonly used radiotracer for cardiac and
parathyroid imaging, 99mTc- sestamibi, a lipophilic cation
that accumulates in accordance with the charge potential of
mitochondrial membranes, has been leveraged for imaging
indeterminate renal masses.53,54 Sestamibi localizes to on-
cocytomas and other low- grade oncocytic neoplasms on the
basis of high mitochondrial content in these lesions, while at
the same time it is actively expelled from aggressive RCCs
by multidrug resistance pumps.55 This inexpensive approach
has been adopted across several studies, with meta- analytic
sensitivity of 92% and specificity of 88%,56 for the identifi-
cation of renal oncocytomas.
The difficulty of characterizing renal masses is likely
to mean that multiple techniques will need to be used for
complete nonsurgical characterization. The use of molecu-
lar imaging with confirmatory biopsy140 and emerging ge-
nomic approaches,141 if properly used in a risk- stratification
approach, can decrease the number of unnecessary renal
tumor resections. A proposed workup algorithm, based on142
and incorporating molecular imaging with 99mTc- sestamibi
SPECT, is shown in Figure 3.141,142 This approach is cost-
effective, treats the fewest number of benign/indolent tu-
mors, and leaves the least number of aggressive tumors
untreated,140 suggesting high value to patients with indeter-
minate renal masses.
Cancer Imaging With 2- Deoxy- 2- [18F]Fluoro- D- Glucose
So transformative to oncology imaging has been the wide-
spread clinical adoption of 2- deoxy- 2- [18F]fluoro- D-
glucose (18F- FDG) that entire textbooks have been written
on the subject.57 18F- FDG localizes in most types of malig-
nancy because of its glucose- analog structure, which leads
to uptake via GLUT1 transporters in cells undergoing gly-
colytic metabolism.57 The strength of 18F- FDG is its lack
of specificity— the universality of its mechanism of uptake
makes it broadly useful for staging, restaging, and therapeu-
tic monitoring of numerous malignancies, from head and
neck squamous cell carcinoma63 to bronchogenic carcino-
mas,64 lymphomas,65 and myeloma.66
However, the weakness of 18F- FDG PET is also its
lack of specificity. 18F- FDG uptake is seen in numer-
ous nononcologic conditions,67 including posttreatment
changes (eg, postoperative or postradiation inflammatory
change), infections, and granulomatous and nongranulo-
matous systemic inflammatory processes. Nonetheless,
despite these pitfalls, the ability of 18F- FDG PET to
identify the presence of small volumes of malignant dis-
ease in morphologically normal structures, as well as to
assess the metabolic activity of morphologically abnormal
structures, has revolutionized the modern practice of on-
cology. Perhaps nowhere is this more apparent than in the
contemporary approach to the imaging of most Hodgkin
and non- Hodgkin lymphomas, in which metabolic assess-
ments on serial 18F- FDG PET images are a key determi-
nant of response assessment and patient therapy selection
(Fig. 4). The Lugano classification is an extensively vali-
dated 5- point scale that categorizes posttherapy 18F- FDG
PET scans on the basis of any residual or new metabolic
activity and the implications for such activity on the pres-
ence of viable lymphoma.68
Although new radiotracers are being increasingly used
for specific types of cancer, and other agents in early clini-
cal development may challenge the role of 18F- FDG as the
predominant, generalized cancer imaging radiopharmaceu-
tical,69 several advances are likely to keep 18F- FDG highly
relevant in years to come. For example, 18F- FDG PET can
be used to adapt therapy in patients with Hodgkin lym-
phoma. Johnson et al studied a cohort of 1214 patients with
newly diagnosed Hodgkin lymphoma70 The authors ran-
domly assigned patients who had negative 18F- FDG PET
scans after 2 cycles of doxorubicin, bleomycin, vinblastine,
and dacarbazine (ABVD) to receive either 4 more cycles of
ABVD or 4 cycles of AVD (ie, with bleomycin omitted).70
They concluded that the use of ABVD led to lower pul-
monary toxicities without a significant decrease in efficacy.70
One can imagine using 18F- FDG PET as a means to adapt
therapy in a wide variety of different cancers. Furthermore,
18F- FDG is an inexpensive and readily available radiotracer
whose widespread applicability and time- tested clinical

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protocols will make it difficult to displace as a general cancer
imaging agent. Other than those cancers that have limited
hypermetabolism, the one- size- fits- all approach of using
18F- FDG, in which the same patient preparation, dose, up-
take time, and scanner protocol can be applied for all can-
cers, is likely to hold sway over oncology molecular imaging
for the near future.
Somatostatin Receptor- Based Imaging and Therapy
Tumors comprised of cells of neuroendocrine origin will
often express large amounts of somatostatin receptors
(SSTRs) on their surfaces, particularly SSTR subtype 2.
This provides a means of imaging and therapy through the
application of high- affinity SSTR ligands. For many years,
the SPECT radiotracer 111In- pentetreotide (OctreoScan)
was used in this context, generally for imaging,143 although,
with high doses, therapy was possible.112
However, the current molecular imaging and ther-
apy paradigm for neuroendocrine tumors is based on the
PET radiotracer 68Ga- DOTATATE (or one of several
closely related agents) and its therapeutic analog, 177Lu-
DOTATATE. Relative to OctreoScan, 68Ga- DOTATATE
FIGURE 3. Proposed Workup Algorithm for Indeterminate Renal Masses Incorporating Molecular Imaging with Technetium- 99m (99mTc)- Sestamibi Single-
Photon Emission Computed Tomography (SPECT). This algorithm is derived from a previously published figure (Kang SK, Bjurlin MA, Huang WC. Management
of small kidney tumors in 2019. JAMA. 2019;321:1622- 1623142). CT indicates computed tomography; MRI, magnetic resonance imaging; SPECT, single- photon
emission computed tomography.

Molecular imaging
342 CA: A Cancer Journal for Clinicians
leverages the advantages of PET (eg, improved spatial and
contrast resolution) to produce images with higher sensitiv-
ity and higher uptake in sites of disease.71 Figure 5 is a rep-
resentative example.
177Lu- DOTATATE was approved by the US Food and
Drug Administration for the treatment of patients with well
differentiated midgut neuroendocrine tumors after the re-
sults of the NETTER- 1 phase 3 clinical trial (ClinicalTrials.
gov identifier NCT01578239).113 In NETTER- 1, 229 pa-
tients were randomized to receive either 177Lu- DOTATATE
and best supportive care or long- acting nonradioactive
octreotide.113 Treatment with 177Lu- DOTATATE and
best supportive care yielded significant improvements in
progression- free survival and the response rate, as well as
preliminary evidence of improved overall survival, versus
nonradiative octreotide.113 In the United States, the results
of the NETTER- 1 trial and subsequent approval of 177Lu-
DOTATATE fundamentally changed the approach to the
treatment of patients with midgut neuroendocrine tumors,
and those patients are now routinely being treated with
177Lu- DOTATATE.
177Lu- DOTATATE has rapidly become the targeted
radiopharmaceutical therapy archetype whose routine use
is forcing nuclear medicine groups in the United States to
adopt a more patient- centered focus, or they risk irrelevance
in the current theranostics revolution.114 With PSMA- based
imaging and therapies on the horizon of regulatory approval
(see PSMA- Targeted Imaging and Therapy, below), the
model in which nuclear medicine physicians play a central
role in the multidisciplinary care of patients with metastatic
cancer115 is a priority for the field.
PSMA- Targeted Imaging and Therapy
Unlike most malignancies, PCa often does not undergo gly-
colytic metabolism and is often poorly imaged by 18F- FDG,
although there may be times when 18F- FDG is appropriate.72
However, the insensitivity of 18F- FDG in many scenarios has
led to the development of several molecular imaging agents
to image PCa, including those based on imaging metabolic
pathways (eg, 11C- choline73 and 18F- fluciclovine74) as well
as those targeted to specific cell- surface targets (eg, PSMA75
and gastrin- releasing peptide receptor76).
Multiple radiotracers have received regulatory approval
for imaging PCa, although the degree to which these
agents have been used in clinical practice has varied widely.
However, one of the important contributions of modern
molecular imaging has been the development and burgeon-
ing clinical adoption of small- molecule radiotracers that
target PSMA for imaging and therapy.77 For diagnostic pur-
poses, these agents have generally been labeled with 18F78 or
68Ga,79 allowing high- contrast- resolution PET imaging of
sites of PCa.
The clinical applications of PSMA- targeted imag-
ing agents are widely varied, and a complete accounting
FIGURE 4. A 24- Year- Old Man With Epstein- Barr Virus– Associated Lymphoma Before and After Systemic Therapy. (A) This maximum intensity projection
(MIP) 2- deoxy- 2- [18F]fluoro- D- glucose (18F- FDG) positron emission tomography (PET) image before the initiation of therapy demonstrates numerous sites of
abnormal radiotracer uptake throughout lymph nodes and skeletal structures, consistent with widespread lymphomatous involvement. Axial (B) 18F- FDG, (C)
computed tomography (CT), and (D) fused 18F- FDG PET/CT images through the pelvis demonstrate a particularly prominent right external iliac lymph node
with intense uptake, consistent with a site of disease (red arrows). (E) In this MIP 18F- FDG PET image after completion of therapy, all of the abnormal uptake
has resolved (note that the apparent focus of uptake in the left arm is a result of motion artifact). Axial (F) 18F- FDG, (G) CT, and (H) fused 18F- FDG PET/CT
images through the pelvis show that the left external iliac node has decreased in size, although it remains enlarged (red arrows). Despite the residual anatomic
abnormality, the uptake has been reduced to blood pool levels, consistent with a complete metabolic response. This example demonstrates the ability of
18F- FDG PET to characterize residual anatomic lesions after therapy.

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is beyond the scope of the current article. Several detailed
reviews have been written, such as those by Rowe et al,75
Kiess et al,80 and Maurer et al.81 However, there are ap-
plications that merit specific mention here. The first of
those indications is primary staging in patients at risk of
locoregional nodal or distant metastatic disease. In general,
single- center studies82,83 have reported higher sensitivity
for otherwise occult sites of disease compared with multi-
center studies.84 In the OSPREY study (ClinicalTrials.gov
identifier NCT02981368), for example, 252 patients with
high- risk PCa underwent imaging with PSMA- targeted
18F- DCFPyL (a highly selective, small- molecule PET ra-
diotracer) and then proceeded to radical prostatectomy
with pelvic lymph node dissection.84 The median sensitivity
from 3 central readers compared with histopathology was
40.3%, although the very high median specificity (97.9%)
led to high median positive and negative predictive values
(86.7% and 83.2%, respectively).84 Regardless of sensitivity,
the presence of visible disease on the scan has prognostic sig-
nificance because these patients have worse outcomes than
those who have false- negative scans.85
Perhaps the most common indication for a PSMA PET
study is in men who had previously attempted curative ther-
apy for their PCa but then had recurrence of a detectable/
rising serum prostate- specific antigen (PSA) level. This state
is known as biochemical recurrence (BCR) and is defined by
the American Urological Association as a serum PSA level
of 0.2 ng/mL in a patient who underwent prior surgery and
had achieved an undetectable PSA level86 or as a PSA rise
of 2.0 ng/mL over nadir in a patient who received prior ra-
diation therapy.87 Serum PSA is such a remarkably sensi-
tive means of detecting recurrence that subtle rises suggest
the presence of residual or recurrent disease. At low PSA
levels, however, the volume of disease may be very small,
limiting the value of anatomic imaging in localizing the site
of PCa responsible for the rise in PSA. The high- contrast
resolution of PSMA PET allows high- sensitivity detection
of small foci of disease at low PSA levels.88,89 Prospective,
multicenter studies have now borne out the use of PSMA
PET for localizing recurrent PCa.88,90 For example, the de-
tection efficiency was 475 of 635 (75%) at the patient level
in a 2- center study using the 68Ga- PSMA- 11 radiotracer.88
Figure 6 is an example of a patient who had a small- volume
recurrence imaged with PSMA- targeted 18F- DCFPyL.
Both in men with BCR and in those with limited vol-
ume metastatic disease, ie, oligometastatic PCa,91 the role
of PSMA PET imaging is the localization of disease to
potentially allow for nonsystemic curative therapies. In the
FIGURE 5. A 74- Year- Old Woman With Metastatic Small Bowel Neuroendocrine Tumor. (A) This maximum intensity projection, gallium- 68 (68Ga)- DOTATATE,
positron emission tomography (PET) image shows numerous sites of abnormal uptake in lymph nodes and bones. Axial (B) 68Ga- DOTATATE PET, (C) computed
tomography (CT), and (D) fused 68Ga- DOTATATE PET/CT images demonstrate that many of the bone lesions are easily visible on the PET image but are occult
on the corresponding CT anatomic images (red arrows). This case demonstrates the high sensitivity that is achievable with optimized PET radiotracers and
that normal- appearing anatomic structures can harbor disease that is well visualized with molecular imaging.

Molecular imaging
344 CA: A Cancer Journal for Clinicians
ORIOLE trial (ClinicalTrials.gov identifier NCT02680587),
men with small- volume metastatic disease were randomized
to observation versus stereotactic ablative body radiation
(SABR) to visible sites of disease on conventional imag-
ing.92 In a post- hoc analysis, it was found that men who
had received SABR to all PSMA- avid sites of disease had
improved progression- free and distant- metastasis- free sur-
vival relative to those whose SABR plan had not included all
PSMA- positive disease.92
In men with widespread metastatic PCa, the presence of
high uptake of PSMA- targeted PET radiotracers in their
sites of disease would suggest that PSMA- based thera-
peutic molecules may be effective. Although many early
studies showing the promise of this approach were retro-
spective,116 there have been multiple, recent, key prospec-
tive trials establishing the effectiveness of 177Lu- labeled
agents in treating PSMA- positive PCa. These key studies
include the LuPSMA trial (ClinicalTrials.gov identifier
NCT04663997), which prospectively demonstrated the ef-
ficacy of treatment with 177Lu- PSMA- 617117; the TheraP
trial (ClinicalTrials.gov identifier NCT03392428), which
demonstrated that patients who received 177Lu- PSMA- 617
had better oncologic outcomes and less toxicities compared
with those who received cabazitaxel118; and participants in
the VISION trial (ClinicalTrials.gov NCT03511664). The
VISION trial has recently been shown to meet its primary
end points of increased overall survival and time to radio-
graphic progression over best standard- of- care therapy in
patients with PSMA- expressing, metastatic, castration-
resistant disease.119
With a recent limited US Food and Drug Administration
approval of 68Ga- PSMA- 11 at 2 sites in the United States144
and nationwide approval of 18F- DCFPyL,145 we are on the
precipice of PSMA PET imaging revolutionizing the care of
men with PCa in the United States. Soon after approval of
the imaging agents will likely come the approval of PSMA-
based therapeutics, beginning with 177Lu- PSMA- 617.
Coming years will see a flood of studies to define the utility
of PSMA PET imaging, uncover imaging biomarkers for
patient prognosis, and understand the role of PSMA ther-
apy in the broader therapeutic landscape for PCa. Already,
PSMA- based imaging is a new standard of care for the stag-
ing or restaging of men with either primary disease or BCR
who are at risk of metastases. The majority of men who are
imaged with PSMA PET will undergo a change in treat-
ment plan, indicating profound clinical impact.
FIGURE 6. A 64- Year- Old Man Who Was 11 Years Postprostatectomy for Gleason 4 + 5 = 9, Grade Group 5 Prostate Cancer and Presented for Prostate-
Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) With a Prostate- Specific Antigen Level of 2.2 ng/mL. (A) This maximum intensity
projection, fluorine- 18 DCFPyL (18F- DCFPyL) (a highly selective, small- molecule PET radiotracer), PSMA- targeted PET image demonstrates subtle uptake at
multiple sites of small, morphologically normal lymph nodes (red arrows). Axial (B) 18F- DCFPyL PET, (C) computed tomography (CT), and (D) fused 18F- DCFPyL
PET/CT images demonstrate focal uptake in a 2- mm left supraclavicular (Virchow) node (red arrows), consistent with low- volume systemic nodal disease.
Conventional imaging with bone scan and CT had not indicated a site of disease.

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Fibroblast- Activation Protein- Based Imaging
Fibroblast- activation protein (FAP) is a rapidly emerging
target for imaging and therapy of various cancers. FAP is
an excellent target for molecular imaging applications be-
cause of its limited normal tissue distribution combined with
high expression on cancer- associated fibroblasts.93 To date,
the literature on imaging with FAP ligands is primarily ret-
rospective and single- center; however, there are promising
potential applications already emerging. For example, pan-
creatic ductal adenocarcinoma can be difficult to image with
conventional anatomic imaging or 18F- FDG PET. Rohrich
et al have reported that a 68Ga- labeled inhibitor of FAP
(68Ga- FAPI) changed the staging in 10 of 19 patients (53%)
from a mixed cohort with recurrent/progressive and newly
diagnosed disease.94
In addition to improved sensitivity for some cancer types
that may have low or heterogeneous uptake of 18F- FDG, the
low background uptake of 68Ga- FAPI in normal tissues may
also imbue 68Ga- FAPI PET with added specificity in some
circumstances. As one example, Serfling and coworkers re-
cently imaged 8 patients who were suspected of having cancer
of unknown primary source within the Waldeyer ring.95 Often,
18F- FDG PET is limited in its ability to discriminate small
primary tumors in the Waldeyer ring from background uptake
in lymphoid tissue. Although the primary lesions were more
visually conspicuous with 68Ga- FAPI PET, metastatic lymph
node detection was found to be inferior to 18F- FDG PET.95
Given the intrinsic advantages of 18F- labeled compounds,
investigators have begun labeling FAPI- based radiotracers
with radiofluorine, including the use of 18F- aluminium flu-
oride in place of 68Ga in the chelator moieties of existing
compounds.96 A subset of such radiotracers has been found
to have favorable pharmacokinetics with high tumor- to-
background ratios.97
With burgeoning interest in imaging the tumor micro-
environment and the early success of FAP ligands in many
clinical studies to date, one can expect this class of radiotrac-
ers to be extensively explored for a variety of indications in
coming years. Successful clinical acceptance of FAP- targeted
PET imaging will depend on prospective studies that prove
clinical utility in specific disease states as well as the devel-
opment of expertise in the imaging community, with imag-
ing specialists being trained to recognize known pitfalls of
interpretation.98 Figure 7 is an example of FAPI PET im-
aging in a woman with metastatic lung cancer and demon-
strates the ability of FAPI- targeted uptake to be higher than
18F- FDG uptake in some hypermetabolic cancers and also
suggests that FAP- based therapy may be effective in some
patients with metastatic disease.99
Infection Imaging
Although infection imaging may seem to be a tangent
from the primary focus of this review, it is exceptionally
important for patients with underlying cancers. Many pa-
tients with cancer are immunocompromised because of
the use of chemotherapy, immunotherapy, stem cell trans-
plants, and other treatment modalities. As such, they are
susceptible to infections with many organisms, both typi-
cal community acquired pathogens and atypical viruses,
bacteria, and fungi. Patients with cancer are also frequently
imaged, meaning that even subclinical infections may
come to light. For these reasons, below, we briefly discuss
the emerging role of molecular imaging in characterizing
infections.
Anatomic imaging modalities often provide nonspe-
cific information regarding the presence of infection versus
sterile inflammation.146 All types of inflammation, whether
infected or sterile, can lead to infiltrative inflammatory
changes, edema, and abnormal contrast enhancement.146
Furthermore, other than a small number of imaging patterns
seen with specific pathogens,147 anatomic imaging does not
provide information on the specific causative agent in an
infection.
As noted above, 18F- FDG can have uptake in infectious
and inflammatory processes, although the lack of speci-
ficity of 18F- FDG146 limits its utility for identifying and
characterizing infections. To date, no definitive indication
for imaging with 18F- FDG in suspected infection exists,
although evaluation of patients with cardiac devices may
be a reasonable situation in which to pursue 18F- FDG.100
Other scenarios in which complex anatomy can make con-
ventional imaging evaluation difficult— such as musculo-
skeletal periprosthetic infections101,102 and the diabetic foot/
Charcot arthopathy103,104— have yielded mixed results with
18F- FDG PET.
The radically different metabolic pathways possessed
by most pathogens relative to the human host suggest
that bacteria- specific molecular imaging may be possi-
ble. Several radiotracers that leverage unique pathogen
metabolism have been investigated,105,106 with varying
degrees of success. This should remain an active area of
investigation, given the importance of identifying patho-
gens that may otherwise be difficult to obtain through
invasive sampling and the impact that proper antibiotic
therapy can have on averting morbidity and mortality. For
example, Ordonez et al demonstrated that Enterobacterales
infections can be specifically imaged with 2- deoxy- 2- [18F]
fluoro- D- sorbitol, a radiolabeled sugar derivative that is
not used by mammalian cells.107 Figure 8 is an example of
the uptake of 2- deoxy- 2- [18F]fluoro- D- sorbitol in a pa-
tient with known Enterobacterales infections and demon-
strates the potential utility of this agent to follow response
to therapy.107 The utilization of radiotracers for bacteria-
specific metabolic pathways may dovetail with further
investigations into agents that have higher specificity for
host inflammatory cells than 18F- FDG.108

Molecular imaging
346 CA: A Cancer Journal for Clinicians
Limitations to bacteria- specific molecular imaging in-
clude a difficult patient population (potentially very sick
patients with many underlying comorbidities), clinical
workflows that emphasize early administration of antibi-
otics in patients suspected of having infection, and host
factors that may limit blood flow and radiotracer delivery
to an area of concern.105 Whether these limitations can
be overcome so that bacteria- specific molecular imaging
can provide actionable information to clinicians remains
to be seen.
Nonbacterial pathogens can also be evaluated with mo-
lecular imaging. For example, fungal uptake of siderophores
has been leveraged as a means for imaging clinically rele-
vant fungal organisms, as was demonstrated by Petrik et al
in a preclinical model of Aspergillus fumigatus infection.109
Carefully selected siderophores are orthogonal to human
physiology and may offer significant specificity advantages
relative to metabolic radiotracers.110 Specific imaging of
Aspergillus species can also be achieved through the use of a
humanized monoclonal antibody to the Galf fungal- specific
antigen.111 The relatively common nature of fungal infec-
tions in immunocompromised patients and the inherent dif-
ficulties with obtaining and culturing specimens emphasize
the need for noninvasive means of diagnosis. Molecular im-
aging may provide that, although clinical studies will need to
be successfully carried out.
Challenges, Potential, and Future Directions
With a wide array of modalities and numerous probes and
techniques available, molecular imaging is not a techno-
logically constrained field. The pace of preclinical discov-
ery tracks far ahead of the rate at which new discoveries
are clinically translated. Some of this is related to intrinsic
advantages of preclinical work, with the availability of fac-
ile techniques such as BLI as well as the quickness with
which meaningful oncologic outcomes (eg, overall sur-
vival) can be determined. However, there is also an over-
riding regulatory environment that curtails the effective
translation of new molecular imaging agents in the United
States.
Generally, in the United States, new radiotracers
for SPECT and PET require an Investigational New
Drug (IND) application with the US Food and Drug
Administration. Such radiotracers are subject to the same
regulatory restrictions as therapeutic agents that are ad-
ministered under an IND. This is despite implementation
FIGURE 7. As Theranostics Becomes an Ever- Increasing Aspect of Cancer Therapy, Our Ability to Image Relevant Targets Becomes More Important. (A,B)
These images are from a 46- year- old woman with newly diagnosed metastatic lung cancer. In B, not only does (right) a gallium- 68– labeled inhibitor of
fibroblast- activation protein (FAP) positron emission tomography demonstrate higher uptake, but it also suggests that FAP- directed therapy may be effective
for some patients with metastatic cancers. Reprinted from: Wu J, Wang Y, Liao T, et al. Comparison of the relative diagnostic performance of [68Ga]Ga- DOTA-
FAPI- 04 and [18F]FDG PET/CT for the detection of bone metastasis in patients with different cancers. Front Oncol. 2021;11:737827.99

CA CANCER J CLIN 2022;72:333–352
347VOLUME 72 | NUMBER 4 | JULY/AUGUST 2022
of the tracer principle and the subpharmacologic mass
doses that are typically administered to patients. The clin-
ical translation of new diagnostic imaging agents and the
execution of phase 1 and 2 studies that would examine
human feasibility could be streamlined with a modified
regulatory process. Mitigating the onerous requirements
for development and submission of an IND would im-
prove the efficiency with which new SPECT and PET
radiotracers could be delivered to patients and would also
put the United States on a more even footing with other
nations as a leader in new radiopharmaceutical innovation.
PSMA- targeted PET imaging of PCa for some clinical
scenarios had already been incorporated into practice
guidelines in Europe148 before any such agents were ap-
proved in the United States. Although prospective clinical
trials in Europe with novel agents or indications are gov-
erned by Clinical Trial Applications, in some countries in
Europe, compassionate use doctrines can be used to pro-
vide access to new molecular imaging agents and support
retrospective research studies.
Regardless of the regulatory environment in the United
States, novel molecular imaging approaches will continue to
be adopted throughout the world as a means of improving
the diagnosis and therapy of cancer. Theranostics, specifi-
cally, are primed for a rapid expansion in coming years.149
As noted above, it will be incumbent upon nuclear medicine
physicians to lead in ensuring that patients have access to
new radiopharmaceutical therapies and that those therapies
can be safely and effectively administered in nuclear medi-
cine departments.
The increasing use of theranostic agents for managing
cancer will dovetail with the use of AI for several relevant
applications. In this context, we will generally be referring
to weak AI, ie, AI algorithms based on neural networks that
can learn from existing data and make relevant and accurate
determinations when exposed to new data.150 With AI for
automated whole- body image interpretation, disease seg-
mentation, and burden determination,151 it will be possible
to apply the principle of theranostics in powerful ways to
improve patient care. Among the many foreseeable appli-
cations of the information derived from AI are patient se-
lection for an appropriate theranostic agent, prognostication
based on imaging and clinical parameters, and selection of
an appropriate dose that balances efficacy with tolerable side
effects.
AI can also be used to uncover imaging biomark-
ers associated with the response of tumors to different
treatments. Mu and coworkers used a type of AI known
as deep learning to analyze 18F- FDG PET/CT scans
to identify features that were associated with epidermal
growth factor receptor (EGFR) status.152 Higher EGFR
deep- learning scores (EGFR- DLS) were positively asso-
ciated with longer progression- free survival intervals for
patients who received tyrosine kinase inhibitors targeted
to EGFR mutants, whereas EGFR- DLS was negatively
associated with multiple outcome measures, including
longer progression- free survival intervals, in patients who
received immunotherapy.152
The utilization of AI- derived imaging biomarkers to
guide clinical decision making regarding appropriate therapy
will almost certainly expand exponentially in coming years.
Characteristics of primary tumors may be leveraged for the
prediction of occult metastatic disease, allowing for the ap-
propriate selection of local or systemic therapy. Predictive
algorithms will also be developed that will allow for the se-
lection of new therapies for patients undergoing progression
or dedifferentiation— before those changes in tumor biology
can be appreciated by the human eye.
FIGURE 8. Whole- Body 2- Deoxy- 2- F Fluorine- 18 [18F]Fluoro- D- Sorbitol (18F-
FDS) Images of a 33- Year- Old Man Who Had Left Leg Osteomyelitis. (Left)
This imaging study was obtained at baseline. (Right) This image was obtained
after attempted therapy. The yellow arrows show that uptake at the site of
infection decreased but did not resolve; clinically, the patient had persistent
infection after therapy. These images suggest that 18F- FDS positron emission
tomography may be a means of following and determining the adequacy
of antimicrobial therapy. SUV indicates standard uptake value. Reprinted
with permission from: Ordonez AA, Wintaco LM, Mota F, et al. Imaging
Enterobacterales infections in patients using pathogen- specific positron
emission tomography. Sci Transl Med. 2021;13:eabe9805.107 Copyright ©
2021 American Association for the Advancement of Science. doi:10.1126/
scitr anslm ed.abe9805

Molecular imaging
348 CA: A Cancer Journal for Clinicians
In short, the confluence of AI and molecular imag-
ing promises to radically alter our approach to imaging
in the diagnosis of disease. These 2 fields will influence
each other in a synergistic manner. Current molecular
imaging agents will continue to be used, generating large
data sets that can be leveraged for the development of AI
algorithms. The important biological information derived
from molecular imaging will be particularly high- yield in
driving the ability of AI to generate meaningful clinical
outcomes prediction. In turn, AI will drive the develop-
ment of new molecular imaging radiotracers, will help
abstract important information from molecular imaging
studies too subtle for human visual detection, and will
provide powerful prognostic information for referring cli-
nicians and patients.
Conclusions
Since the term was coined in the late 1990s, molecular imaging
has rapidly evolved as a field of tremendous potential to improve
the diagnosis and management of patients. Molecular imaging
provides information beyond that available from anatomic im-
aging modalities, allowing for more fundamental insights into
pathophysiologic processes. With the concurrent rise of AI and
the development of new imaging agents to interrogate novel
biological pathways, molecular imaging may soon be among
the most important elements in clinical management. ■
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