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Nuclear Medicine

Therapy
Side Effects and Complications
Luca Giovanella
Editor

123
Nuclear Medicine Therapy
Luca Giovanella
Editor

Nuclear Medicine
Therapy
Side Effects and Complications
Editor
Luca Giovanella
Nuclear Medicine and PET/CT Centre
Oncology Institute of Southern Switzerland
Bellinzona
Switzerland

ISBN 978-3-030-17493-4    ISBN 978-3-030-17494-1 (eBook)


https://doi.org/10.1007/978-3-030-17494-1

© Springer Nature Switzerland AG 2019


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Preface

In the last two decades, the demand for a personalized therapeutic approach
has been constantly increasing, mainly due to the need to develop ever more
effective therapeutic regimens, to improve outcome, and to avoid unneces-
sary treatments. Theranostics is an invaluable tool in personalized medicine;
it is a treatment strategy in which the same (or very similar) agents are used
for both diagnostic and therapeutic purposes. Particularly, theranostics is
based on the integration of a diagnostic test and a specific treatment, and it
relies on the idea of selecting patients through a diagnostic study that could
detect whether a patient will benefit from a certain therapy or not.
Nuclear medicine is ideally placed to play a central role in this field by
allowing visualization of molecular targets and thus enabling so-called
in vivo immunohistochemistry, by which noninvasive biomarkers can be pro-
vided to select targeted drugs labeled with therapeutic radionuclides. The
theranostic procedures are based on radiolabeling compounds of interest and
performing tailored low-dose molecular imaging to provide the necessary
pretherapy information on biodistribution, critical organ or tissue, dosimetry,
and the maximum tolerated dose. If the imaging results then warrant it, it
would be safe and appropriate to follow up designing higher-dose targeted
molecular therapy with the greatest effectiveness and safety.
Holding a wide and in-depth knowledge of the advantages and disadvan-
tages that ensue from the application of theranostics is an essential require-
ment to properly exploit this tool in clinical management. Conscious of its
limits, theranostics can be successfully applied as a powerful strategy in can-
cer treatment, and nuclear medicine owns the tools to play a central role in
this field. Our scope is to provide essential but exhaustive information on
nuclear medicine theranostics with emphasis on clinical management of side
effects and potential complications.

Bellinzona, Switzerland Luca Giovanella

vii
Contents

1 Nuclear Medicine Theranostics:


Between Atoms and Patients�������������������������������������������������������������   1
Alice Lorenzoni, Antonella Capozza, Ettore Seregni,
and Luca Giovanella
2 Radioiodine Therapy of Benign Thyroid Diseases����������������������   11
Alfredo Campennì, Desiree Deandreis, Monica Finessi,
Rosaria Maddalena Ruggeri, and Sergio Baldari
3 Radioiodine Therapy of Thyroid Cancer������������������������������������   35
Frederik A. Verburg
4 Peptide Receptor Radionuclide Therapy for
Neuroendocrine Tumors����������������������������������������������������������������   43
Flavio Forrer
5 131I-MIBG Therapy of Malignant Neuroblastoma and
Pheochromocytoma������������������������������������������������������������������������   65
Arnoldo Piccardo, Luca Foppiani, Sergio Righi, Alberto
Garaventa, Stefania Sorrentino, and Egesta Lopci
6 Radiometabolic Therapy of Bone Metastases ����������������������������   85
Gaetano Paone and Egbert U. Nitzsche
7 Selective Internal Radiotherapy (SIRT) of Primary
Hepatic Carcinoma and Liver Metastases����������������������������������  101
Niklaus Schaefer
8 Radioimmunotherapy of Lymphomas ����������������������������������������  113
Clément Bailly, Caroline Bodet-Milin, François Guerard,
Nicolas Chouin, Joelle Gaschet, Michel Cherel, François
Davodeau, Alain Faivre-­Chauvet, Françoise Kraeber-Bodéré,
and Mickaël Bourgeois

ix
Nuclear Medicine Theranostics:
Between Atoms and Patients 1
Alice Lorenzoni, Antonella Capozza,
Ettore Seregni, and Luca Giovanella

In the last two decades, the demand for a person- ized approach is more likely to ensure that each
alized therapeutic approach has been constantly patient receives an effective drug and drug dose
increasing, mainly due to the need to develop ever that has acceptable and definable tissue effects,
more effective therapeutic regimens, to improve keeping the highest safety margin [3].
outcome, and to avoid unnecessary treatments. A theranostic diagnostic agent should enable
Theranostics is an invaluable tool in personalized the disease localization and state, as a sur-
medicine; it is a treatment strategy in which the rogate for a potential therapeutic agent with
same (or very similar) agents are used for both similar chemical properties; should allow the
diagnostic and therapeutic purposes. Particularly, examination of its biodistribution as predictive
theranostics is based on the integration of a diag- of off-target (adverse) effects of the potential
nostic test and a specific treatment and it relies on therapeutic agent; should be useful in determin-
the idea of selecting patients through a diagnos- ing the optimal therapeutic dosage or activity to
tic study that could detect whether a patient will be administered, based on the predictive tumori-
benefit from a certain therapy or not [1, 2]. cidal doses measured in the tumor site; and should
Allowing the stratification of patients into be useful in monitoring treatment response [4, 5].
those responding and likely to respond to the This concept is not specific to radiopharmaceuti-
therapy and those better treated in another man- cals but is easily applicable in nuclear medicine.
ner, useless and time-wasting therapy can be Personalized genomics, proteomics, and molecu-
avoided. A step forward, from personalized ther- lar imaging are among technologies currently
apeutic pathways, is represented by the individu- used for theranosis.
alization of treatment. Although a fixed approach Nuclear medicine is ideally placed to play a
to therapy may be more practical, an individual- central role in this field by allowing visualization
of molecular targets and thus enabling so-called
in vivo immunohistochemistry, by which noninva-
A. Lorenzoni · A. Capozza · E. Seregni sive biomarkers can be provided to select targeted
Nuclear Medicine Unit, Fondazione IRCCS Istituto drugs labeled with therapeutic radionuclides [5].
Nazionale dei Tumori, Milan, Italy
e-mail: alice.lorenzoni@istitutotumori.mi.it; The theranostic procedures are based on radio-
antonella.capozza@istitutotumori.mi.it; labeling compounds of interest and performing
ettore.seregni@istitutotumori.mi.it tailored low-dose molecular imaging (single-pho-
L. Giovanella (*) ton emission computed tomography/computed
Clinic for Nuclear Medicine and Molecular Imaging, tomography SPECT/CT or positron emission
Oncology Institute of Southern Switzerland, tomography/computed tomography PET/CT) to
Bellinzona, Switzerland
e-mail: luca.giovanella@eoc.ch provide the necessary pretherapy information on

© Springer Nature Switzerland AG 2019 1


L. Giovanella (ed.), Nuclear Medicine Therapy, https://doi.org/10.1007/978-3-030-17494-1_1
2 A. Lorenzoni et al.

biodistribution, critical organ or tissue, dosimetry, identify, diagnose, and treat a particular disease, is
and the maximum tolerated dose. If the imaging the core of nuclear medicine [2]. The possibility of
results then warrant it, it would be safe and appro- labeling the same agent with γ- or positron-emit-
priate to follow up designing higher-dose targeted ting radionuclide well suited for imaging, as well
molecular therapy with the greatest effectiveness as a α- or β-emitting nuclide suitable for therapy,
and safety [4]. makes nuclear medicine one the most appropriate
The theranostic approach finds its main discipline to exploit theranostics.
application in the oncology field. Cancer is an From the early experiences in 1940s and
extremely heterogeneous disease, as it varies through the years, several theranostic approaches
from patient to patient and it might include, in the have been studied, performing a diagnostic
same individual, a diverse collection of malignant molecular imaging followed by a personalized
cells harboring distinct molecular signatures with treatment decision based on the predictive value
differential levels of sensitivity to treatment [1]. of the diagnostic scan.
This heterogeneity might result in a nonuniform
distribution of distinct tumor-cell subpopulations
across and within disease sites or temporal varia- 1.1 Theranostics: Brief History
tions in the molecular makeup of cancer cells.
Heterogeneity is the source of resistance to treat- From an historical perspective, radioiodine
ment; all accessible therapies are effective for was the first theranostic radiopharmaceutical in
only limited patient subpopulations and at dis- nuclear medicine, which was proposed for imag-
criminatory stages of disease development [6]. ing and therapy in thyroid diseases.
Therefore, an accurate characterization of tumor In 1937, the first studies on radioactive iodine
is essential for treatment planning and targeting started, based on the known facts of thyroid
approaches are gaining increasing interest. physiology that indicated that iodine is selec-
Designing a specific targeting/killing combina- tively taken up by the thyroid gland and that in
tion is a tailoring process. Significant and rapid some measure gland’s function is regulated by
advances in molecular biology continue to lead to its iodine content. From this knowledge sprang
a better understanding of cancer, and many biolog- the idea of potentially using “tagged” radioac-
ical vehicles, such as monoclonal antibodies, spe- tive iodine as a physiologic indicator of thyroid
cific proteins, and peptides, have been identified. functions [7]. Early experiments, by Hertz and
A variety of molecules has been designed to serve Roberts, involved the administration of radioac-
as systemic carriers, able to selectively deliver tive iodine (iodine-128) to rabbits. Their tissues
imaging photons to diagnose disease, or thera- were, then, collected and analyzed, in order to
peutic electrons to deliver cytotoxic radiation, in detect radioactive distribution with a Geiger-
a highly localized manner. These developments Müller counter. One rabbit, whose thyroid had
have led to a renewed interest in the possibility of been previously rendered hyperplastic through
treating disseminated malignancies with the sys- the injection of anterior pituitary extract (thyro-
temic administration of radionuclides [4]. In this tropin—TSH), showed particular iodine distri-
scenario, theranostics finds a soil to grow. bution: in none of the tissues or fluids examined
Although the term has been coined recently and were quantities of iodine found (exception made
theranostics is proposed as an innovative approach, for the urinary tract), compared with that taken
the concepts underlying theranosis are not new up by the thyroid. They, therefore, proved that
at all in the field of nuclear medicine and have the normal thyroid gland concentrated iodine
been applied in patient care for almost a century. and the hyperplastic gland took up even more,
Detecting and targeting a pathological process, and, for the first time, hypothesized that their
using the same or at least very similar molecules findings may be of therapeutic significance [7].
(tracer), either labeled with different isotopes or Researches proceeded and, in 1938, some longer-
nuclides or given in different amount, in order to lasting radioisotopes of iodine were discovered:
1  Nuclear Medicine Theranostics: Between Atoms and Patients 3

iodine-126 (13 days half-life), iodine-130 (12.5 h 1.2 Theranostics: An Overview


half-life), and iodine-131 (8  days half-life), by
Livingood and Seaborg and at the University of For theranostic purposes, diverse combination of
California, Berkeley [8]. radiopharmaceuticals can be proposed: gamma-
Later on, two collaborators from Berkeley and beta-emitters radionuclides administrated in
published the first data that showed how radio- different activities, different isotopes of the same
iodine was taken up by the human thyroid, and element, different nuclides linked to the same
that it could be detected in vivo: a realistic test for carrier.
thyroid function was now in sight [9]. Nowadays, scintigraphy and radionuclide
From late 1940, Hertz and Roberts used cyclo- therapy with iodine-123/131 are used in the treat-
tron’s radioiodine to study more patients with ment and follow-up of patients with thyroid dis-
Graves’ hyperthyroidism. Soon they were able to eases, particularly differentiated thyroid cancer
calculate thyroid radioiodine uptake and moved and hyperthyroidism. Gamma-camera can visu-
on from the concept of “diagnostic tracer” to the alize accurate localization of sites of pathologi-
intention to treat hyperthyroidism with radioac- cal radioiodine uptake, such as metastasis lesions
tive iodine. In 1941 they started the adminis- or residual thyroid in patients with differentiated
tration with therapeutic purposes and the first thyroid cancer who have undergone total thyroid-
reports, suggesting the use of radioactive iodine ectomy, because the lesions are highly efficient
to cure hyperthyroidism of Graves’ disease, at trapping circulating iodine by expression of
were published on the Journal of the American sodium-iodide symporter. Iodine-131 has been
Medical Association (JAMA) in May 1946 [10, successfully used for the therapy of primary and
11]. The evidence was clear, the two published metastatic lesions of differentiated thyroid cancer
papers found the treatment successful and, only for many years. Scintigraphic scan using radio-
a month after, the Manhattan Project announced active iodine can predict treatment efficacy, can
on the journal Science that radioactive iodine iso- potentially alter the decision to treat the patient,
topes were available for distribution on request can finalize the subsequent therapeutic dose, and
for scientific purposes [12]. could be employed to perform dosimetric evalu-
Shortly after, the first report of the use of ation. Radioactive iodine dose selection is gener-
radioactive iodine for the treatment of metastatic ally based on patient risk factors. Since the release
thyroid cancer was published by Seidlin et  al. of radiation has high energy (364 keV γ-rays),
in 1948 [13]. Iodine-131 was administered to a whole body scintigraphy with 131I has low spatial
patient who was clinically hyperthyroid despite resolution and poor image quality [14].
having had a thyroidectomy for thyroid cancer. Iodine-123, a lower 159 keV γ-emitter, has a
Pulmonary metastases were identified using a higher counting rate compared to 131I and pro-
Geiger counter and the first rudimentary dosim- vides a higher lesion-to-background signal, so 123I
etry was performed. This report was followed scanning offers excellent image quality compared
by many case-reports that confirmed that meta- to 131I imaging, in thyroid carcinoma patients.
static thyroid cancer lesions could concentrate Moreover, with the same administered activity,
radioiodine. 123
I delivers an absorbed radiation dose that is
Only with the benefit of hindsight, today, it is approximately one-fifth that of 131I, decreasing
possible to acknowledge that these experiences patients’ radiation exposure. However, the clini-
represent the first applications of theranostics cal application of 123I is limited by high cost due
in molecular imaging and therapy, targeting the to accelerator production and report showed that
sodium-iodine symporter. Since then, the admin- diagnostic scans undervalue the disease burden
istration of radiolabeled iodine for diagnostic compared to 131I scans after treatment, especially
imaging and therapy has represented an estab- in children and in other patients with prior radio-
lished and accepted theranostic approach in thy- iodine therapy and/or distant metastasis. Few
roid diseases. researches compared the diagnostic sensitivities
4 A. Lorenzoni et al.

of 123I and 131I whole-body imaging in differenti- remained above 95%, but sensitivity varies with
ated thyroid cancer in thyroidectomized patients the tumor nature: close to 90% for intra-adrenal
and found that 123I appears adequate for imaging pheochromocytomas but 70% or less for para-
of residual thyroid tissue but is less sensitive than gangliomas. Although diagnosis by radiolabeled
131
I for imaging thyroid cancer metastases [14]. mIBG has been supplemented and sometimes
Iodine-124 (124I) is a PET radiopharmaceuti- surpassed by newer scintigraphic agents, imaging
cal with higher energy (511, 603, 723, 1690 keV) with this radiopharmaceutical remains essential
and a 4.2 days half-life, which potentially offers for optimal care of selected cases. The radiation
higher sensitivity and better imaging character- delivered by high concentrations of 131I-mIBG in
istics. Preliminary studies proved a high level of malignant pheochromocytomas, paragangliomas,
agreement between pre-therapeutic 124I PET and carcinoid tumors, and medullary thyroid carci-
post-therapeutic 131I imaging in detecting iodine- noma has reduced tumor volumes and lessened
positive thyroid cancer metastases. In addition, excretions of symptom-inflicting hormones, but
124
I-PET proved to be a superior diagnostic tool its value as a therapeutic agent is being fulfilled
in detecting residual, recurrent, and metastatic primarily in treatment of neuroblastomas [16].
lesions with a higher sensitivity than the conven- A well-established theranostic nuclides’
tional 131I scans. As an Auger electron emitter (9.2 pair is represented by Gallium-68 (68Ga) and
per decay), there are potential therapeutic uses for Lutetium-177 (177Lu) or Yttrium-90 (90Y). They
this tracer, as well. Due to its cost and diagnostic are currently applied in the field of neuroendo-
reasons, 124I PET/CT imaging is more common crine tumors (NETs), replacing, despite its large
than 123I scans but rarer than 131I scans [14]. use in the previous decade, Indium-111 (111In).
The role of radioactive iodine doesn’t end NETs, in approximately 80% of the cases,
with thyroid diseases. Iodine isotopes could be overexpress somatostatin receptors (SSTRs)
used to label different compound: a well-known on cell surface, both in primary and in related
example is represented by metaiodobenzylguani- metastasis. SSTRs presence allows theranostic
dine (mIBG). application and targeting with peptide receptor
mIBG is a guanethidine derivative developed radionuclide therapy (PRRT). PRRT consists
in the late 1970s as diagnostic agent for imag- in the systemic administration of a radiolabeled
ing of adrenal medulla. It is an aralkylguanidine synthetic analog with a suitable beta-emitting
which is structurally similar to the neurotransmit- radionuclide, which, once internalized through a
ter norepinephrine and is taken up by tumor orig- specific receptor, irradiate tumor tissue. SSTRs
inating from the neural crest. Since it is actively have five subtypes termed SSTR1 to SSTR5, all
uptaken and stored in cytoplasmatic vesicles of of these receptors bind to natural somatostatin
tumor cells, whole-body imaging using radiola- with high affinity. However, natural somatosta-
beled mIBG has been used to stage, treat, and tin exhibits a very short in vivo half-life of only
monitor therapy response in several endocrine 2–3 min; therefore, applications of natural soma-
tumors, since 1981 [15]. tostatin are limited. Considering these findings,
Iodine-123/131 mIBG scintigraphic scans various long-lived somatostatin analogs (SSAs)
are both well-established imaging modalities for have been synthesized for medical imaging and
diagnosis, staging, and restaging of tumors deriv- therapy. Several radiolabeled SSAs have been
ing from the neural crest. However, for clinical proposed for PRRT and they are different in
practice, the superiority of 123I- over 131I-labeled terms of radionuclide, somatostatin analog, and
mIBG, for diagnostic purposes, has been ascer- chelator [17].
tained. Indeed, for its physical properties, 123I- The first nuclide applied to neuroendocrine
allows to perform planar, whole-body and SPECT tumors was 111In. The physical properties of 111In
high-count scans, providing better spatial resolu- make it suitable for both diagnostic (γ-decay
tion than 131I-mIBG, while delivering a lower 245 keV and 171 keV) and therapeutic purposes
radiation dose. The specificity in diagnosis has (Auger electron emission). Auger electrons
1  Nuclear Medicine Theranostics: Between Atoms and Patients 5

are high linear energy transfer particles, able the dosimetry of 90Y-peptides, but its use, suit-
to deliver high doses within a very short range able for diagnostics, is not recommended for
(<10 μm). However, the high cytotoxic potential dosimetric purposes, due to its different kinetics
of the Auger electrons requires close proximity of and receptor affinity properties [17]. Similarly,
the 111In-labeled peptide within the nucleus, pref- 68
Ga-peptides are striking diagnostics trac-
erably intercalating with the DNA chain [17]. ers but not suitable to simulate therapy, due to
Indium-111 decay characteristics enable also the short physical half-life (68  min) of 68Ga as
dosimetric treatment planning. Dosimetry is compared to the biological half-life of peptides,
facilitated by the γ-ray emission and the relatively which impedes to derive the washout trend on the
long half-life (2.83 days), which matches the pep- time-activity curves. Furthermore, it is not clear
tide biologic half-life. Therefore, a suitable num- whether the 68Ga properties might slightly alter
ber of scintigraphic images can be obtained over the whole molecule behavior as compared to the
3 days [17]. therapeutic radiopharmaceuticals.
111
In-DTPA-octreotide, binding to SSTR2, was Labeled-SSAs diagnostic imaging and PRRT
the first and most widely used radiopharmaceuti- have been also applied in the diagnosis and
cal for detecting, staging and treat NETs. At diag- treatment of recurrent meningiomas, malignant
nostic activity, its sensitivity is almost 80%, but paragangliomas and pheochromocytomas and
its detection rate decreases with smaller lesions; medullary thyroid cancers [18].
at therapeutic activity, it has been employed with The success of the theranostic approach in the
a good overall treatment effects [17, 18]. management of NETs with SSTRs targeting also
Despite its large use, in the previous decade, prompted a case for exploring the possibility of
111
In was abandoned and replaced by nuclides targeting other peptide receptors. The expression
that guarantee a higher resolution in diagnostics, of several bombesin receptor subtypes has been
and good overall survival, improvement of qual- demonstrated in NETs, including the gastrin-
ity of life, and less side effects in therapeutics. releasing peptide (GRP) receptors. Particularly,
Through the years, in the diagnostic field, sev- the bombesin receptor antagonist demobesin
eral PET tracers have been proposed for functional showed superior in  vivo stability, high tumor
imaging of NETs. Three 68Ga- labeled somatosta- uptake and retention, and rapid pancreatic and
tin analogs are currently routinely used in clini- renal clearance. The effective labeling and pre-
cal practice, thanks to their high affinity binding clinical studies with GRP receptor antagonists
to SSTR2: 68Ga-DOTA-D-Phe-Tyr3-octreotide has opened up a novel theranostic prospect in
(DOTATOC), 68Ga-DOTA-1-Nal(3)-octreotide GRP receptor-positive tumors, including neuro-
(DOTANOC), and 68Ga-DOTA-D-Phe-Tyr3- endocrine tumors with 68Ga-/177Lu-labeled GRP
octreotate (DOTATATE). Whereas in the thera- receptor antagonists like demobesin [18].
peutic field, the most commonly used isotopes Another application of the “theranostic cou-
for treatment-intended radiolabeling of soma- ple” 68Ga and 177Lu can be found in the manage-
tostatin analogs are the 90Y (β-emitting isotope, ment of prostate cancer.
Emax 2.28  MeV) or 177Lu (decay β- 498 KeV, The prostate-specific membrane antigen
γ- 208 KeV) with DOTATOC or DOTATATE (PSMA) is a transmembrane protein, upregu-
[13]. The recently published randomized Phase lated in poorly differentiated, metastatic, and
III NETTER-1 trial unequivocally demonstrated hormone-refractory prostate carcinomas, while
the efficacy of PRRT, using 177Lu-DOTATATE, physiological expression is restricted to only a
in patients with metastatic and progressive NETs few sites (such as the kidneys). In recent years,
with minimal side effects [19]. a number of PSMA-targeted nuclear imaging
Specifically, in case of 177Lu-peptide therapy, agents were developed [20, 21].
the isotope decay enables imaging, dosimetry, Thanks to its selective expression, PSMA tar-
and therapy with the same compound. Whereas geting is of particular interest for the management
111
In-octreotide was firstly proposed to depict in prostate cancer. Radiolabeled PSMA-617, a
6 A. Lorenzoni et al.

1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴- However 86Y, a positron emitter yttrium isotope,


tetraacetic acid (DOTA)-functionalized PSMA could be a good choice as a surrogate pre-therapy
ligand, has been designed to enable a successful PET isotopically matched surrogate for 90Y radi-
application for PET imaging (68Ga) and radionu- ation doses estimations [23].
clide therapy (177Lu) in clinical practice, reveal- In recent years, molecular imaging using
ing favorable kinetics with high tumor uptake the positron emitter 89Zr for antibody labeling
and, consequently, opening the way towards a has increased. Zirconium-89 physical half-life
theranostic approach. Clinical studies performed (78.4  h) generally matches the serum half-life
so far demonstrated the promising potential of of most mAbs and antibody-related therapeu-
68
Ga- and 177Lu-labeled PSMA-617 in metastatic tics in vivo, thus achieving high tumor-to-back-
prostate cancer management [20, 21]. ground ratios, and it allows a stable link with
An ever-growing part of target therapy is rep- mAbs and antibody-related therapeutics (such as
resented by radiolabeled monoclonal antibodies 89
Zr-labeled trastuzumab and cetuximab) [22].
(mAbs). Radioimmunoimaging has long been Copper-64 is a useful and practical theranos-
developed in parallel with radioimmunotherapy tic radionuclide. It enables both PET-imaging
as a means for evaluating targeting and dosim- and radionuclide therapy, because it is character-
etry of radiolabeled monoclonal antibodies. ized by β+ decay (0.653 MeV, 17.4%), β− decay
Technetium-99  m (99mTc), Copper-64 (64Cu), (0.574 MeV, 40%), and electron capture (42.6%).
68
Ga, Yttrium-86 (86Y), Zirconium-89 (89Zr), The photons generated from electron–positron
111
In, 123I, 124I, 131I, and 177Lu are the radionuclides annihilation can be detected by PET, and the β−
most commonly used for molecular imaging particles and Auger electrons emitted from this
with mAbs and antibody-related therapeutics. nuclide can damage tumor cells’ DNA. Clinical
Selecting a suitable radionuclide generally starts PET studies using 64Cu-labeled agents, such as
by matching the serum half-life of the mAb or 64
Cu-diacetyl-bis (N4-methylthiosemicarbazone)
antibody-related therapeutic and the physical (64Cu-ATSM) and 64Cu-labeled trastuzumab,
half-life of the radionuclide. This step is essen- have shown the utility of 64Cu- for imaging
tial to minimize the time of exposure to radiation in humans. Data from many preclinical stud-
while ensuring that radioactivity to be detected ies have also demonstrated the therapeutic
long enough for the drug to bind the target [22]. effectiveness of 64Cu-labeled agents, such as
In case of metal-based nuclides, such as 64
Cu-ATSM, 64Cu-labeled Arg-Gly-Asp peptide,
64
Cu, 68Ga, 86Y, 89Zr, 111In, and 177Lu, a chelator and 64Cu-labeled antibodies. Recently, a first-
is required. For human use, the chelator choice in-human study of radionuclide therapy with
relies on the radionuclide, the stability of the 64
CuCl2 was conducted in Europe, and it was
chemical link, and the validation of clinical reported that the patient showed a remarkable
applicability. Analyzing the mAbs behavior, after reduction of tumor volume without side effects,
binding the target, is of fundamental importance supporting the applicability of 64Cu in clinical use
as well; radiometal-labeled drugs are metabo- for therapy [24].
lized and the nuclide is trapped intracellularly, An unconventional theranostic application can
thus guaranteeing a higher tumor-to-blood ratios. be found in the use of labeled microspheres for
Whereas, iodine-labeled drugs are characterized selective hepatic treatment. Radioembolization
by rapid renal clearance of the radionuclide from is an interventional oncologic treatment dur-
tumor cells [22]. ing which radioactive microspheres are admin-
A well-known application of radioimmuno- istered in hepatic arterial vessels supplying the
therapy is the Food and Drug Administration- liver and its tumors. 166Ho-poly(l-lactic acid)
approved agent Zevalin (Spectrum microspheres have been developed as an alter-
Pharmaceuticals, Inc., Henderson, NV). Zevalin native to 90Y-microspheres specifically to enable
is labeled with pure beta-emitter therapeutic the in vivo visualization of microspheres biodis-
isotope 90Y that provides no imaging emission. tribution after radioembolization. The physical
1  Nuclear Medicine Theranostics: Between Atoms and Patients 7

properties of 166Ho- (β- decay Emax 1.85  MeV, the reproducibility of what previously diagnosed
γ- decay Emax  =  0.081  MeV) enable SPECT with low-dose.
and MRI imaging. They may, therefore, rep- In the second best situation, a radionuclide
resent a step forward from 90Y-microspheres, pair (imaging photon emitter, either gamma or
allowing not only post-therapy imaging but also positron, and a counterpart therapeutic particle
theranostic application. Even though a scinti- emitter, with the same electronic structure) can
graphic scan, acquired after the administration be used as well. Although many theranostic
of 166Ho-microspheres at “tracer activity,” is imaging/therapy radionuclide pairs may have
not properly a diagnostic tool per se, it still has the same electronic structure, their production
a predictive intent on treatment outcome and and processing methodologies may be signifi-
could also enable dosimetric purposes, in order cantly different. Consequently, their chemistry
to design a personalized treatment planning, on and in  vivo behavior may be different as well,
the base of tumor and healthy liver doses [24]. because of differences in chemical species,
A mention aside from radionuclide therapy charge, specific activity, and/or the amount of
should be made. In recent years, a 99mTc-labeled chemical and radionuclidic chemical impurities,
chemotherapy analog has been developed which which cannot be totally removed [4]. An example
can be used for the selection of patients with can be found in the fact that, even when using the
tumors expressing folate receptors, enabling same chelator, the chemical properties of 68Ga-
the selection of those patients who will benefit and 177Lu-labeled compounds are not identical
from chemotherapy with folate receptor-targeted due to the different coordination chemistry of
agents while sparing those patients who do not these radiometals, which may result in different
express this receptor a potentially toxic but prob- in vivo kinetics [21].
ably ineffective course of treatment [2]. Another issue, that has to be dealt with, is the
The above is just a small selection of an ever- fact that half-life of the imaging PET nuclide, in
growing number of examples which clearly most cases, might be much shorter than the usu-
illustrate that nuclear medicine has had both a ally (desirable) longer half-life of the therapeu-
rich history and an evolving role in theranostics, tic nuclide. In most situations, the determination
contributing to the birth of the concept itself, of longer-term biodistribution would be crucial
applying it and modernizing it, as time passed for dosimetry, but this information would not
by, therefore contributing to the development of be achievable using the shorter-lived positron-
personalized medicine. emitter for pretherapy imaging.
A sore point to deal with is the limited resources
for establishing the evidence base that usually
1.3 Theranostics: Critical accompanies registration and approval of cancer
Analysis and Future therapies. There has been a lack of randomized
Perspectives controlled trial data comparing radionuclide ther-
apies with other forms of therapy and virtually
Theranostics is currently applied in clinical none testing the integrated theranostic approach.
management on a daily basis. It is, therefore, Aside from randomized NETTER-1 clinical trial,
important to have a comprehensive look at both whose preliminary results showed the potential-
advantages and disadvantages of this strategy. ity of PRRT at the 2016 Gastrointestinal Cancers
Ideally, for theranostic use, the radiopharma- Symposium, there is a strong need of further, ran-
ceutical employed should be constituted with the domized, controlled experiences, in order to gain
same dual-purpose radionuclide, with both imag- deserved visibility in clinician world [19].
ing and therapeutic emissions. In this first-case On the other hand, nuclear medicine has
scenario, even though using the same nuclide, gained more than 80 years of experience in ther-
the administration of high-dose radiopharma- anostics. From thyroid cancer management with
ceutical, for therapeutic purposes, might impair radioiodine and forth, it is possible to obtain
8 A. Lorenzoni et al.

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Radioiodine Therapy of Benign
Thyroid Diseases 2
Alfredo Campennì, Desiree Deandreis,
Monica Finessi, Rosaria Maddalena Ruggeri,
and Sergio Baldari

2.1 Hyperthyroidism: Definition a form of thyrotoxicosis due to excessive syn-


and Epidemiology thesis and secretion of thyroid hormone(s) by
the thyroid [1]. It is generally defined as overt
Thyrotoxicosis represents a clinical condition that or subclinical, depending on the severity of bio-
results from excess thyroid hormone(s) levels and chemical abnormalities. Overt hyperthyroidism
action in peripheral tissues, either with or with- is defined as a low (usually undetectable) serum
out increased synthesis of thyroid hormone(s) thyrotropin (TSH) with elevated serum levels of
by the gland. It has multiple different etiologies triiodothyronine (T3) and/or free thyroxine (free
and potential therapies; therefore, an accurate T4). By contrast, subclinical hyperthyroidism is
diagnosis is mandatory for appropriate treatment defined as serum free T4 (FT4) and total or free
[1]. In general, thyrotoxicosis can be the conse- T3 (FT3) levels within their respective reference
quence of (1) active production of excess thyroid ranges in the presence of abnormal serum TSH,
hormone(s) by the thyroid or (2) passive release and it is further subdivided into a mild (low TSH,
of stored hormone(s) in the bloodstream because <0.4  mU/mL) and severe (undetectable TSH
of gland inflammation or mechanical insult. <0.01 mU/mL) form [1, 2]. Both overt and sub-
More rarely, thyrotoxicosis can occur as the clinical disease may lead to characteristic signs
consequence of exposure to either endogenous and symptoms, although subclinical hyperthy-
or exogenous extra-thyroidal sources of thyroid roidism is usually considered milder [2, 3].
hormone(s) (Table  2.1) [1]. Hyperthyroidism is The overall prevalence of hyperthyroidism is
estimated to be ∼2–3% in women and 0.2–0.5%
in men. Incidence is highest in Caucasians and in
A. Campennì (*) · S. Baldari iodine-deficient areas and rises with age [4–6].
Department of Biomedical and Dental Sciences
and Morpho-Functional Imaging, Nuclear Medicine The main causes of hyperthyroidism include
Unit, University of Messina, Messina, Italy Graves’ disease (GD), toxic adenoma (TA), and
e-mail: acampenni@unime.it; sbaldari@unime.it toxic multinodular goiter (TMNG). GD accounts
D. Deandreis · M. Finessi for ∼80% of cases in iodine-sufficient areas
Department of Medical Sciences, Nuclear Medicine and is more prevalent among smokers, whereas
Unit, University of Turin, Turin, Italy autonomously functioning thyroid nodules
e-mail: desiree.deandreis@unito.it
(either TMNG or TA) are more common than
R. M. Ruggeri GD in iodine-deficient areas, especially in older
Department of Clinical and Experimental Medicine,
Unit of Endocrinology, University of Messina, patients [1, 4, 7, 8].
Messina, Italy
e-mail: rmruggeri@unime.it

© Springer Nature Switzerland AG 2019 11


L. Giovanella (ed.), Nuclear Medicine Therapy, https://doi.org/10.1007/978-3-030-17494-1_2
12 A. Campennì et al.

Table 2.1  Multiple etiologies, different mechanism, and main diagnostic features of thyrotoxicosis
Etio-pathogenetic mechanism Diagnostic features
Thyrotoxicosis with hyperthyroidism
Graves’ disease Thyrotropin receptor antibodies Diffuse goiter. Orbitopathy may be present.
(TRAb) stimulate the TSH-R Increased RAIU and diffuse radioisotope uptake
on thyroid scan. Positive TRAb and TPO-Ab
Toxic adenoma Monoclonal autonomously Increased or normal RAIU; radioisotope focal
functional benign lesion. uptake in the nodule with suppressed uptake in
Activating mutations in TSH the surrounding thyroid tissue on scan;
receptor or G proteins TPO-Ab and TRAb absent
Toxic multinodular goiter Functional autonomy within Increased or normal RAIU; multiple focal
multiple monoclonal benign areas of increased and reduced uptake on scan;
lesions. Activating mutations in TPO-Ab and TRAb absent
TSH-R receptor or G proteins
Familial congenital Activating mutations in TSH-R Diffuse goiter. Increased RAIU and diffuse
hyperthyroidism ß or G proteins radiotracer uptake on thyroid scan. TRAb and
TPO-Ab absent.
TSH secreting pituitary Pituitary adenoma Raised serum TSH and α-subunit with raised
adenoma peripheral serum thyroid hormones
Pituitary resistance to thyroid Mutation of T3 receptor β Raised or normal serum TSH with raised
hormone THRB peripheral serum thyroid hormones
Gestational thyrotoxicosis Stimulation of TSH-R by First trimester; often in the setting of
human chorionic gonadotropin hyperemesis or multiple gestation.
Choriocarcinoma/ Molar Stimulation of TSH-R by Molar pregnancy
pregnancy human chorionic gonadotropin
Drug-induced hyperthyroidism Induction of thyroid Increased RAIU and diffuse radioisotope
(checkpoint inhibitors, autoimmunity (Graves’ disease) uptake on thyroid scan. Positive TRAb and/or
interferon alfa,…) TPO-Ab
Iodine or iodine-containing Jod-Basedow phenomenon; Low to undetectable RAIU
drugs (amiodarone-induce excess iodine results in
thyrotoxicosis type 1) unregulated thyroid hormone
production
Thyrotoxicosis without hyperthyroidism
Painless, postpartum and/or Autoimmune, release of stored Low to undetectable RAIU and radioisotope
sporadic thyroiditis thyroid hormones uptake on thyroid scan; TPO-Ab present.
Postpartum form occurs within 12 months after
pregnancy
Subacute (granulomatous, de Viral; thyroid inflammation Neck pain. Low to undetectable RAIU and
Quervain’s) thyroiditis with release of stored thyroid radioisotope uptake on thyroid scan; low or
hormone absent TPO-Ab
Acute infectious thyroiditis Bacterial or fungal thyroid Neck pain. Low to undetectable and RAIU and
infection; release of stored radioisotope uptake on thyroid scan
thyroid hormones
Iatrogenic thyrotoxicosis (drugs, Inflammatory thyroiditis with Low to and low radioisotope uptake on thyroid
such as lithium, interferon alfa, destruction of thyroid follicles scan and radioisotope uptake on thyroid scan;
checkpoint inhibitors; and release of stored hormones low or absent TPO-Ab
radiation…) Amiodarone-­
induced thyrotoxicosis type II
Extra-thyroidal sources of thyroid hormone
Struma ovarii Functional autonomy within an Low to undetectable RAIU and radioisotope
ovarian teratoma with uptake on thyroid scan; raised uptake in the
differentiation into thyroid cells pelvis
Widely metastatic functional Thyroid hormone production Differentiated thyroid carcinoma with bulky
follicular thyroid carcinoma by large tumor masses with metastases; tumor radioactive iodine uptake on
foci of functional autonomy whole-body scan.
Exogenous thyroid hormone Iatrogenic or factitious excess Low to undetectable RAIU and radioisotope
(thyrotoxicosis factitia) ingestion of thyroid hormone uptake on thyroid scan; low or absent TPO-Ab
TSH Thyrotropin, TSH-R Thyrotropin receptor, TRAb Thyrotropin receptor antibodies, TPO-Ab Thyroperoxidase anti-
bodies, RAIU radioiodine uptake
2  Radioiodine Therapy of Benign Thyroid Diseases 13

2.1.1 Graves’ Disease gene and the gene encoding the α subunit of the
stimulatory GTP-binding protein (Gsα) represent
Graves’ disease (GD) represents the most com- the main cause of TA [18]. TMNGs typically
mon cause of persistent hyperthyroidism in occur in patients who have had a known history of
adults from iodine-sufficient areas, with an inci- nontoxic goiter for many years or decades. Such
dence peak between 30 and 50 years of age and patients experience a progressive increase in size
a higher prevalence in women (1:5–7) [7–10]. Its and number of nodules, resulting from chronic
annual incidence is estimated to be 20–50 cases TSH stimulation in response to low iodine intake,
per 100,000 individuals/year [8, 10]. and may develop autonomous growth and func-
GD is autoimmune in etiology and is due to the tion over time. Somatic mutations of TSHR and/
loss of immune tolerance to thyroid self-­antigens or Gsα gene have also been described in many—
with production of organ-specific autoantibodies but not all—TMNG, as well as in TA, accounting
that specifically target the gland [8, 10]. In par- for development of autonomy [18–20].
ticular, GD is associated with a humoral response
against the TSH receptor (TRH-R): autoantibod-
ies against TRH-R, the so-­called TRAb, pro- 2.1.3 N
 atural History and Clinical
mote thyroid growth and function via TRH-R Features
activation, leading to hyperthyroidism and goi-
ter [8, 10]. Presentation is mainly related to the severity
Additional peripheral manifestations include and duration of hyperthyroidism, with a variable
Graves’ orbitopathy (GO), acropachy, and pre- expression [2, 3, 8–10].
tibial mixedema, which can vary greatly in fre- GD is typically characterized by sudden
quency and intensity. The cause of peripheral appearance of hyperthyroidism, mostly overt
tissue involvement is less clear. Given the pres- form, and diffuse goiter. By contrast, nodular
ence of THSR in orbital and skin fibroblasts, autonomy (either due to TA or TMNG) progress
these organs might be targeted by TRAb [3, 11]. gradually from subclinical to overt hyperthyroid-
Underlying these processes there is a complex ism over the years, and it is quite common that
interplay between genetic and environmental fac- administration of pharmacologic amounts of
tors: such an organ-specific autoimmune disease iodine (e.g., amiodarone, iodinated contrast) may
develops in genetically susceptible individuals trigger overt hyperthyroidism in such patients.
triggered by several different environmental and Remission is rare in nodular autonomy, which is
existential factors [8, 10]. Patients often have a usually progressive, while it can occur in up to
family history or past medical history of other 30% of GD, especially in mild forms [4, 8, 9].
autoimmune diseases (e.g., rheumatoid arthri- Clinical manifestations include local symp-
tis, vitiligo, pernicious anemia, celiac disease) toms (i.e., dysphagia, dysphonia, or dyspnea),
[12–14]. usually in individuals with large goiters, and
systemic manifestations related to hyperthyroid-
ism [3, 8] (Table 2.2). Given the broad action of
2.1.2 T
 oxic Nodular Disease thyroid hormones on most organs and tissues,
(TA and TMNG) the signs and symptoms of hyperthyroidism
are numerous and greatly variable also in rela-
Autonomously functioning thyroid nodules— tion to patient’ age and underlying comorbidi-
either isolated or in the context of a multinodu- ties (Table 2.2). Younger patients tend to exhibit
lar goiter—are a relatively common finding in symptoms of sympathetic activation, such as anx-
iodine-deficient areas, when they largely outnum- iety, hyperactivity, heat intolerance, and tremor,
ber GD as the leading cause of hyperthyroidism, while older patients present more frequently
mostly in elderly [2, 15–17]. Somatic activating with unexplained weight loss and cardiovascu-
mutations of the thyrotropin receptor (TSHR) lar symptoms/signs [8, 21]. Atrial fibrillation can
14 A. Campennì et al.

Table 2.2  Clinical features of Graves’ disease and autonomously functioning thyroid nodule(s)
Signs Symptoms
Systemic
manifestations Tremor, hyperkinesis, hyperreflexia Palpitations
related to Tachycardia (50%), atrial fibrillation (>10% of Increased perspiration, heat
hyperthyroidism ≥60-year-old patients), systolic hypertension, intolerance, fatigue, muscle weakness,
cardiac failure increased appetite, weight loss
Wet/warm skin, palmar erythema and onycolysis Thirst and polyuria
Weight loss, muscular hypotrophy Dermopathy Pruritus
(pretibial myxoedema) Acropachy Menstrual disturbances in women
rare: thyroid storm (oligo- or amenorrhea), loss of libido
Diarrhea
Anxiety, altered mood, nervousness
Apathy, lethargy (apathetic
thyrotoxicosis, in the elderly)
Local manifestations Palpable/enlarged thyroid and/or nodules Mechanical symptoms (dysphagia,
related to large goiter dyspnea, dysphonia)
Graves’ Orbitopathy Soft tissues involvement Increased lacrimation
(GO) Palpebral swelling/erythema, caruncle swelling, Foreign body sensation
conjunctivae hyperemia, chemosis Photophobia
Eyelid lag, retraction, or both Ocular pain (spontaneous/at gaze),
Proptosis (exophthalmos) Diplopia
Corneal involvement (exposure keratitis) Blurred vision, reduced visual acuity
Extraocular muscles involvement (movement
limitations)
Optical nerve involvement (up to dysthyroid optic
neuropathy, DON)

occur in more than 10% of 60-year-old individu- chemical appearance of hyperthyroidism, overt
als or older, and it can be the first and only mani- or even subclinical (low TSH with high or nor-
festation in elderly [21–23]. Increasing age, male mal levels of FT3 and FT4, respectively). FT3/
sex, and underlying cardiovascular disease are FT4 ratio is generally increased. A T3 toxicosis
risk factors for atrial fibrillation, an independent (low/suppressed TSH with high FT3 and nor-
predictor of mortality [2, 22]. mal FT4) may represent the earliest stage of
Clinical presentation of GD is also character- hyperthyroidism, mainly due to TMNG and/or
ized by the peculiar involvement of peripheral TA.  Serum antithyroid antibodies (anti-thyro-
tissues [3, 8–11]. GO, the most common and seri- peroxidase or TPO Ab, and anti-thyroglobulin
ous extra-thyroidal manifestation, affects up to or Tg-Ab) are usually absent in autonomously
50% of GD patients [8, 11]. GO usually appears functioning thyroid nodules, while present in
together with the thyroid affection or slowly after GD.  Positivity of TRAb (99% sensitivity and
its onset [11]. It comprehends various degrees of specificity) represents the diagnostic hallmark
exophthalmos, soft tissue inflammation, and mus- of GD.  However, TRAb may decline and may
cular impairment and it threatens sight as a conse- not be detectable in very mild GD or if measured
quence of corneal breakdown or optic neuropathy after antithyroid drugs have been commenced [1,
in 3–5% of affected patients (Table 2.2) [11]. 4, 8, 10]. If TRAb is negative end/or the diag-
nosis is unclear, 131-radioiodine uptake (RAIU)
and thyroid scintigraphy with either 123-radio-
2.1.4 Diagnosis and Treatment iodine or 99mTc-­pertechnetate are indicated. First
of all, RAIU allows distinguishing causes of
Apart from a detailed personal and familiar his- thyrotoxicosis with elevated or normal uptake
tory and an accurate clinical examination, the over the thyroid gland (hyperthyroidism) from
diagnosis of hyperthyroidism relies on the bio- those with near-­ absent uptake (thyrotoxicosis
2  Radioiodine Therapy of Benign Thyroid Diseases 15

without hyperthyroidism) [1] (Table 2.1). RAIU especially in elderly patients and those with car-
is usually elevated in patients with GD and nor- diovascular disease [1].
mal or high in toxic nodular disease, while it is
very low or absent in painless, postpartum, or
subacute thyroiditis, factitious ingestion of thy- 2.2 Radioactive Iodine Therapy
roid hormone or iodine-­induced thyrotoxicosis. (RAIT) in Hyperthyroid
Thyroid scintigraphy reveals an increased and Patients
diffuse uptake in both lobes in GD, and a focal
uptake in TA with suppressed uptake in the sur- In 2016, the nuclear medicine community cel-
rounding and contralateral thyroid tissue. In ebrated the first 75 years of 131-radioiodine use
TMNG the scintiscan demonstrates one or more to cure patients in hyperthyroid status. It was a
“hot” nodules alternating with areas of reduced/ ­fundamental step back then in the management
suppressed uptake [1, 4, 8]. However, coexistent of hyperthyroid patients since, for the first time,
nontoxic nodules or fibrosis in GD, large areas the toxic thyroid disease [diffuse or (multi)-nodu-
of autonomy in TMNG or interfering factors lar] could definitively be treated without the need
(i.e., administration of iodinated contrast in the of using a surgical approach, thus drastically
preceding 1–6 months) make hard the diagnosis reducing both side effects due to surgery (e.g.,
on the sole basis of radionuclide uptake. Thyroid nerve palsy, hypoparathyroidism, hemorrhage)
ultrasonography represents a useful tool in dif- and healthcare costs.
ferential diagnosis of thyrotoxicosis. In GD, From its first use, millions of people have
thyroid US demonstrates an enlarged, hypoecoic been treated, worldwide. The rationale under-
gland, with or without nodules, with an impor- lying nuclear medicine therapy is the ability of
tant increase of vascularization at color flow follicular thyroid cells to uptake 131-radioiodine
Doppler evaluation. Doppler flow evaluation can (like iodine absorbed in the diet).
be helpful in distinguishing between GD and Today, 131-radioiodine represents the first
destructive thyroiditis, particularly when radio- example of “theranostic” radiotracer: its (−ve)-
nuclide administration is contraindicated, such beta electrons allow us to obtain the therapeutic
as during pregnancy and lactation [1, 4]. In TA effect, while gamma-emission shows its distribu-
and mostly in TMNG, autonomously function- tion in the gland.
ing thyroid nodules can be exactly identified by 131-Radioiodine therapy has two main aims:
matching thyroid US and scintigraphy. Also US the first is to correct hyperthyroidism reaching a
provide useful information concerning nodule’s euthyroid state as soon as possible (the optimal
size and ecographic features. result for patients affected by (multi)-nodular
The treatment of hyperthyroidism is aimed toxic disease) or a hypothyroid state (the optimal
to restore euthyroidism and is based on either result for patients with diffuse toxic disease); the
medical treatment with antithyroid drugs (titra- second is to reduce whole gland or toxic (multi)-
tion or block and replace regimen) able to block nodular volume.
the excessive thyroid hormone production, or on
ablation/reduction of thyroid mass using surgery
or radioactive iodine [1]. Antithyroid drugs (the 2.2.1 Patients Preparation
thionamides, carbimazole, methimazole, and for Radioiodine Therapy
propylthiouracil) can be used as a first-line treat-
ment in GD, since they achieve long-term remis- Specific antithyroid drugs (ATD) [i.e., methima-
sion in approximately 30% of cases. They can zole (MMI), carbimazolo, or propylthiouracil
also be used as a pretreatment in selected patients (PTU)] such as Levo-Thyroxine, and iodine-­
prior to radioactive iodine therapy or prior to sur- containing products (e.g., toothpaste, disinfec-
gery. Beta-adrenergic blockade is recommended tant, hair dye) should be discontinued or avoided
in patients with symptomatic thyrotoxicosis, before radioactive iodine therapy (RAIT) as they
16 A. Campennì et al.

can reduce radioiodine thyroid uptake thus reduc- be pregnant, a blood test must be performed
ing the success rate of the treatment. Should a within 72  h before RAIT since pregnancy is an
patient be undergoing amiodarone therapy, RAIT absolute contraindication for RAIT. A pregnancy
must be postponed for at least six months after test is not necessary in female patients with docu-
the last amiodarone administration. However, in mented hysterectomy/ovariectomy or tubal liga-
these patients it is obligatory to evaluate radioio- tion. Finally, pregnancy must be avoided for six
dine thyroid uptake (RAIU) before RAIT [1, 24]. months after RAIT [25, 27].
Similarly, RAIT must be postponed in patients Breastfeeding must be interrupted: RAIT
who have undergone radiographic studies with should not be performed before 6 weeks after
contrast agent administration (i.e., computed breastfeeding withdrawal to avoid high ­radioiodine
tomography (CT), from several weeks to many uptake in hypertrophied breast, thus lowering the
months after, taking into account contrast agent absorbed radiation dose [1, 25, 28].
type (i.e., lipophilic or water soluble) [25, 26]. A
special diet is not required before RAIT. However,
some food types (e.g., fish, eggs, and milk), nutri- 2.2.2 D
 iffuse Toxic Goiter (Graves’
tional supplements, seaweeds, and iodine salt Disease—GD)
should be reduced or avoided for at least 7 days
before RAIT, mainly in patients with low radio- RAIT is a safe, effective therapeutic option for
iodine uptake values. In patients whose diet is GD patients [29].
mainly based on seaweed or is rich in supple- GD patients may undergo RAIT as a first
ments containing iodide, an iodine urine mea- option care if: (1) they are >10  years, any gen-
surement should be performed before RAIT [1] der, and have small to medium goiter and inac-
(Table 2.3). In young female patients who could tive Graves’ orbitopathy (GO); (2) they are
>10 years, any gender, and have small to medium
goiter and low to mild active GO (using gluco-
Table 2.3 Thyroid drugs, medications, and iodide-­
containing supplements that can reduce radioiodine thy- corticoid therapy in patients with higher risk
roid uptake features, like smokers); (3) they have comorbidi-
Recommended time of ties increasing surgical risk (i.e., heart failure,
Type of medication withdrawal pulmonary hypertension, systemic hypertension
Water-soluble intravenous 6–8 wka, assuming refractory to drugs, laryngeal nerve palsy); (4)
radiographic contrast agents normal renal there are contraindications to ATD (or patients
function
with already documented adverse reaction); (5)
Lipophilic intravenous 1–6 mob
radiographic contrast agents there is recurrent disease after surgical therapy;
Thyroxine 3–4 wk (6) they are elderly with comorbidities (in par-
Triiodothyronine 10–14 dc ticular metabolic comorbidities); (7) access to a
Antithyroid drugs 5–7 d high volume thyroid surgeon (mainly if children)
(methimazole, carbimazolo, is limited or not possible [1, 30].
propylthiouracil)
On the contrary, RAIT is not administered in
Nutrition supplements 7–10 d
containing iodide GD patients: (1) who are pregnant; (2) with the
Kelp, agar, carrageenan, Lugol 2–3 wk., depending (multi)-nodular variant of GD with suspected
solution on iodide content or confirmed thyroid cancer; (3) with very large
Saturated solution of 2–3 wk. goiter; (4) with active GO of moderate to severe
potassium iodide degree and high TRAb levels (mainly if smok-
Topical iodine (e.g., surgical 2–3 wk.
ers); (5) who are ≤5 years [1, 30–35].
skin preparation)
Amiodarone 3–6 mo or longer RAIT should be delayed as much as possible
in children between 5 and 10 years of age. In any
a
wk = weeks
b
mo = months case, in the pediatric setting, RAI administered
c
d = days activity should not be higher than 370 MBq [1].
2  Radioiodine Therapy of Benign Thyroid Diseases 17

The first aim of RAIT is to change the clini- a few days (2–5) before RAIT, thus reducing
cal status of patients from hyperthyroid to hypo- the risk of the so-called “thyroid storm.” This
thyroid according to the current “ablative dose approach may be more important in elderly
concept” based on evidence that the definitive patients and/or in patients with comorbidities
success rate is much higher than that obtained (e.g., cardiovascular, cerebrovascular, systemic
according to the previous “function oriented or pulmonary hypertension, renal failure) [1, 24,
concept” (>90% vs. < 70%, respectively) aiming 55–59]. ß-­Adrenergic block drugs should be used
at euthyroidism [1, 27, 36–38]. Hypothyroidism accurately both before and after RAIT [60, 61].
is the goal for RAIT, also in children, and thus Finally, if possible, the use of ATD should be
risks will be lower both in persistent/recurrence avoided in the days/weeks after RAIT since they
disease and in developing thyroid neoplasm in can reduce therapy efficacy, as already demon-
non-­irradiated thyroid tissue [27, 39–43]. strated [24].
The second goal is to reduce gland volume
(in particular in patients with medium gland vol-
ume), thereby correcting both mechanical issues 2.2.3 T
 oxic Multinodular Goiter
(e.g., dysphagia, dyspnea) and anti-esthetic fea- (TMNG) or Toxic Adenoma (TA)
tures of the neck [44].
The success of RAIT is mainly linked to both RAIT is a safe, effective therapeutic option for
radioiodine administered activity (and its kinetics toxic (multi)-nodular goiter patients [29].
in the gland: i.e., effective half-life) and thyroid TMNG or TA patients may undergo RAIT
volume, as already demonstrated [1, 27, 45–48]. as first option care if: (1) they have a solitary
According to the “function oriented concept” hyperfunctioning nodule; (2) they have multiple
an adsorbed dose of 150 Gy is necessary to obtain hyperfunctioning nodules in multinodular goi-
euthyroidism [27, 49]. ter without suspected or confirmed thyroid can-
On the contrary, obtaining hyperthyroidism cer; (3) they are advanced in age; (4) they have
correction according to the “ablative dose con- comorbidities (e.g., cardiovascular, cerebrovas-
cept” (i.e., hypothyroidism), it is necessary to cular, systemic or pulmonary hypertension) that
deliver an absorbed dose ranging from 200 to produce higher surgery risks; (5) they have a
300  Gy to the target [27, 37, 49, 50]. The fre- previous history of surgery and/or irradiation of
quency of persistent hyperthyroidism is very neck; and (6) there is limited or no access to a
low (8%) delivering an adsorbed dose close to high volume thyroid surgeon [1].
300 Gy to the target [37]. TMNG or TA patient are not advised to
However, Krohn and colleagues [51], in their undergo RAIT if: (1) they are pregnant or breast-
retrospective analysis, reported how not the total feeding; (2) they have suspected or confirmed
thyroid absorbed dose but the maximum dose rate thyroid cancer; (3) they have large TMNG; and
(≥2.2 Gy/h) may be important to achieve hypo- (4) there are signs and/or symptoms of compres-
thyroidism. To date, however, their preliminary sion on neck structures [1].
data have to be confirmed by prospective studies. In TMNG or TA patients, the goal of RAIT is
Finally, in pediatric GD patients, the absorbed to correct the hyperthyroid status (subclinical or
dose for delivery to target should range from overt), restoring euthyroidism. In addition, as a
120 Gy to 300 Gy [39, 52–54]. second goal, it is possible to improve mechani-
Strategies that can be used to choose radioio- cal issues (i.e., dysphagia, dyspnea) reducing the
dine activity, to obtain the adsorbed dose reported volume of toxic thyroid nodule(s) and/or thyroid
above, are described in the specific section. goiter (if extranodular thyroid parenchyma is not
Since RAI can produce an increase of serum suppressed) by 35% within three months, and up
thyroid hormone levels, patients should be to 45% over 24 months after RAIT [44, 62, 63].
treated in a euthyroid state, discontinuing ATD If RAIT is aimed at the latter objective, the use
(i.e., MMI, carbimazole or propylthiouracil) of rhTSH in both TMNG and nontoxic-MNG
18 A. Campennì et al.

patients produces greater thyroid volume reduc- Since RAI may produce a temporary wors-
tion. In addition, the use of rhTSH may be use- ening of hyperthyroidism, ß-adrenergic block
ful in TMNG with low RAIU values. However, drugs should be used both in elderly patients and
its use is off-label and in TMNG patients could in patients with comorbidities (even if asymp-
produce an exacerbation of hyperthyroidism tomatic). For the same reason, and in the same
[46, 48, 64–69]. patients’ setting, it may be useful to reassume
Also in TMNG and TA patients, the success ATD some days (3–7) after RAIT (1).
rate of RAIT is mainly linked to both radioiodine
administered activity (and its kinetics in toxic
thyroid nodule(s): i.e., maximum RAIU uptake 2.2.4 Strategies to Perform RAIT
and effective half-life) and thyroid volume, as
already demonstrated [1, 70]. As is known, the aim of RAIT is to achieve a
In particular, higher RAI activities quickly non-­ hyperthyroid status reaching euthyroidism
produce resolution of hyperthyroidism (more in both TA and TMNG patients, or definitive
than 70% of TA patients are no longer hyper- hypothyroidism in GD patients.
thyroid 3  months after RAIT) even if the risk However, choosing the best radioiodine activ-
of developing early hypothyroidism is higher ity to definitively correct hyperthyroidism avoid-
[1, 71]. However, the incidence of hypothyroid- ing hypothyroidism in TA and TMNG patients,
ism increases over time and regards about 60% avoiding persistent/recurrent hyperthyroidism in
of treated TA patients in the 20 years following GD patients, and, finally, reducing the radiation
RAIT [71–75]. The risk of hypothyroidism is dose to the body (in particular to stomach and
higher for treated patients >45  years old, with bladder) is a challenge because it is not possible
higher RAIU, partial suppression of extra toxic to evaluate all of the variables affecting outcome
thyroid nodule(s) parenchyma and pre-treated in both the early and late phases.
with ATD (since they normalize serum TSH There is an ongoing debate regarding the opti-
levels) [73]. Similarly, also in TMNG patients, mal approach to use in clinical practice to choose
the incidence of hypothyroidism increases over the radioiodine activity that can be administered:
time, regarding about 64% of all patients in the first, the so-called “fixed dose” method, an estima-
24 years following RAIT (many of them having tion method usually based on evaluation of either
undergone two or more RAIT) [74]. the gland or nodule(s) size by palpation, thyroid
On the contrary, the risk of persistent or ultrasonograhy (TUS) measurement or thyroid
recurrent hyperthyroidism in TMNG patients scintigraphy (TS); second, the “calculation dose”
is higher than in other patients, reaching up to method, a dosimetric, tailored, approach based on
20% of all treated patients, as already reported RAIU and gland/nodule(s) volume calculation by
[1, 44, 62, 76, 77]. TUS rather than TS [27, 49].
To correct hyperthyroidism, it is necessary In daily practice, both methods have advan-
to deliver an absorbed dose to the target(s) that tages and disadvantages. The more relevant
ranges from 150 to 300 Gy [27, 78–81]. Higher advantages of the “fixed dose” method are linked
absorbed doses (i.e., up to 400  Gy) slightly to its simplicity in terms of pretreatment proce-
improved the success rate of RAIT in an already dures, for both physicians and patients. Generally,
published comparative study [81]. a fixed dose between 370–555 and 370–740 MBq
Overall, in these patients, the success rate (i.e., is used to treat patients affected by GD and TA/
definitive correction of hyperthyroidism) is very TMNG, respectively [1, 25]. On the contrary, this
high, ranging from 81% to 94% of TMNG and method, lacking diagnostic accuracy during pre-
TA patients, respectively [1, 27, 44, 78–81]. treatment procedures, runs the risk of under- or,
Strategies that can be used to choose radioio- mainly, over-treatment, as already described [82].
dine activity, to obtain the adsorbed dose reported Thus, taking literature data into account, the
above, are described in the specific section. cumulative incidence of persistence/recurrence
2  Radioiodine Therapy of Benign Thyroid Diseases 19

hyperthyroidism (in particular in GD and mainly, to reduce both the incidence of hypo-
TMNG) or, on the contrary, of hypothyroidism thyroidism or persistent/recurrent disease and
(in particular in TA without extranodular paren- unjustified radiation exposure to patients, rela-
chyma suppression) may also be due to an inac- tives, and non-­ family environments [27, 50,
curacy of the “fixed dose” method [44, 72, 73]. 93–97].
The “calculated dose” method is used mainly Finally, the most recent European Union
in young patients (<45  years), with the aim to Council Directive (EUROTOM 13/59) has indi-
determine the optimal RAI activity to administer cated personalized dosimetry (i.e., the “­ calculated
to achieve the highest success rate, reducing, at dose” method) as the preferred approach to per-
the same time, the adsorbed dose to both normal form nuclear medicine therapies.
thyroid parenchyma (i.e., non-target tissue in TA
and TMNG patients) and whole body (in particu-
lar to so-called “critical organs”, such as stom- 2.3 Adverse Effects
ach and bladder), thus respecting the “as low as of Radioactive Iodine
reasonably achievable” (ALARA) principle and Therapy (RAIT)
the European Union Council Directive (97/43/
EURATOM) [49, 83–85]. Despite RAI therapy being a safe and generally
The “calculated dose” method is based well-tolerated treatment, either acute or late side
on both a measured volume of the gland (GD effects may occur, principally related to insuf-
patients) or nodule(s) (TA or TMNG patients) by ficient clinical control of hyperthyroidism and
TS (planar and SPET images) or, better, TUS and active thyroid orbitopathy [98]. Indeed, uncon-
RAIU [25, 27, 49]. trolled hyperthyroidism and severe active thyroid
The activity to be administered should be orbitopathy can be considered as relative con-
calculated as already reported in the European traindications to RAI treatment [99]. Main side
Nuclear Medicine Association guidelines [27]. effects are summarized in Table 2.4.
Recently, Amato and Campennì [70] pro-
posed calculating both the “net” volume of hot
nodule(s) by subtracting the volume of involu- 2.3.1 Early Side Effects
tion area(s) always evaluated by TUS (thereby
reducing the total amount of treated volume Early side effects can occur immediately or dur-
and, consequently, the prescribed activity) and ing the first week after RAI treatment. They are
RAIU comprising three uptake assessments (3 to mainly related to thyroid volume and hyperthy-
6–24—168 h) to improve diagnostic accuracy of roidism control before RAI treatment.
the “calculated method.”
The main disadvantage of the “calculated 2.3.1.1 Thyroid Swelling
dose” method may be its complexity for both Patients with large goiter after RAI therapy could
physicians and patients. However, a simplified manifest thyroid pain and sensation of thyroid
calculated dose approach, at least for the treat- growth due to inflammation process caused by
ment of GD patients, has been proposed by using irradiation of thyroid tissue. In some cases, even
99mTc- scintigraphy [86, 87]. if very rare, in patients with both toxic and non-
In conclusion, to date, there is no agreement toxic goiter an acute thyroid enlargement for
on the superiority of the “calculated dose” over edema could cause tracheal compression and
the “fixed dose” method [37, 72, 82, 84, 88–92] dyspnea.
in the treatment of hyperthyroid patients. For example, the use of Recombinant Human
However, according to the latest evidence in Thyrotropin (rh-TSH) administration to enhance
literature, use of the “calculated dose” method RAI effect in nontoxic goiter was associated with
should be preferred in children to young- more frequent tracheal compression with stridor-
adult patients, to increase the success rate and, ous respiration [100].
20 A. Campennì et al.

Table 2.4  Summary of early and late side effects


Side effect Onset Pathophysiology Symptoms Therapy
Thyroid swelling Early Inflammatory Thyroid pain It solves in short time without medical
reaction to Sensation of thyroid intervention;
irradiation growth Treatment with nonsteroidal anti-inflammatory
Dyspnea in patients with agent for 24–48 h after
large goiter. RAI administration can be indicated
Corticosteroids could be beneficial.
Radiation Early Transient rise in Exacerbation of Good selection of the optimal time point of
thyroiditis and fT3 and fT4 hyperthyroidism RAI treatment administration
post-therapy levels symptoms. Beta-adrenergic blockade
thyrotoxicosis Thyroid storm (rare): ATDs therapy before or after RAI treatment in
–  high fever patient with uncontrolled hyperthyroidism
– central nervous Thyroid storm requires advanced medical
system manifestations, treatment with ATDs, inorganic iodide
gastrointestinal and administration
hepatic manifestations beta-AAs, corticosteroids and antipyretics.
–  heart failure.
Radioiodine-­ Early/ Concentration in Swelling, Lemon juice (5 mL) or salivation-­inducing
Induced late salivary of Periductal pressure Duct snacks (lemon candy)
sialadenitis iodide due to the constriction Pain Start 24 h following RAI therapy
sodium iodine Xerostomia
symporter Taste dysfunctions
expression
Immunogenic Early Release of RAI therapy causes the Pretreatment with ATDs
effects thyroid antigens transient increase of
from destroyed TRAb.
follicular cells
with increase of
TRAb,
Hypothyroidism: Late Transient Transient hypothyroidism: Transient hypothyroidism spontaneously
transient or hypothyroidism: no symptoms or sign, recovers in few months
persistent unclear cause only biochemical. Persistent hypothyroidism requires
Persistent Persistent administration of Levo-thyroxine replacement
hypothyroidism: hypothyroidism: therapy.
Thyroid Typical sign of
irradiation hypothyroidism
Graves’ Late B-cells and Worsening or appearance In case of high risk to develop/worsening of
orbitopathy macrophages of orbitopathy orbitopathy:
activation with prophylactic steroids oral administration: daily
cytokines dose (daily 0.3–0.5 mg prednisone/kg for
secretion 15–30 days starting after RAI treatment)
In case of mild GO:
local treatment such as artificial tears and also a
6 months selenium supplementation is
supplementation are suggested.
In case of moderate to severe active GO:
intravenous administration steroids is suggested
– intermediate-dose protocol with
methylprednisolone:
– starting dose of 0.5 g once weekly for
6 weeks, followed by 0.25 g once weekly
for 6 weeks,
– high-dose protocol with
methylprednisolone:starting dose of 0.75 g
once weekly for 6 weeks followed by 0.5 g
once weekly for 6 weeks),
both with a cumulative dose that should not
exceed 8.0 g.
Contraindications: recent viral hepatitis,
psychiatric disorders, advanced cardiovascular
disease and hepatic dysfunction, diabetes and
hypertension.
Second-line treatment: rehabilitative surgery.
2  Radioiodine Therapy of Benign Thyroid Diseases 21

Table 2.4 (continued)
Side effect Onset Pathophysiology Symptoms Therapy
Cancer incidence Late Irradiation of No significant data are There is no evidence of increased risk of RAI
thyroid tissue, available on cancer induced malignancy
bone marrow, incidence after RAI Tailored dosimetry and patient education can
bladder therapy for benign limit the risk
conditions.
Teratogenicity Late Irradiation of No increased risk of Pregnancy represents an absolute
and gonadic gonadic cells long-term infertility, contraindication to RAI therapy
function miscarriage, induced Testing on blood sample for pregnancy is
abortions, stillbirths, or recommended before RAI treatment
offspring neonatal Conception should be delayed:
mortality or congenital in women for 4–6 months or longer in men at
defects. least for 3–4 months
Transient reduction of
testosterone and T/LH
ratio.

To avoid this rare side effect in patients with receptor antagonists (beta-AAs) corticosteroids,
large volume goiter, surgery is still the first thera- and antipyretics [101].
peutic option if feasible. If thyroid storm is a rare condition, in the early
The lack of controlled trial and the great period after RAI a mild to severe worsening of
inter-­individual variations do not allow a pro- thyrotoxicosis occurs in 10% of patients [58]. In
phylactic therapy strategy in large goiter, but particular, patients with poorly controlled hyper-
in case of moderate thyroid swelling or tender- thyroidism are most likely at risk to present this
ness, these symptoms usually vanish in short condition. A good selection of the optimal time
time without medical intervention. Nevertheless, point of RAI treatment administration and a cor-
in some cases treatment with nonsteroidal anti-­ rect premedication are mandatory to limit these
inflammatory agent for 24–48  hours after RAI side effects.
administration can be indicated to limit symp- A beta-adrenergic blockade if not already
toms and the use of corticosteroids could also be installed and in the absence of contraindication
probably beneficial. has to be implemented after RAI treatment to
avoid cardiac side effect such as tachycardia or
2.3.1.2 Radiation Thyroiditis and Post-­ cardiac arrhythmia.
therapy Thyrotoxicosis The antithyroid drugs (ATDs) are frequently
Radiation thyroiditis may occur in 1% of used in the treatment management of this condi-
patients during the first weeks after RAI and it tion to accelerate the return to an euthyroidism
could be associated with a transient rise in free status but there is disagreement about the effects
Triiodothyronine (fT3) and free Tiroxine (fT4) of their administration before or after RAI ther-
levels that, in patients with poorly controlled apy. Pretreatment with ATD allows these patients
hyperthyroidism before RAI, could lead to exac- to start from a lower baseline value of thyroid
erbation of symptoms up to the so-called “thy- hormones, but RAI efficacy can be compromised
roid storm” [29]. and a most rapid increase in thyroid hormone lev-
Thyroid storm is rare but it is a life-­threatening els can be observed [58].
condition regarding decompensations of mul- Pretreatment with ATDs, in particular
tiple organs with high fever, central nervous sys- Carbimazole, could decrease iodine uptake with
tem manifestations, gastrointestinal and hepatic a higher risk of treatment failure, despite under-
manifestations, and heart failure [56, 101]. It lying mechanism is not fully understood. In
requires comprehensive and advanced medical ­particular, it reduces the cell damage produced
treatment with the administration of antithyroid by synthesis of oxygen free radicals subsequent
drugs (ATDs), inorganic iodide, beta-adrenergic to RAI administration [102]. A withdrawal of
22 A. Campennì et al.

Carbimazole for only a few days before RAI Sometimes it is difficult to differentiate between
administration is enough both to restore the suc- post-therapy thyrotoxicosis and persistent hyper-
cess of RAI and to avoid the risk of exacerbation thyroidism for treatment failure: RAI reaches
of hyperthyroidism. the goal in 3–6 months and delayed response to
Also pretreatment with propylthiouracil treatment can be confused as persistent/transient
(PTU) is associated with an higher risk of RAI thyrotoxicosis. No-responders patients to RAI
therapy failure [103]. In a study conducted in treatment usually continue to manifest the same
1997 [103] this risk of treatment failure was sta- symptoms and signs of thyrotoxicosis, so in cases
tistically significant after discontinuation of PTU of persistent hyperthyroidism 3 months after RAI
for 4–7  days before RAI (P  =  0.039), while it patients could be retreated with a second dose of
was not significant after discontinuation for lon- RAI [109].
ger than a week. Others authors [104] suggested
that PTU administration should be avoided in 2.3.1.3 Radioiodine-Induced
patients with Graves’ disease before RAI admin- Sialadenitis
istration because it could lead to higher risk Sialadenitis represents both an acute and a late
of treatment failure compared to methimazole side effect of RAI therapy and it is one of the
(MMI) administration or absence of any ther- most frequent complication in case of RAI treat-
apy (P  <  0.05). A systematic review published ment for thyroid cancer ablation, while it is less
in 2007 compared the rates of treatment fail- frequent after RAI treatment for Graves’ disease
ure and the short- and long-term side effects in or toxic goiter.
patients with hyperthyroidism treated with RAI Salivary gland can concentrate iodide due to
with or without adjunctive ATDs and found out the sodium iodine symporter expression and then
that the risk of treatment failure defined as per- secrete into saliva [110]. This mechanism is prin-
sistent or recurrent hyperthyroidism or need for cipally mediated by ductal epithelium of parotid
further RAI treatment was significantly higher gland and during this process salivary glands are
in adjunctive ATDs group compared with con- exposed to dose-related damage.
trol (P = 0.006); no significant differences were Clinical manifestations of radioiodine-­
found between different ATDs [24]. induced sialadenitis, transient in more cases,
Several studies investigated the potential are swelling and pain, xerostomia or taste dys-
role of lithium administration. The concomitant functions, mainly represented by salty taste for
administration of lithium with RAI could lead to reduction of reabsorption of sodium and chloride
a better control of hyperthyroidism [105], prob- from the saliva, [110] in as many as 20–30% of
ably related to the lithium-induced blockade of cases [111].
RAI and thyroid hormone release, without effect Swelling increases periductal pressure with
on thyroidal RAI uptake [106, 107], and it may duct constriction and obstructive symptoms for
also prevent worsening of thyrotoxicosis after the formation of jelly-like plug [110] secondary
ATDs interruption or RAI therapy [108], but it is to obstruction and mucus precipitation that often
not routinely used. increases in the eating period.
To avoid the decrease of RAI efficacy in case Because this common side effect can affect
of persistent thyreotoxicosis it is suggested to rein- quality of life of patients, several authors pro-
troduce soon ATDs after RAI administration [24]. posed various radioprotective procedures to
Radiation thyroiditis like subacute thyroiditis diminish RAI damage to salivary gland.
should be treated also with nonsteroidal anti-­ A valid method is the stimulation by lemon
inflammatory agents as anti-inflammatory action: juice that lead to a faster secretion from salivary
corticosteroids should be used when patients fail gland [112]: after administration of 5  mL of
to respond to nonsteroidal anti-inflammatory lemon juice, RAI in salivary gland declined in
drugs or present initially with moderate to severe 4 min, followed by a re-accumulation period of
pain and/or thyrotoxic symptoms [1]. 20–40 min of the same initial activity.
2  Radioiodine Therapy of Benign Thyroid Diseases 23

Another method is the assumption of immunogenic hyperthyroidism in these patients


salivation-­
inducing snacks, like lemon candy represents an exacerbation of a preexisting and
[113], starting 24  h following RAI therapy. On occult immunogenic thyroid disorder.
the other hand an early administration of lemon An aggravating factor of thyroid immunity
juice or substitutes is not recommended because in addition to autoantibodies expression is the
of increased side effects on salivary gland func- reduction of T-lymphocyte suppressor after RAI
tion [114] because acid stimulation increases not simultaneously to a rise of both pro-­inflammatory
only salivary flow, but also salivary gland blood and anti-inflammatory cytokines [98].
flow and RAI uptake in iodine-avid tissue rises The most serious consequence of re-activa-
up in 24  h and then reaches a plateau [113]. tion of thyroid immunity after RAI therapy with
Subsequent continuous assumption of lemon severe impact to patient’s quality life is the acti-
juice or similar helps RAI clearance from the vation or new onset of Graves’ orbitopathy (GO)
salivary glands. [98]. A period of pretreatment with ATDs may
diminish the TRAb rise after RAI [119, 120]
2.3.1.4 Immunogenic Effects contributing to the suppression of TSH receptor
Various therapeutic approaches such ATDs, RAI, antibodies with their immunosuppressive action.
or thyroidectomy for hyperthyroidism condition Furthermore methimazole probably interferes
may influence disease activity. Normally during with antigen macrophages processing, leading to
follow-up, TSH receptor antibodies (TRAb) level decreased T cell response and antibodies produc-
tend to disappear from serum after all types of tion [120].
therapeutic modalities [115].
On the other hand, radioactive iodine therapy
could induce a transient increase of TRAb sec- 2.3.2 Late Side Effects
ondary to the release of thyroid antigens from
destroyed follicular cells and this event is more 2.3.2.1 Hypothyroidism: Transient or
evident during the first days after RAI adminis- Persistent
tration. Patients that underwent surgery or ATDs The great part of patients can develop hypothy-
showed a gradual fall of TRAb in serum and roidism after RAI treatment, especially after
after 1  year 50–60% of patients demonstrated high-doses administration, and it could be both
the disappearance of TRAb. Underlying mecha- transient and persistent. Even if it is counted
nism of TRAb reduction in not well established: among side effects, hypothyroidism in most
one hypothesis is that hyperthyroid state may cases is considered the goal of the treatment.
maintain autoimmune abnormalities while Transient hypothyroidism may manifest
euthyroid state after medication or surgery 2–5  months after RAI therapy and spontane-
decrease autoimmune reaction with decrease in ously recover in few months without develop-
TRAb levels [115]. ment of symptoms or sings of hypothyroidism:
No correlation has been found between the a predominant problem is to differentiate from
entity of TRAb rise neither with RAI activity permanent type in early months after treatment
administered nor with baseline fT3 and fT4 levels to establish the best treatment option. The cause
[116]. TRAb levels rise occurred as a generalized remains unclear and no prognostic factors have
phenomenon, despite corticosteroids prophylaxis been identified to predict its onset [121].
after RAI. Authors suggest different hypothesis in patho-
The incidence of immunogenic hyperthyroid- genesis of transient hypothyroidism.
ism/Graves’ disease after RAI therapy for auton- Several authors speculated that thyroid-­
omous nodules has been described [117] and this stimulating antibody (TSAb) may play a role in
risk has also been associated to high levels of recovery of follicular cells function after RAI [121,
thyroid peroxidase (TPO) antibodies before RAI 122], so the measurement of TSAb levels could
administration [118], fitting the hypothesis that early differentiate transient hypothyroidism to
24 A. Campennì et al.

permanent one. Thyroid-stimulating antibody ing or development of ophthalmopathy. A recent


levels could decrease after several months and systematic review [132] compared its occurrence
patients could develop permanent hypothyroid- in patients treated with thyroidectomy, ATDs, or
ism, furthermore the mean estimated time to RAI.  This review included nine studies with a
develop permanent hypothyroidism is shorter total of 1773 patients and found out that RAI ther-
compared to patients with transient hypothyroid- apy represents a significant risk to develop/worse
ism: for these reasons a strict follow-up is needed orbitopathy compared to ATDs (P  <  0.00001).
in these patients. Prophylactic per os or by intravenous administra-
Other authors [123] supposed that an tion of steroids has been demonstrated effective
impaired thyroid function could be secondary in preventing this event (P = 0.002), especially in
to hibernation-­ like conditions (or stunning). patients with prior orbitopathy.
Patients with transient hypothyroidism may man- Several concomitant risk factors, beyond high
ifest an impaired organification of iodide, with TRAb levels, are associated with the develop-
normal iodide trapping by the thyroid; on the ment or deterioration of orbitopathy, such as
other hand, in patients with permanent hypothy- smoking, high fT3 levels, and post-RAI hypothy-
roidism, iodide trapping is markedly diminished roidism [133, 134].
and do not recover. To discriminate transient In particular, cigarette smoking has been
versus permanent hypothyroidism, early iodine investigated by several authors as a major inde-
uptake measurements may be useful to establish pendent risk factor involved in ophthalmopathy.
substitutive therapy. A systematic review [135] including 15 stud-
Finally, other authors suggested that transient ies with a total of 1880 patients underlined the
hypothyroidism is caused by an hypothalamic-­ strong association between smoking and orbi-
pituitary axis dysfunction [124], like recovery topathy, despite biological mechanism remaining
delay, but subsequent studies did not confirm this unknown. Moreover, smoking had been demon-
hypothesis [125]. strated to be associated with poor outcome even
in case of prophylactic administration of steroids
2.3.2.2 Graves’ Orbitopathy after RAI therapy, but also in case of radiation
Graves’ orbitopathy (GO) is an inflammatory therapy and high-dose i.v. glucocorticoid treat-
autoimmune disorder linked to thyroid disease ment in patients with severe ophthalmopathy
due to several antigens shared between orbital [133]. For these reasons smoking cessation
and thyroid tissue [126] as T-lymphocytes. should be encouraged in all patients with Graves’
T-lymphocytes reach orbital tissue and interact disease, especially with orbitopathy.
with antigens exposed by B-cells and macro- Thyroid function is also a crucial point to con-
phages activating several reactions like cytokines sider for development or deterioration of orbitop-
secretion that maintain orbital fibroblasts prolif- athy. Both hypothyroidism and hyperthyroidism
eration and extraocular infiltration muscles with conditions must be avoided: in fact hypothyroid-
increased volume of orbital content [11, 127]. ism after RAI therapy for Graves’ disease rep-
Furthermore, orbital fibroblasts express TSH resent a risk factor for ophthalmopathy; for this
receptors that represent the primary target for reason early (after 2 weeks from RAI) substitu-
TRAb, working like autoantigen and worsening tive therapy with levothyroxine has been pro-
inflammatory reactions [128]. posed to prevent this event [134]. On the other
TRAb are expressed by the most part of hand, also high pretreatment fT3 levels must be
patients with Graves’ disease, including euthy- avoided: serum concentration ≥5  nmol per liter
roid ones. Generally, high TRAb levels are asso- has associated with development or worsening of
ciated with a more aggressive orbitopathy and orbitopathy [136].
worse prognosis [129–131]. Selection of the best therapy option is based
Several studies demonstrated a significant on activity and severity of GO. Activity is mea-
association between RAI therapy and worsen- sured by the clinical activity score (CAS) [137]
2  Radioiodine Therapy of Benign Thyroid Diseases 25

that considered seven clinical criteria: spontane- twice daily, corresponding to 93.6 μg of elemen-
ous retrobulbar pain, pain on attempted upward tal selenium/day) significantly improved not only
or downward gaze, redness of eyelids, redness quality of life and overall ocular involvement in
of conjunctiva, swelling of caruncle or plica, the selenium group, but also the rate of progres-
swelling of eyelids, and chemosis. Active GO is sion of GO to more severe forms was signifi-
defined when CAS point is major or equal to 3/7. cantly lower in selenium group versus placebo
Severity is classified as mild, moderate to group (P < 0,001).
severe, and sight threatening (or very severe). Guidelines by EUGOGO group [139] recom-
Mild GO is defined when orbitopathy have a mended intravenous administration of steroids
minor impact on daily life and does not requires only in moderate to severe active GO with the
therapy, moderate-to-severe GO is defined when exception of patients with recent viral hepatitis,
orbitopathy requires immunosuppression or sur- psychiatric disorders, advanced cardiovascular
gical treatment and very severe GO that requires disease and hepatic dysfunction and with particu-
immediate intervention, is defined when patients lar regard to patients with diabetes and hyperten-
present dysthyroid optic neuropathy (DON) and/ sion. They proposed both intermediate-dose and
or corneal breakdown [138]. high-dose protocols of methylprednisolone, with
In 2016 the European Group on Graves’ a starting dose of 0.5 g once weekly for 6 weeks,
Orbitopathy (EUGOGO) published the guide- followed by 0.25  g once weekly for 6  weeks
lines for the management of GO [139]. They and a starting dose of 0.75  g once weekly for
recommended that patients with GO should be 6  weeks, followed by 0.5  g once weekly for
referred to specialized centers with both endo- 6  weeks, respectively, both with a cumulative
crinologist and ophthalmological expertises, to dose that should not exceed 8.0 g. Patients should
stop smoking attitude should be recommended be monitored to evaluate response to treatment
even in absence of GO and euthyroid status and to early identify possible adverse events of
should be promptly restored and maintained in steroids to considerer other treatment modality.
patients with severe GO, RAI treatment should Second-line treatment for moderate to severe
not be the first therapeutic option. If other treat- and active GO include rehabilitative surgery (for
ment option are not feasible, in patients at high example orbital decompression) when orbitopa-
risk of development/worsening of orbitopathy thy is associated with visual disfunction, and in
and candidate to RAI treatment prophylactic case of dysthyroid optic neuropathy (DON) onset,
steroids oral administration are recommended, it must be suddenly treated with very high dose
starting with a daily dose of 0.3–0.5  mg pred- of steroids (500 mg–1 g of methylprednisolone)
nisone/kg after body weight per day. Original for three consecutive days or on alternate days
schedule suggested to continue steroid prophy- during the first week and proceed with orbital
laxis for 3 months after treatment [139, 140], but decompression in case of no or poor response
subsequently was shown that a lower daily dose after 2 weeks of high-dose steroids protocol.
of 0.2 mg prednisone/kg body weight per day for
6 weeks was equally effective [139]. 2.3.2.3 Cancer Incidence
On the other hand, in low-risk patients lower Few data are available on cancer incidence after
doses can be used while patients with inactive RAI therapy for benign conditions in adults.
orbitopathy may receive RAI without steroid Data available on higher activities employed for
cover. ­treatment in patients with thyroid cancer are not
For mild GO local treatment, artificial tears reliable, due to different RAI pharmacodynamics
and a 6 months selenium supplementation that has and pharmacokinetics related to the absence of
demonstrated improvement in eye manifestation thyroid gland in these patients [98].
are suggested. A large multicenter, double-­blind A study published in 2007 [142] evaluated the
study published in 2011 [141] demonstrated that cancer incidence in 2793 patients with hyper-
a supplementation with sodium selenite (100 μg thyroidism treated with RAI, with an average
26 A. Campennì et al.

follow-­up of 10 years and reported a higher risk tered, RAI remains an ideal treatment modality
of cancer development in patients treated with for Graves’ disease in the pediatric population
RAI compared to control population (rate ratio and that higher rather than lower doses of RAI
[RR], 1.25). Moreover an increased incidence should be given for the increased risk of thyroid
of kidney (RR, 2.32), stomach (RR, 1.75), and cancer associated with low dose of RAI, as previ-
breast (RR, 1.53) cancer was reported in RAI ously described.
group with relative risk of cancer increasing with Another study [146] with a long follow-
higher RAI doses. up (36  years) analyzed 116 patients, aged of
A subsequent study suggested that hyperthy- 3–19 years, treated with RAI for Graves’ disease
roidism itself is a serious clinical condition that between 1953 and 1973. Despite the small sample
could lead to an increased incidence of mortality, size resulting in an inadequate statistical power,
independently from treatment modality [143]. no thyroid cancer or leukemia and no increase in
Furthermore, although the data suggested a small the rate of spontaneous abortion or in the number
increase in the risk of upper gastrointestinal can- of congenital anomalies were reported.
cer in elderly men, other risk factors particularly In 2007 a conflicting study [147] suggested to
relevant in these tumors were not recorded, such perform surgery instead of RAI both in children
as smoking history, dietary history, or family his- and in young adults for lacking of long-term,
tory. In this study data about increased risk of prospective, randomized control trials. Other rea-
leukemia or thyroid cancer after RAI treatment sons to support surgery instead of RAI are the
are also not available [143]. On the other hand, potential risk of internal and external radiation
one issue is the risk of thyroid cancer after expo- exposures inducing hyperparathyroidism and the
sure to RAI in childhood. slightly higher cardiovascular and overall mortal-
It is known that the thyroid gland of children, ity rates induced by RAI compared to patients not
is especially sensitive to the carcinogenic action receiving RAI.
of ionizing radiation, with a direct relationship Furthermore [148], thyroid cancer risk may
between dose of radiation and effect, especially be associated with the underlying thyroid disease
for lower dose levels (on the order of 0.10 Gy), and a tailored dosimetry and patient education
compared to higher dose levels that resulted in are necessary.
cell killing [1, 144]. Carcinogenic effect of RAI Nevertheless at this moment RAI treatment
exposure of children remains uncertain. is still considered a valid option to treat hyper-
A paper published in 2005 [145] analyzed the thyroidism in children because there is no a clear
risk of thyroid cancer in 276 patients younger than evidence of increased risk of RAI-induced malig-
15 years at the time of Chernobyl nuclear power nancy. International guidelines do not recom-
plant accident in April 1986 and investigated other mend RAI Treatment only in very young children
concomitant factors that could possibly influence (<5 years).
this risk. A direct relationship between radiation
dose to the thyroid and thyroid cancer risk was 2.3.2.4 Teratogenicity and Gonadic
found (P < 0.001); moreover the risk of radiation- Function
related thyroid cancer was three times higher in Radiation is known to be mutagenic and the
iodine-deficient areas (relative risk [RR]  =  3.2, majority of studies focused on pregnancy out-
95% CI = 1.9–5.5) than elsewhere indicating that come and gonadic function after RAI regards
use of a dietary iodine supplement can reduce the only patients treated for thyroid carcinoma.
risk of RAI-related thyroid cancer. Pregnancy represents an absolute contraindi-
In 2007 a study was performed to identify cation to RAI therapy and a pregnancy test on
both risk and benefits of RAI treatment, com- blood sample is recommended 72 h before RAI
pared with other therapies for hyperthyroidism administration [1, 27].
condition due to Graves’ disease in children [42]: Fetal thyroid begins to develop at 5–6 weeks
this study concluded that, if properly adminis- and colloid production begins at 10–12 weeks of
2  Radioiodine Therapy of Benign Thyroid Diseases 27

gestation: inadvertent RAI therapy administra- of infertility in these patients is minimal, also in
tion before 10 weeks of gestation has been asso- patients that underwent multiple administrations
ciated with normal fetus [149]; on the other hand, for persistent or metastatic thyroid cancer [152].
a later administration results in high thyroid The effects of RAI treatment for hyperthyroid-
radiation dose (20–600  Gy) with thyroid abla- ism on male gonadal function was investigated
tion and neonatal hypothyroidism [98].The rate in one study [153]. Nineteen male hyperthyroid
of induced abortion, miscarriage, stillbirth, pre- patients were enrolled, seventeen with Graves’
maturity, birth weight below the tenth percentile disease and two with toxic adenoma, and dem-
for the gestational age, congenital abnormality, onstrated a significant reduction of both serum
and death during the first year of life was investi- testosterone (T) (P  =  0.04) and T/LH ratio
gated in 2008 in a study on 2673 pregnancies in (P = 0.007) 45 days after RAI with return to basal
patients treated with RAI for thyroid cancer with- levels after 12  months. A significant increase
out significant external radiation to the ovaries in progressive motility after RAI therapy was
[150]. Incidence of miscarriages was 10% before observed (P = 0.01) without significant variations
any treatment for thyroid cancer and frequency in sperm concentration and percentage of normal
was not significantly higher in women treated forms. In conclusion RAI treatment for hyperthy-
with RAI during the year before conception, even roidism has a minor impact on gonadic function
in case of higher activity administration. Also the and it should keep in mind that also thyroid dys-
incidence of stillbirths, prematurity, low birth functions may affected sperm quality and motil-
weight, congenital malformations, and death ity [154]. Based on recommendation for RAI
during the first year of life were not significantly treatment in thyroid cancer, also in case of RAI
different before and after RAI therapy, and inci- treatment for hyperthyroidism it would be better
dences of thyroid and non-thyroid cancers were to delay conception in women for 4–6  months
similar in children born either before or after the or longer until euthyroidism is reached and in
mother’s exposure to radioiodine. men at least for 3–4 months to allow turnover of
A systematic review published in 2008 [151] sperm production [143].
evaluated the gonadic and reproductive effects
of RAI therapy in women and adolescents survi-
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Radioiodine Therapy
of Thyroid Cancer 3
Frederik A. Verburg

3.1 Introduction 3.1.1.1 Histology and Clinical


Behaviour
3.1.1 Differentiated Thyroid Cancer
PTC
Although it concerns fewer than 1% of all can- The classical form of PTC is an unencapsulated
cer cases, and its incidence varies throughout tumour with papillary and follicular structures. It
the world [1], differentiated thyroid carcinoma is characterized by overlapping cell nuclei that
(DTC) is the most common endocrine malig- have a ground-glass appearance and longitudinal
nancy [2]. This comprises the so-called papil- grooves, with invaginations of cytoplasm into the
lary thyroid carcinoma (PTC) and follicular nuclei [6, 7]. PTC histologic variants among oth-
thyroid carcinoma (FTC). These tumours derive ers include the encapsulated, follicular, tall-cell,
from the follicular thyrocytes and are referred to columnar cell, clear-cell, diffuse sclerosing, solid
as “differentiated” thyroid cancer because the or trabecular, and oxyphilic forms [2, 8]. PTCs
tumour cells retain some of normal thyrocytes’ are often multifocal, with many of the lesions of
properties. Most importantly the ability to take different clonal origin, i.e. arising independently
up and store iodine and to respond to thyrotro- [9]. PTC metastasis tends to be lymphogenic,
pin (thyroid-­stimulating hormone, TSH) stimu- before spreading to the lungs and bones.
lation is retained, which allows for treatment
and imaging using radioactive iodine analogues. FTC
DTC cases typically have a good prognosis, with FTC is characterized by follicular differentiation,
long-­term survival ranging from about 70% to without the nuclear changes seen in PTC [6, 7].
more than 95%, depending on the extent of dis- FTCs are encapsulated tumours, distinguishable
ease at the time of diagnosis [3]. Consequently, from follicular adenomas by the presence of inva-
in >85% of DTC patients, life expectancy is sion of the capsule and/or vessels. According to
unimpaired [4, 5]. the pattern of invasion, FTCs can be divided into
two categories: minimally invasive and widely
invasive. FTCs are less often multifocal than are
PTCs. FTC tends to metastasize to the lungs,
bone and liver; regional lymph node metastases
are much less common than in PTC.
F. A. Verburg (*) Hürthle cell carcinoma is a variety of FTC that
Department of Nuclear Medicine, University Hospital consists of at least 75% oxyphilic cells [8]. An
Marburg, Marburg, Germany
e-mail: verburg@med.uni-marburg.de important characteristic of Hürthle cell c­ arcinomas

© Springer Nature Switzerland AG 2019 35


L. Giovanella (ed.), Nuclear Medicine Therapy, https://doi.org/10.1007/978-3-030-17494-1_3
36 F. A. Verburg

is their reputedly poor or even absent iodine uptake, related to DTC were much lower in patients
which renders this entity more difficult to treat. who received radioiodine treatment (RIT) after
surgery than in those who did not receive I-131
3.1.1.2 DTC Treatment [13]. In fact, now that I-131 therapy belongs to
In the treatment of DTC, multiple modalities the standard treatment of DTC, life expectancy in
are involved, each of which will be discussed patients without extensive neck or distant metas-
separately. tases is unimpaired [4].
I-131-NaI closely approaches the ideal onco-
Surgery logic drug. It is one of the earliest and longest
Surgery is the first and most important component used examples of selective targeted therapy [23].
of the primary treatment of DTC. In Europe, the It can be used both for imaging the drug distribu-
Americas, and much of Australasia, (near) total tion and for diagnostics and treatment. I-131-
thyroidectomy is usually performed in almost NaI is a very specific radiopharmaceutical for
all patients. Only for papillary microcarcinoma targeting cancer cells that have retained the nor-
hemithyroidectomy is deemed to suffice by most mal thyrocytes’ functional attributes as the
patients [9–17]. body’s main iodine reservoir and primary locus
The most serious potential complications of of expression of the sodium-iodide symporter
thyroid surgery are hypoparathyroidism and (NIS) [24], making I-131 largely specific for the
recurrent laryngeal nerve damage [18, 19]. target cancer cell.
Identification and electronic monitoring of the In clinical practice, post-operative, adjuvant
recurrent laryngeal nerve can significantly reduce I-131 therapy is primarily applied to destroy
the rate of nerve damage [20]. The incidence and remaining occult small DTC foci, thus decreas-
impact of complications can be reduced by per- ing the long-term risk of recurrent disease [10,
forming the procedure in expert centres [19] as 13, 25–27]. Furthermore, by eliminating remain-
well as intensive post-operative monitoring, ing normal thyroid tissue the specificity of serum
especially serum calcium levels should be moni- thyroglobulin and diagnostic whole-body scans
tored frequently in the immediate post-operative (dxWBS) as markers for persistent or recurrent
phase. DTC are improved [2, 26, 28]. Additionally,
given the multiclonal nature of many DTC cases
Thyroid Hormone Replacement Therapy [9] by destroying healthy thyroid cells ablation
As by definition the production of endogenous may prevent neoplastic transformation from
thyroxine is discontinued by thyroidectomy occurring again [29]. As an added bonus I-131
procedure, DTC patients require thyroid hor- ablation allows sensitive post-ablation whole
mone (levothyroxine, LT4) replacement ther- body scanning (rxWBS) for detecting previously
apy [21]. unknown persistent locoregional disease or dis-
Differentiated thyroid cancer cells still react tant metastases [30, 31]. The latter does not how-
to TSH stimulation; for this reason LT4 in more ever in itself constitute a goal or justification for
advanced cases is usually administered in such I-131 ablation.
doses that TSH levels fall to very low levels of The effectiveness of I-131 ablation in the pre-
<0.1  mU/L [22]. Especially for low-risk vention of recurrent disease and DTC-related
patients TSH suppression is not generally advo- death has been shown sufficiently in multiple
cated [21]. studies, especially in high-risk patients or in
cases of non-radical surgery [13, 32, 33].
Radioiodine (I-131) Therapy I-131 therapy has been used for treating DTC
A landmark study by Mazzaferri and Jhiang for over 75 years [23]. However, there still is no
published in 1994 on a population of over 1500 agreement on the activity of I-131 to use for
patients followed for four decades or more clearly which clinical situation, let alone on what param-
showed that both recurrence rates and death rates eters to use to determine the activity. As a reflec-
3  Radioiodine Therapy of Thyroid Cancer 37

tion of this lack of evidence and procedural 3.3  alivary and Lacrimal Gland
S
guidance physicians often still administer stan- Damage (Sicca Syndrome)
dard Iodine-131 dosages as fractions or multiples
of “millicuries” although SI-units for the amount One of the most frequent long-term complica-
of radioactivity have been converted to tions of I-131 therapy concerns the salivary
“Becquerels” more than 30 years ago. Most often glands. As these physiologically take up I-131 as
I-131 ablation or therapy is administered in the well, in some patients this causes a sufficient irra-
form of a standard activity. The simplest approach diation of the organ to cause permanent salivary
to individualize I-131 ablation using fixed activi- gland dysfunction. This results in a permanent
ties is the empirical variation of this fixed activity xerostomia (dry mouth) which severely impairs
according to stage and histological findings of patients’ quality of life.
the surgical specimen. Current guidelines are Attempts have been made to protect the sali-
largely in consensus that the primary goal of ini- vary glands during I-131 therapy by the intra-
tial I-131 therapy, adjuvant post-surgical thyroid venous administration of 500 mg/m2
remnant ablation, adjuvant treatment or therapy S-2-(3-aminopropylamino)-ethylphosphorothioic
of remaining local or metastatic disease, should acid (amifostine) prior to therapy. In a double-
influence the therapeutic activity; to what extent blind trial the administration of amifostine leads
is however subject of discussion [34–36]. In chil- to an unchanged salivary gland function com-
dren, if no dosimetry is performed, the activity pared to the pre-therapeutic situation, whereas
should furthermore be individualized according patients who did not receive amifostine showed a
to body weight, in which the calculation is usu- highly significant reduction of the salivary gland
ally based on an activity per kg bodyweight given function [49]. Treatment with a lower dose of
to a 70 kg adult [37–39]. 300  mg/m2 in a later trial was shown not to be
effective [50]. The concept of amifostine protec-
tion has not been explored further since, possibly
3.2 rhTSH due to potential side effects of the substance.
Traditionally it was thought that stimulation
High thyrotropin levels (above 30  mU/L) are of the salivary glands using, e.g. lemon drops
usually recommended for I-131 therapy in order and/or chewing gum would lead to a lower radia-
to induce sufficient I-131 uptake [34–36]. Such tion exposure to the salivary glands through an
high TSH levels can be achieved either by thy- increased washout of I-131 in the excreted saliva.
roid hormone withdrawal (THW) for 3–4 weeks However, several recent studies have shown that
or by intramuscular injections of recombinant this strategy, at least when applied immediately
human TSH. Through avoidance of hypothyroid- after I-131 administration, may on the contrary
ism, the use of rhTSH results in an unimpaired lead to an increased radiation exposure through
quality of life [40–42]. A further advantage an increase in blood flow to the salivary glands,
of rhTSH is that it results in a lower radiation resulting in an increased I-131 uptake [51]. There
exposure to the remainder of the body, including is some clinical evidence that delaying the start
the bone marrow [43], the reproductive system of stimulation to at least 24 h after the ingestion
and the salivary glands [44, 45], thus at least in of I-131 may in fact lead to a lower rate of sali-
theory reducing the risk of complications. Over vary gland dysfunction [52].
time, many studies have shown the equivalence Less known than the damage to the salivary
of rhTSH to THW both for TSH-stimulated Tg glands is the damage that may be caused to the
testing with or without concurrent dxWBS [46] lacrimal glands by I-131 therapy, the latter occur-
and for initial I-131 ablation of patients with- ring with a much lower frequency. Nonetheless,
out distant metastases. Furthermore, rhTSH is the occurrence of both these phenomena is clearly
likely cost-effective from several points of view less frequent subjectively than objectively, with
[47, 48]. objective xerostomia occurring objectively in the
38 F. A. Verburg

great majority of patients even after only 3.7 GBq liferative tissue may in the long term contribute
I-131 (38/46 patients; [53]) and in all patients to the induction of malignant neoplasms.
after 14.8 GBq or more. However, only a minor- Recently, new data were published which
ity of patients complained of this in the lower showed again that it is not unlikely that I-131
activity groups. Xerophthalmia was present in a therapy of DTC may cause secondary haemato-
lower percentage of patients (9/46 objectively, logical malignancies [60, 61]. Although these
7/46 subjectively after 3.7 GBq I-131 to 3/5 sub- reports show a significant increase in the risk of
jectively and 4/5 objectively in patients receiving such secondary malignancies, these studies can
14.8 GBq I-131 or more; [53]). nonetheless also be regarded as evidence in sup-
port of radioiodine therapy in DTC.  As was
detailed in calculations by Piccardo et  al. [62],
3.4 Malignant Sequellae the data presented by Molenaar et  al. allow the
calculation of the absolute excess risk of haema-
Originally hailed in the popular press as a form tological malignancies in DTC patients treated
of magic, it quite soon became evident that even with I-131. This risk approximately amounts to
this very specific, targeted drug is not without one case per ten million patient years [62]. Even
its long-term side effects and complications. assuming that all these cases will result in a fatal-
First reports of acute myeloid leukaemia in ity—which is hardly likely the case—I-131 may
DTC patients treated with I-131 were already still compare favourably to not giving I-131, e.g.
published in the 1950s [54] by the group who by missing the diagnosis of and thereby timely
first introduced I-131 for DTC.  In the ensu- treatment of distant metastases when this treat-
ing decades, many more scientific publications ment modality is omitted. In fact, this excess risk
which examined the role of I-131  in inducing is so small as likely to be unnoticed in the indi-
secondary malignancies emerged with differ- vidual physicians’ life-long practice. So small in
ing results: some reports allege that I-131 does fact, that it may be less risky in terms of risk of
induce not only haematological but also possibly mortality to perform I-131 than to make a patient
solid malignancies [55], whereas others could drive to the attending physicians’ office more
show that excess non-thyroid malignancy rates often, than taking an aspirin [63], or many other
are observed in similar heights before as well as environmental risks from daily life.
after I-131, making a causal relationship with
I-131 unlikely [56].
Nonetheless, that exposure to radioactive 3.5 Haematological
iodine might cause an increase in the rate of sec- Complications
ondary haematological (or other) malignancies
is not implausible. I-131 will, after oral or i.v. As detailed above, I-131 may affect the red bone
application, first circulate systemically before marrow. Not only does this contribute to an ele-
being taken up in DTC cells. Well-perfused vated risk of secondary haematological malig-
organs such as the bone marrow are therefore nancies but also to a risk of impairment of bone
exposed to similar radiation absorbed doses as marrow function. Molinaro et al. detailed in 2009
the blood itself—as was already shown in the that one year after I-131 ablation, white blood
1960s [57]. As the red bone marrow is a highly cell and platelet count was still significantly
proliferative tissue, it is also highly sensitive to lower than at baseline, even though the difference
any DNA-damaging agents or interventions (this was minor and not clinically relevant [58]. Long-­
is not just limited to radiation, but may also term data were not reported by these authors.
include cytotoxic chemotherapy), which may Verburg et  al. reported on the effects of dosi-
cause a short-term depression in complete blood metrically determined high activities of I-131 on
cell counts (CBCs) [58, 59]. Furthermore, at blood cell counts and found that, although there
least in theory, DNA damage to this highly pro- was a marked but non-critical effect in the short
3  Radioiodine Therapy of Thyroid Cancer 39

term, there was no remaining drop in blood cell advisable to regularly monitor pulmonary func-
counts in the long term [59]. tion in patients with pulmonary metastases and
to refrain from further I-131 therapy in patients
in whom a reduction in pulmonary function is
3.6 Fertility suspected. Furthermore, safety of I-131 therapy
can be increased by performing a dosimetry
Just like the red bone marrow, especially male before administration of therapy, setting the
gonadal tissue cells are highly proliferative and limit at 3  GBq or 40  MBq per kg body weight
therefore generally susceptible to radiation. From whole body retention 48  h after administration
external radiation therapy, it is known that this of therapy.
effect is cumulative.
In men, after I-131 therapy effects like an
increased follicle stimulating hormone (FSH), an References
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Peptide Receptor Radionuclide
Therapy for Neuroendocrine 4
Tumors

Flavio Forrer

4.1 Introduction including carcinoid syndrome, hypoglycemia,


hyperglycemia, or Zollinger-Ellison syndrome.
Neuroendocrine tumors (NETs) are rare malig- The carcinoid syndrome (diarrhea, skin-flushing,
nancies originating from neural crest cells. These abdominal cramps, nausea, vomiting, and val-
cells belong to the amino precursor uptake and vular heart disease) is the most common clini-
decarboxylation (APUD) system and can there- cal syndrome and it is related to the production
fore accumulate and decarboxylate amine pre- of serotonin and histamine. Many tumors may
cursors. These cells can produce amines or remain asymptomatic for many years. In 20–50%
hormones, such as histamine, serotonin, adrena- of cases, the primary origin cannot be identified
line, gastrin, and somatostatin (SST) that contrib- and only liver or skeletal metastatic disease is
ute to the onset of symptoms [1]. On the basis of detectable [1]. However, the sensitivity of detect-
symptoms NETs can be classified as functional ing the primary increased significantly over the
(30–50%) and nonfunctional. Neural crest cells last years by improved imaging, in particular the
are characterized by the expression of neuroen- use of Ga-68-labeled somatostatin analogues for
docrine markers such as synaptophysin and chro- PET-imaging [4].
mogranin A [2]. More than 90% of NETs express somatostatin
Neuroendocrine cells are sparse throughout (SST) receptors [5]. SST is a peptide occurring
the whole body even though they are mainly con- in a 14-aminoacid isoform and in a 28-aminoacid
centrated in the gastrointestinal tract and the pan- isoform. SST is ubiquitous in the body, occurring
creas. Therefore NETs can originate in different prevalently in the central and peripheral nervous
parts of the body, mainly in the gastrointestinal system, the gut, and the endocrine glands. SST
tract (most frequently in jejunum, ileum, appen- exerts inhibitory effects on various hormonal
dix and rectum) and in the endocrine pancreas systems and physiological functions, including
(glucagonoma, insulinoma, vipoma, gastrinoma). cell growth. Five subtypes of the SST receptor
However, NETs may originate in other anatomi- (SST1–5) have been identified and cloned. There
cal sites as it is the case of bronchial carcinoid, are five human SST receptor subtypes (SST1–
neuroblastoma, and medullary thyroid cancer [3]. SST5); all are expressed on tumors to some
Secreting tumors may cause specific syndromes, extent, but SST2 is by far the most abundant,
whereas SST4 is seldomly found. In particular, in
neuroendocrine tumors SST2 is by far the most
F. Forrer (*) often expressed receptor subtype. As typically
Clinics of Radiology and Nuclear Medicine, SST2 is expressed homogeneously and in a high
Kantonsspital St. Gallen, St. Gallen, Switzerland
e-mail: flavio.forrer@kssg.ch

© Springer Nature Switzerland AG 2019 43


L. Giovanella (ed.), Nuclear Medicine Therapy, https://doi.org/10.1007/978-3-030-17494-1_4
44 F. Forrer

density makes this receptor an excellent target for over the last three decades as awareness of the
molecular radionuclide imaging and therapy [6]. disease and diagnostic techniques have improved.
This increase has been attributed primarily to the
detection of clinically silent disease [1].
4.2 Classification of Nets

Traditionally NETs were subdivided according to 4.4 Diagnosis


the section of the embryonal primitive gut from
which they originated, i.e., foregut, midgut, and The diagnosis of neuroendocrine tumor is typi-
hindgut [7, 8]. cally achieved through the complementary use of
However, nowadays a widely accepted, stan- laboratory and imaging techniques. Biochemical
dardized classification system for GEP NETs evaluation of secretory peptides and hormone
with implications for clinical management as should be performed. Computed tomography
well as for prognosis as introduced by Rindi et al. (CT), ultrasonography, angiography, and mag-
using a TNM classification system analogous netic resonance imaging (MRI) are often per-
to the TNM classification used for other solid formed subsequently. These techniques have good
tumors should be used [9]. Grading schemes for sensitivity but suffer from limited specificity.
neuroendocrine tumors (NETs) use mitotic count; Nuclear medicine techniques take advantage
the level of the nuclear protein Ki-67, which is of the strong overexpression of SST receptors on
associated with cellular proliferation; and assess- NETs. As mentioned previously, the expression
ment of necrosis. The World Health Organization is vastly higher than on non-tumor tissues [5, 15].
(WHO) and the European Neuroendocrine Tumor SST2 receptors are the target of radioactive trac-
Society (ENETS) both incorporate mitotic count ers used for somatostatin receptor scintigraphy
and Ki-67 proliferation for the classification of (SRS) or positron emission tomography (PET)/
gastroenteropancreatic NETs (GEP-NETs) [9, CT. For this reason, these techniques have higher
10]. In the 2010 World Health Organization clas- specificity than CT or MRI.  For SRS several
sification scheme NETs are classified as grade Indium-111 or Technetium-99m labeled com-
(G) 1 NETs, G2 NETs, neuroendocrine carcino- pounds are available. [111In-DTPA0]-octreotide
mas (NEC G3), and mixed adenoneuroendocrine (Octreoscan®), a specific radiolabeled agonist
carcinomas (MANEC). Histologic grades are for SST receptors that binds preferably to SST2
dependent on mitotic counts and the Ki-67 label- receptors, is the best characterized compound.
ing index. In the most recently published 2017 However, SRS suffers from sensitivity for lesions
revision for pancreatic neuroendocrine tumors inferior to 1 cm also when tomographic acquisi-
NEC G3 are subdivided into neuroendocrine tion (SPECT or SPECT/CT), rather than planar
tumors NET G3 and neuroendocrine carcinoma acquisition, is performed. Overall SRS has a
NEC G3 [11]. sensitivity of approximately 57–77% for non-­
insulinomas and 25% for insulinomas [16].
Nowadays PET/CT can be regarded as the
4.3 Epidemiology gold standard for well-differentiated neuroen-
docrine tumors. DOTA peptides labeled with
NETs are considered as rare tumors. However, [68Ga] are most frequently used. These include
the incidence is about up to five cases per 100,000 [68Ga]DOTATOC, [68Ga]DOTANOC, and [68Ga]
inhabitants, and since 5-year survival rates in DOTATATE [17]. All DOTA peptides bind to
patients with NETs, irrespective of stage of dis- SST2 and with varying affinity to SST5 receptors
ease, are over 60% [8, 12–14], this results in a as well. An example of [68Ga]DOTATATE ­PET/
considerable prevalence. Non-localized disease CT of a patient suffering from a metastatic NET
at diagnosis occurs between 22% and 47% of G1 of the small bowel is shown in Fig. 4.1.
patients [12, 13]. Moreover, the prevalence and Using another mechanism of accumulation
incidence of NETs have increased substantially 3,4-dihydroxy-6-18F-fluoro-L-phenylalanine
4  Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors 45

Fig. 4.1  68Ga-DOTATATE PET/CT of a patient with met- lymph nodes. Panel (b) is a representative axial slice of
astatic NET G1 of the small bowel. Panel (a) shows the the combined PET/CT through the abdomen. Intense
maximum intensity projection (MIP) data. There is evi- focal uptake can be seen in two liver metastases in seg-
dence of several liver metastases as well as of a focus on ment 4a and 7. High, physiological uptake is seen in the
right thoracic side. Physiological uptake is seen in the spleen. A soft tissue metastases in the right teres major
pituitary gland, in the salivary glands, in the thyroid, in the muscle is presented in Panel (c). This lesion was diag-
liver, in the spleen, in the adrenals, and in the gall bladder. nosed on the PET scan. Only retrospectively a corre-
Additionally there is unspecific uptake in the bowel. sponding focal contrast media accumulation was seen on
Inguinal there is evidence of uptake in inflammatory the CT scan

(18F-DOPA), an aromatic amino acid that is being 4.5  herapy (Except Peptide
T
trapped within neurotransmitter vesicles of NETs, Receptor Radionuclide
can be used for diagnosis and staging as well with Therapy)
high sensitivity and specificity. However, in contrast
to the SST binding compounds 18F-DOPA is not suit- Treatment is typically individualized and based
able to select patients for radiopeptide therapy [18]. on tumor stage, tumor burden, and symptoms
However, imaging can only provide local- [19–24]. The best therapeutic choice for individ-
ization of tumor lesions and demonstrate the ual patients will depend on whether the main aim
presence of SST.  Therefore, ultimate diagnosis of treatment is to slow tumor growth, to amelio-
requires histological demonstration of NETs rate symptoms by inhibition of the secretion of
after surgery or biopsy [11]. bioactive agents, or cure. An additional difficulty
46 F. Forrer

lies in the fact that there are no well-defined cri- shown effective in significantly reducing the
teria to anticipate which tumors will respond to a tumor load [32].
particular modality or to assess rigorously thera- In the last years, the efficacy of molecular tar-
peutic efficacy. geting therapies for the therapy of NETs has been
Surgery is essential for many patients with investigated. These treatments include angiogen-
NETs. In patients with limited disease burden, esis inhibitors, single or multiple tyrosine kinase
surgery represents the primary method of cure inhibitors, and the SST analogue pasireotide. The
[25]. For patients with advanced disease, cytore- drugs with the highest evidence of efficacy are
ductive surgery should be considered to increase sunitinib and everolimus (RAD-001). Both lead
the quality of life. The major limit to surgery is to extension of progression-free survival (PFS)
that more than 80% of patients have lymph node of patients with advanced pancreatic NET.  For
or liver metastases at the time of diagnosis [8, 26]. everolimus, an mTOR inhibitor, there is evidence
Therapy with SST analogs, such as octreotide and of efficacy in controlling NET arising from other
lanreotide, reduced amine production in function- sites associated with the carcinoid syndrome
ally active NETs. SST analogues were shown to [33]. The most developed antiangiogenic drugs
significantly lengthen time to tumor progression are sunitinib and the anti-VEGF antibody beva-
compared with placebo in patients with function- cizumab. In a phase II study bevacizumab in
ally active and inactive metastatic midgut NETs combination with octreotide LAR led to partial
and are considered to be the first-­line therapy in tumor remission in 18% of patients and stable
metastatic, well-differentiated tumors that cannot disease in 77% [34]. An international phase III
be cured by surgery [27]. The most effective and study of sunitinib versus placebo in patients
patient-friendly drugs are represented by long- with progressive, well-differentiated endocrine
acting octreotide acetate (Sandostatin LAR®) and pancreatic tumor was interrupted prematurely
lanreotide autogel (Somatuline®). SST analogues due to the striking superiority of sunitinib evi-
have a wide therapeutic range and are apparently dent by a PFS of 11.1 vs. 5.5 months [35]. The
free from major side effects. Minor gastrointes- objective remission rate was less than 10%.
tinal side effects are generally reported [27, 28]. The drug is approved by the US FDA and the
Interferon-α may also be used for therapeutic European Medicines Agency for the treatment
purposes. However, side effects are prominent of advanced and progressive well-differentiated
for interferon-α, which limits its clinical use. A pancreatic NETs. Everolimus has been studied in
randomized study using lanreotide alone or in more than 1000 patients with NET and has been
combination with interferon-α reported a 5% par- included in several clinical trials (RADIANT-1,
tial response rate and a 25% stable disease rate RADIANT-2, RADIANT-3 trials, RAMSETE
over 12 months [29, 30]. trial). Antitumor activity of everolimus has been
Chemotherapy is performed using several confirmed in RADIANT-1  in patients with pro-
drugs, including streptozotocin in combination gressive metastatic pancreatic NETs after failure
with fluorouracil or doxorubicin, cisplatin and of at least one line of cytotoxic chemotherapy.
etoposide, and dacarbazine. Recently, some The trial studied 160 patients divided into two
new chemotherapeutic agents have come into groups with or without monthly intramuscu-
use, such as temozolomide, oxaliplatin, and lar octreotide acetate therapy. The combination
capecitabine [31]. Chemotherapy has been rec- therapy showed s­ignificantly longer PFS (16.7
ommended only for patients with poorly dif- vs. 9.7  months) [36]. The efficacy of everoli-
ferentiated or rapidly progressing NETs or for mus has been confirmed in a large international
patients that do not respond to SST analogues placebo-controlled trial, including 410 patients
or interferon-α. With reference to histologi- with progressive pancreatic NET (RADIANT-3)
cal types, chemotherapy is indicated especially [37]. Everolimus significantly reduced the risk of
in patients with pancreatic NETs, where it was disease progression and led to a prolongation of
4  Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors 47

PFS by 6.4 months (11 vs. 4.6 months) compared 4.6.1 Contraindications


to placebo. Objective tumor response was low
(4.8% partial remissions). Disease control rate All contraindications must be considered in the
(partial response + stable disease) was, however, context of the other therapeutic options avail-
higher with everolimus than with placebo with able, the patient’s life expectancy, and whether
best supportive care (77.7% vs. 52.7%). Side the intent of treatment is symptom palliation or
effects were rarely grade 3 or 4; the most fre- oncological control. Most are relative rather than
quently reported side effects included stomatitis, absolute contraindications.
anemia, and hyperglycemia. Pregnancy or ongoing lactation is regarded as
Pain control in patients with NET is important an absolute contraindication. With regard to the
when treating such patients. Pain therapy follows health status severe hepatic impairment indicat-
the general principles in oncology [38]. ing biosynthetic liver failure (i.e., total biliru-
bin >3 upper limit of normal or both an albumin
<25  g/L and prothrombin time increased >1.5
4.6 Peptide Receptor upper limit of normal) and severe cardiac
Radionuclide Therapy impairment (New York Heart Association
grade III or IV) are considered as absolute
Peptide receptor radionuclide therapy (PRRT) contraindications.
is another very attractive option for patients In the individual patient’s context relative con-
with metastatic NETs. Typically patients with traindications are:
progressive disease or symptomatic disease in
whom surgery is no longer feasible are regarded • Significant sites of active disease as deter-
as suitable candidates for this treatment modality mined by unequivocal contrast-enhancing
[39]. PRRT is attractive because it is a systemic lesions on CT or MRI that lack SSTR expres-
therapy that targets all SST-positive lesions, i.e., sion, which can be confirmed by 18  F-FDG
the primary tumor as well as distant metastases, PET/CT if available (use of concomitant che-
and it is generally well tolerated by the patients. motherapy may be an option in such cases).
Careful selection of patients is necessary to • Moderate to severe renal impairment (i.e., cre-
optimize the effects and minimize the potential atinine clearance <50  mL/min) patients on
side effects of PPRT. PRRT is indicated only in dialysis can be treated with a reduced admin-
patients with histologically documented inop- istered activity to account for lack of urinary
erable disease. The primary selection criterion excretion with dialysis delayed for 24 h after
is evidence of SST2 receptors overexpression treatment, subject to consultation with the
by SST receptor imaging, either convention- managing nephrology team.
ally or by PET/CT with 68Ga-labeled peptides. • Impaired hematological function, i.e., Hb
The intensity of tumor uptake must be equal or <5  mmol/L (8  g/dL); platelets <75. 10 9/L;
higher than in normal liver [40]. Traditionally, white blood cell count <2. 10 9/L$.
patients with evidence of progression of disease • Moderate to severe right heart valvular disease
on CT or SRS have been referred to SRS. More (valve replacement is strongly encouraged
recent data showed that the efficacy of therapy prior to PRRT; in such cases, please refer to
is greater in patients with stable disease than in the guidelines for the management of carci-
patients with progressive disease [41–44], which noid heart disease).
indicated that patients with stable disease should
also be considered for PRRT.  Life expectancy Prior to PRRT and before each therapy cycle
greater than 3  months is a further requirement the following laboratory tests are required:
for treatment. Beside these selection criteria
there is a number of contraindications which • Hematology: hemoglobin, white blood cell
have to be respected: count plus differential, platelet number.
48 F. Forrer

• Kidney function: creatinine and urea with for- The first radiopharmaceutical used in pep-
mal creatinine clearance if abnormal. tide receptor radionuclide therapy (PRRT) was
• Liver function: bilirubin, albumin, ALP, GGT, [111In-DTPA0]-octreotide. This peptide has been
ALT, AST, INR. used since the 1980s for NET diagnosis and stag-
• Electrolytes: serum potassium and corrected ing through SRS. [111In-DTPA0]-octreotide was
serum calcium. used for therapy purpose with activities between
• LDH. 10 and 160  GBq, sizably higher than the activ-
ity (185–222 MBq) used for diagnostic purposes
Additionally it is recommended to moni- [47]. The rational for its use was represented by
tor Chromogranin A and other secretory prod- the fact that, in addition to the gamma-radiation,
ucts including specific hormones, if elevated at which makes 111In suitable for imaging with a
baseline. gamma-camera, 111In emits Auger electrons.
Auger electrons are low-energy electrons with
a very short tissue penetration range of 0.02–
4.6.2 Radiopharmaceuticals 10 μm. Auger electrons have a cytotoxic potential
that requires close proximity of the 111In-labeled
There are different radiopharmaceuticals that may peptide within the nucleus by interacting with the
be used for PRRT.  However, 177Lu-DOTATATE DNA after receptor internalization [48, 49].
([177Lu-DOTA0,Tyr3,Thr8]-octreotide or Although Auger electrons do not display opti-
[177Lu-DOTA0,Tyr3]-octreotate) is the only FDA- mal therapeutic characteristics, [111In-DTPA0]-
approved compound for therapeutic purposes. octreotide was chosen because at that time no
In general, each radiopharmaceutical that other chelated SST analogue was available and
can be used for PRRT is composed by a pep- DTPA itself was not a suitable chelator for the
tide, which binds to the biological target (SST β-emitting radionuclides. Compared to other
receptor), an isotope, that delivers the radio- SST-analogues [111In-DTPA0]-octreotide has only
activity to the tissue, and by a bifunctional a moderate affinity for SST2 receptors. An over-
chelator that is being used to connect the view of the different affinity profiles is given in
radioactive isotope and the peptide by making Table 4.1.
a stable complex between these molecules. In Over time other peptides with higher affin-
vitro studies showed that following the bind- ity towards SST receptors were synthesized
ing with an agonist, the SST receptor under- and used in PRRT.  The peptides include [Tyr3-­
goes internalization. Internalization occurs octreotate] and lanreotide. A major break-
as fast as within 3  min, is extremely efficient through was achieved by the conjugation of
(most of the cell surface receptors are found SST-­analogues with the chelator DOTA (1,4,7
in endosome-like structures), and is revers- ,10-­tetraazacyclododecane-­1,4,7,10-tetraacetic
ible (24  h after the receptors are again found acid). DOTA has, in comparison to DTPA, better
at the cell surface) [45]. Following internal- characteristics to stably bind beta (β-) emitting
ization, the radioactive peptide is trapped in nuclides (90Y and 177Lu) as well as for positron
the cell and exerts cytotoxic damages. SST2 (β+) emitting nuclides, and permits the use of
receptor antagonists do not induce internaliza- such nuclides for therapy and imaging purposes
tion. However, some recently published stud- [50, 51]. The available peptides have different
ies indicate that the tumor-to-background ratio affinities towards the various SST receptors. The
might be even higher when using antagonists affinity of a compound is significantly affected
[46]. Theoretically this should result in a higher not only by the chelator but also by the radionu-
tumor absorbed dose without identical or even clide bound [52, 53]. The physical characteristics
reduced toxicity. However, prospective or com- of the different radionuclides used in PRRT are
parative studies are still lacking. presented in Table 4.2.
4  Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors 49

Table 4.1  Affinity profiles (IC 50) for human sst1–sst5 receptors of a series of somatostatin analogues
Peptide sst1 sst2 sst3 sst4 sst5
Somatostatin-28 5.2 ± 0.3 (19) 2.7 ± 0.3 (19) 7.7 ± 0.9 (15) 5.6 ± 0.4 (19) 4.0 ± 0.3 (19)
Octreotide >10,000 (5) 2.0 ± 0.7 (5) 187 ± 55 (3) >1000 (4) 22 ± 6 (5)
DTPA-octreotide >10,000 (6) 12 ± 2 (5) 376 ± 84 (5) >1000 (5) 299 ± 50 (6)
In-DTPA-octreotide >10,000 (5) 22 ± 3.6 (5) 182 ± 13 (5) >1000 (5) 237 ± 52 (5)
DOTA-TOC >10,000 (7) 14 ± 2.6 (6) 880 ± 324 (4) >1000 (6) 393 ± 84 (6)
Y-DOTA-TOC >10,000 (4) 11 ± 1.7 (6) 389 ± 135 (5) >10,000 (5) 114 ± 29(5)
DOTA-LAN >10,000 (7) 26 ± 3.4 (6) 771 ± 229 (6) >10,000 (4) 73 ± 12 (6)
Y-DOTA-LAN >10,000 (3) 23 ± 5 (4) 290 ± 105 (4) >10,000 (4) 16 ± 3.4 (4)
DOTA-OC >10,000 (3) 14 ± 3 (4) 27 ± 9 (4) >1000 (4) 103 ± 39 (3)
Y-DOTA-OC >10,000 (5) 20 ± 2 (5) 27 ± 8 (5) >10,000 (4) 57 ± 22 (4)
Ga-DOTA-TOC >10,000 (6) 2.5 ± 0.5 (7) 613 ± 140 (7) >1000 (6) 73 ± 21 (6)
Ga-DOTA-OC >10,000 (3) 7.3 ± 1.9 (4) 120 ± 45 (4) >1000 (3) 60 ± 14 (4)
DTPA-[Tyr3]-octreotate >10,000 (4) 3.9 ± 1 (4) >10,000 (4) >1000 (4) >1000 (4)
DOTA-[Tyr3]-octreotate >10,000 (3) 1.5 ± 0.4 (3) >1000 (3) 453 ± 176 (3) 547 ± 160 (3)
In-DTPA-[Tyr3]-octreotate >10,000 (3) 1.3 ± 0.2 (3) >10,000 (3) 433 ± 16 (3) >1000 (3)
Y-DOTA-[Tyr3]-octreotate >10,000 (3) 1.6 ± 0.4 (3) >1000 (3) 523 ± 239 (3) 187 ± 50 (3)
Ga-DOTA-[Tyr3]-octreotate >10,000 (3) 0.2 ± 0.04 (3) >1000 (3) 300 ± 140 (3) 377 ± 18 (3)
All values are IC 50 ± SEM in nM. The number of experiments is in parentheses
Reported after Reubi et al. [53]

Table 4.2  Physical properties of the most common radionuclides used in PRRT
Isotope Half-­life (d) Decay mode Energy Range (max)
111
In 2.81 Auger 0.5–25 keV 10 μm
γ Eγ: 0.173 MeV (87%), 0.247 MeV (94%)
90
Y 2.67 β- Emax: 2.28 MeV Emean: 0.935 MeV Rmax: 11.3 mm Rmean: 4.1 mm
177
Lu 6.71 β- Emax: 0.497 MeV Emax: 0.149 MeV Rmax: 2 mm Rmean: 0.5 mm
γ Eγ: 0.113 MeV (6%), 0.208 MeV (11%)

4.6.3 S
 tudies Using [111In-DTPA0] [57]. Valkema et  al. in the Rotterdam study
octreotide treated 50 patients with different histologi-
cal NETs with cumulative activities of at least
[111In-DTPA0]octreotide, developed initially for 20 GBq up to 160 GBq. PR was detected in 2%
diagnosis [54], was the first radiolabeled SST of patients, MR in 15% of patients, and stabiliza-
analogue used for PRRT in cumulative activities tion of previously progressive tumors in 34% of
ranging from 3.1 to 160 GBq [55–59]. Treatment patients [56].
with high activities often led to symptomatic In the New Orleans study Anthony et  al.
relief; however, tumor shrinkage was rarely reported objective partial radiographic responses
achieved and the number of objective responses in 2/26 (8%) patients with metastatic NETs
was low. The first clinical trial of [111In-DTPA0] treated with [111In-DTPA0]octreotide and total
octreotide for treatment of NETs was performed cumulative activities of about 2  GBq. CT signs
by Krenning et  al. in the Netherlands in 1994. of partial tumor necrosis were detected in 7/26
Preliminary data from this study demonstrated (27%) patients. Moreover, they reported a
the safety of repeated treatments with 333– median survival of 18  months. This value was
666  MBq of [111In-DTPA0]octreotide admin- sizably longer than the expected survival based
istered every 3  weeks for 10  cycles. Tumor on data obtained from historical controls treated
response correlated with receptor expression with nonradioactive octreotide, indicating that
50 F. Forrer

treatment with 111In-pentetreotide might prolong bound in a sufficient stable way by DTPA [61].
survival in GEP NETs [58]. 90
Y as well as 177Lu are “bone seekers,” i.e., free
The most common toxicity was due to bone radionuclides would accumulate in the bone which
marrow suppression. In the study by Valkema consecutively would lead to a high absorbed dose
et al. serious side effects consisted of leukemia to the bone marrow. DOTA is the most frequently
and myelodysplastic syndrome in 3/50 (6%) used chelator in PRRT. DOTA has the ability to
patients who had been treated with total cumula- bind 90Y as well as 177Lu stably under various con-
tive activities of >3.7 GBq (and estimated bone ditions [62].
marrow radiation doses of more than 3 Gy). One The very first report on PRRT using
of these patients had also been treated with che- 90
Y-DOTATOC was published in 1997 by the
motherapy, which may have contributed to or group at Basel University [63]. Biodistribution
caused this complication [56]. Anthony et  al. and clearance of 90Y-DOTATOC were superior to
reported renal insufficiency in one patient, which [111In-DTPA0]octreotide. The kidney-to-tumor
was probably not treatment-related, but due to ratio was 1.9 times lower for 90Y-DOTATOC
preexistent retroperitoneal fibrosis. Transient than for [111In-DTPA0]octreotide. One of the
liver toxicity was observed in three patients with three treated patients received therapeutic
widespread liver metastases [58]. activities (3  GBq) of 90Y-DOTATOC.  Tumor
In another study that was published some progression was stopped in this patient as
years later in NET patients treated with up to shown by follow-up diagnostic studies with
38 GBq in two treatment cycles 53% of patients [111In-DTPA0]octreotide. The patient also ben-
had grade I or II hematological toxicities, and 3% efited clinically from the therapy as lower back
of patients had grade III thrombocytopenia. One and abdominal pain disappeared. These results
patient (3%) had grade II liver toxicity, which were considered particularly promising consid-
appeared 4  weeks after therapy and resolved in ering that this patient had rapidly progressing
the following week. No patient had renal toxic- liver and skeletal metastatic disease unrespon-
ity. The toxicity profile of 111In-pentetreotide was sive to chemotherapy [63]. One year later the
encouraging as the maximum tolerated dose was same group reported the results obtained in a
not achieved in any previously published studies, larger sample of 10 patients. Overall 50% of
and it is possible that larger quantities of radioac- patients experienced a PR and 50% experienced
tivity can be administered safely [59]. a SD [64].
Overall the results obtained with [111In-DTPA0] The first study in a large population was pub-
octreotide were encouraging, especially when lished in 1999 [65]. Otte et al. treated 29 patients
seen in the context of the results that can be with escalating activities of 90Y-DOTATOC in
achieved with other therapy modalities like che- an interval of 6 weeks. Patients received a mean
motherapy [60]. Nevertheless, it appeared that the cumulative activity of 6.1 GBq/m2. They found
antitumor effect of [111In-DTPA0]octreotide is not that 69% of patients showed disease stabilization,
ideal for macroscopic tumors. 7% a partial remission, 14% a reduction of tumor
mass  <  50%, and 10% a progression of tumor
growth [65].
4.6.4 S
 tudies Using [90Y-DOTA0,Tyr3] Few years later, the group of Basel reported the
octreotide (90Y-DOTATOC), results of their first phase-II study [66]. Forty-­one
[90Y-DOTA]lanreotide patients with neuroendocrine GEP and bronchial
and [90Y-DOTA0,Tyr3]octreotate tumors were included. 82% of the patients had
therapy-resistant, progressive disease. The treat-
In order to improve the antitumor effect, subse- ment consisted of four intravenous injections of a
quent studies were performed with 90Y-labeled total of 6 GBq/m2 90Y-DOTATOC, administered at
SST analogues. With the introduction of 90Y the intervals of six weeks. The overall response rate
need of a new chelator arose since it cannot be was 24%. The response rate was higher (36%) in
4  Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors 51

patients with endocrine pancreatic tumors. CR who were given the planned activity, 3 patients
was found in 2%, PR in 22%, MR in 12%, SD had PR, 3 patients had MR, 17 had SD, and 9
in 49%, and PD in 15%. The median follow-up had PD.
was 15  months. The survival at two years was Chelated lanreotide, another SST analogue,
76% (95% confidence interval was 60%–92%). labeled with 111In for diagnostic purposes and
Eighty-three percent of the patients suffering with 90Y for therapeutic use, has been advocated
from the malignant carcinoid syndrome achieved because of its better binding than [111In-DTPA0]
a significant reduction of symptoms. A reduction octreotide to the SST receptor subtypes 3 and 4
of pain score was observed in all patients taking [71]. This claim can be questioned [53]. Although
morphine [66]. The OR in a following study with this compound has been used to treat patients with
different patients was 23% [67]. Similar results GEP tumors, it shows poorer affinity than either
were found in a more extensive study includ- DOTATOC or DOTATATE for SST2 receptors,
ing 116 patients, who were treated with 6.0– which are predominantly overexpressed in GEP
7.4 MBq/m2 body surface (CR = 4%, PR = 23%, tumors.
SD = 62% and PD = 11%) [68]. 90
Y-lanreotide was investigated in a European
The research group from the European multicenter trial (MAURITIUS), in 154 patients
Cancer Institute in Milano used a higher range administered with cumulative treatment activi-
of cumulated activity (5.9 to 11.0  GBq in ties ranging from 1.9 to 8.6 GBq of 90Y-DOTA-­
2  cycles) in 21 patients with NETs, achieving lanreotide. Therapy entry criterion was
an OR of 29%. All patients received amino acid progressive disease at the time of planned ther-
infusion [69]. In a subsequent report extended to apy. Preliminary treatment results in 154 patients
141 patients with various SST-positive tumors, indicated SD in 41% (63 of 154) of patients and
an OR of 26% (CR = 4%, PR = 22%) and a SD PR in 14% (22 of 154) of tumor patients. No
of 56% was reported. Interestingly, the favor- severe acute or chronic hematological toxic-
able response rates were higher in patients ity, change in renal or liver function parameters
that presented with stable disease before ther- caused by 90Y-DOTA-lanreotide treatment were
apy (OR  =  32%, SD  =  64%) than in patients reported [71].
that were already progressive before therapy Cwikla reported on the effect of
(OR = 23%, SD = 53%) [42]. 90
Y-DOTATATE treatment in 60 patients with
Long-term follow-up and survival data for histologically proven GEP NETs [72]. Clinical
90
Y-DOTATOC were published by Valkema et al. responses were assessed 6 weeks after completing
from the group at the University of Rotterdam therapy and then after each of the 3- to 6-month
[43]. In this study 58 patients were treated with intervals. Patients were treated with up to a cumu-
1.7–32.8 GBq of 90Y-DOTATOC. The response lative activity of 15.2  GBq. At 6  months after
rates were comparable to other studies using final treatment, radiological PR was observed
90Y-labeled SST analogues, but in addition a sig- in 13 patients (23%), and the remaining patients
nificant longer overall survival was shown com- had SD. Median progression-free survival (PFS)
pared to a group of historical controls treated with was 17 months, while the median overall survival
[111In-DTPA0]octreotide (37 vs. 12.0  months, (OS) was 22  months. In patients with early PD,
respectively). Interestingly, overall survival was the PFS was 4.5 and OS 9.5  months, while in
significantly better in patients who had SD at those with SD or PR, PFS and OS were 19.5 and
baseline vs. patients who had PD at baseline, 23.5 months, respectively.
in patients without liver metastases vs. patients In summary, OR rates in patients treated
with liver metastases, and in patients with high with 90Y-DOTATOC, 90Y-DOTATATE, and
Karnofsky performance score vs. patients with 90
Y-DOTA-­ lanreotide were in range between
low Karnofsky performance score. 6% and 37% despite differences in the pro-
The same group evaluated 42 patients with tocols used. These results and the prolonged
NETs within a phase I protocol [70]. In 32 patients overall survival represent an improvement in
52 F. Forrer

therapeutic effectiveness compared to the stud- The NETTER-1 trial involved a 1: 1 random-
ies with [111In-DTPA0]octreotide. ization of 229 patients with progressive meta-
static small intestinal NET on 30  mg monthly
Sandostatin LAR to either 177Lu-DOTA-
4.6.5 Studies Using octreotate with continuing Sandostatin LAR
[177Lu-DOTA0,Tyr3]octreotate at 30  mg per month or to dose escalation of
(177Lu-DOTATATE) Sandostatin LAR to 60 mg monthly. The PRRT
and [177Lu-DOTA0,Tyr3] protocol involved 4 cycles of 7.4 GBq (200 mCi)
octreotide (177Lu-DOTATOC) of 177Lu-DOTAoctreotate at 8 weekly intervals.
Most (77%) patients received all planned cycles
In 2003, the first study with 177Lu-DOTATATE of treatment. For the PRRT arm, a median
was published [44]. In this study 35 patients PFS was not reached compared to 8.4  months
with GEP NETs were treated with escalat- (p  <  0.001) for dose-escalated Sandostatin
ing dosages up to a final cumulative activity of LAR.  All predefined subanalysis groups had
22.2–29.6 GBq. An OR of 38% was found. The improved PFS with 177Lu-DOTA-­octreotate
effects of the therapy on tumor size were assessed compared to controls. Although the relatively
in 34 patients. Three months after the last admin- short duration of follow-up at the time of publi-
istration, CR was found in 1 patient (3%), PR in cation limited assessment of OS in either group,
12 (35%), SD in 14 (41%), and PD in 7 patients interim analysis indicated that the estimated risk
(21%), including three patients who died dur- of death was 60% lower in the 177Lu-DOTA-
ing the treatment period. Tumor response was octreotate group than in the control group (haz-
positively correlated with a high uptake on the ard ratio 0.40; p = 0.004). The objective response
octreoscan, limited hepatic tumor mass, and a rate was 18 versus 3% (p < 0.0004). Grade 3 or
high Karnofsky Performance Score. No serious 4 neutropenia, thrombocytopenia, and lympho-
side effects were reported. penia occurred in 1, 2, and 9% of patients in the
In a later evaluation 310 patients were PRRT arm versus none in controls. One case of
treated with up to a cumulative activity of MDS was attributed to PRRT.
27.8–29.6 GBq, usually in four treatment cycles, The most commonly reported acute side
with treatment intervals of 6–10 weeks. Serious effects of PRRT were nausea and vomiting.
adverse events that were likely attributable to These occurred primarily during amino acid infu-
the treatment were myelodysplastic syndrome sion given for renal protection and resolved with
in three patients, and temporary, nonfatal, liver cessation of the infusion. In this trial, commercial
toxicity in two patients. Complete and partial amino acid solutions (Aminosyn II 10% [21.0 g
tumor remissions occurred in 2% and 28% of of lysine and 20.4 g of arginine in 2 L of solu-
310 NETs patients, respectively. Minor tumor tion] or VAMIN-18 [18 g of lysine and 22.6 g of
response occurred in 16% of patients. Thus, OR arginine in 2 L of solution]) were administered.
occurred in 46% of patients. Compared with his- These solutions are more concentrated than those
torical controls, there was a survival benefit of used in most institutional trials, which typically
40–72 months from diagnosis [73]. include only lysine and arginine.
Use of anti-emetic medication was not
reported but is an effective means to reduce these
4.6.6 T
 he First Randomized side effects. Although these results are entirely
Controlled Trial of PRRT: in keeping with other phase I–II institutional
NETTER-1 trials and retrospective analyses of single insti-
tutional experience, final analysis of the longer-
The first results of the to date only reported term toxicity, quality of life, and patient outcome
randomized trial concerning the efficacy data are not yet available through peer-reviewed
of PRRT have recently been reported [74]. publication.
4  Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors 53

Some months later the same group proofed that PRRT with radiosensitizing chemotherapy, which
in addition to improving progression-free survival, has been called peptide receptor chemoradionu-
177
Lu-Dotatate provides a significant quality-of- clide therapy (PRCRT), have shown that this is
life-benefit for patients with progressive midgut feasible with minimal incremental toxicity. This
NETs compared with high-dose octreotide [75]. approach has included studies with infusion of
5-fluorouracil or administration of its oral pro-­
drug, capecitabine [81–84], and a further study
4.6.7 Studies Combining using capecitabine and temozolomide [85].
Radionuclides and Utilizing While according to the data available safe and
Radiosensitizing efficacious, there are currently no data confirming
Chemotherapy whether PRCRT is superior to PRRT. The ratio-
nale for combining chemotherapy with PRRT is
Many trials mentioned above and other institu- strongest for higher-grade NEN.  In lower-grade
tional series suggest that treatment with radio- NETs, which would be expected to have longer
labeled somatostatin analogues is an effective survival independent of therapeutic effects, the
therapeutic modality in the management of patients potential benefits of chemotherapy need to be
with inoperable or metastasized NETs. However, a balanced against the risks of inducing MDS or
significant variability remains in the approach to leukemia, which may be more likely when an
delivering this therapy. While the NETTER-1 trial alkylating agent like temozolomide is used [86].
used a fixed administered activity of 177Lu-DOTA-
octreotate, others have used variable adminis-
tered activities, different radionuclides, routes of 4.6.8 Re-treatment
administration, and intervals between treatments.
Eligibility criteria have also varied. A variation In patients who responded to PRRT the ques-
in the treatment protocol has included the use of tion arises whether re-treatment is useful in
combinations of different radionuclides to opti- case of relapse. The first study dealing with re-
mize delivery to lesions of different sizes. For treatment in PRRT reported the results of using
example, 90Y has theoretical advantages for lager 177
Lu-DOTATOC in 27 patients after relapse
lesions with more heterogeneous uptake due to its from 90Y-DOTATOC therapy. Inclusion crite-
long β-particle path length whereas 177Lu is bet- ria was that the patients achieved at least a SD
ter suited to smaller lesions [76]. Accordingly, after 90Y-DOTATOC treatment and thereafter
using these isotopes in combination might provide were progressive again. After restaging, PR in
better radiation dose delivery across the range 2 patients, MR in 5 patients, SD in 12 patients,
of lesion sizes that is often present in individual and PD in 8 patients was found. It was concluded
patients. Indeed, results of combination therapies that 177Lu-DOTATOC therapy in patients with
are encouraging [77, 78]. Similarly, although most relapse after 90YDOTATOC treatment is fea-
PRRT have involved intravenous administration, sible, safe, and efficacious [87]. Frilling et  al.
liver-dominant disease may benefit from hepatic treated with 177Lu-DOTATOC 20 patients with
arterial administration [79] but no prospective metastatic non-resectable NETs refractory to
comparison studies are currently available. 90
Y-treatment. In eight patients the treatment was
While a standardized approach is likely to repeated more than once. No serious adverse
better meet the regulatory requirements for reim- events were documented. After restaging, a PR
bursement, the need for a more individualized was found in 5 patients, SD in 11 patients, and
approach has also been argued [80]. This includes PD in 4 patients [88].
the potential use of PRRT in combination with A study from the National Cancer Institute
other therapies in a manner analogous to chemo- in Milano reported feasibility and utility of re-­
radiation, which is now widely used in the treat- treatment with 177Lu-DOTATATE in GEP-NENs
ment of various solid tumors. Studies combining relapsed after treatment with 90Y-DOTATOC.
54 F. Forrer

Twenty-six patients were enrolled and the dis- Radiation Dose (MIRD) formalism to calculate
ease control rate was found to be 84.6%. They dosimetry estimates. Commercially available
concluded that patients with GEP-NEN who have software such as MIRDOSE or OLINDA are pro-
previously responded to Y-PRRT are suitable vided with internal model about anatomy (stan-
candidates for Lu-PRRT re-treatment on progres- dard man and woman) and radiopharmaceutical
sion [89]. distribution (uniformity of uptake in source and
target) [91].
Although these models are not necessar-
4.6.9 Dosimetry ily valid in individual patients, they do provide
a practical and standardized model for clini-
Radiation dosimetry aims at calculating the cal end-­users [90]. Dosimetric studies showed
amount of radioactivity absorbed dose by tis- that the median absorbed dose was higher in
sues following PRRT.  The absorbed radiation responsive tumors than in nonresponsive tumors
dose is expressed in grays (Gy), i.e., the amount (230  Gy vs. 40  Gy, respectively); a linear rela-
of transferred energy in Joule per Kg. The ratio- tionship between absorbed dose and develop-
nal of dosimetry stems from the assumption ment of toxicity has not been observed [92].
that patients should be treated with the highest Moreover, clinical trials evidenced large patient
possible activity that does not cause significant variability regarding target and nontarget uptake,
toxicity. The higher the absorbed dose to the and inhomogeneity of uptake within tumor sites
tumor, the greater is the likelihood of a signifi- [93, 94]. For these reasons and for the relative
cant therapeutic effect. However, the dose must complexity in the execution of lengthy dosimet-
not be so high to induce clinically important ric studies, the clinical usefulness of personal-
organ toxicity. Individual patient dosimetry has ized dosimetry has been debated and many
the following goals: (1) to quantify minimum institutions use fixed amount of radioactivity
effective and maximum tolerated effective to all patients or activities based on kg or m2 of
doses; (2) to establish a dose-response relation body surface. It has been stated that “claims for
to predict tumor response and normal organ specific dosimetry have to demonstrate that the
toxicity; and (3) to objectively compare the frequency of excess toxicity and/or tumor under-
dose-response results of different radionuclide dosing significantly decreases” [95]. Dosimetry
therapies [90]. should provide a quantification procedure that is
Radiation dosimetry requires knowledge of primarily of additional benefit over empirical,
the kinetics of the radiopharmaceutical in differ- fixed dosing [90].
ent body compartments so that a mathematical
model may be developed relating the concentra-
tion of the tracer in tissue compartments to tissue 4.6.10 Dosimetry for 90Y- and 177Lu
absorbed dose. Several planar or tomographic
acquisitions are performed starting from tracer The most commonly used 90Y- and 177Lu-labeled
injection to few days post injection and multiple SST analogues concord on some essential aspect
blood and urine samples are obtained. Values of [96]: (1) the pharmacokinetics data show very
organ activity over times are interpolated and fast blood clearance and urinary elimination; (2)
extrapolated to infinity to obtain a time-activity the spleen, kidneys, and liver receive the highest
curve (TAC). The early (growing) part of the absorbed dose; (3) kidneys and bone marrow are
TAC is typically fitted using linear regression the major activity limiting organs for this treat-
while the wash-out (descending) part is fitted ment; and (4) there is a wide inter-patient vari-
using a mono- or bi-exponential function. Fitting ability of the absorbed dose. However, due to
provides measurement of the residence time of the physical characteristics of the radionuclides,
tracers in various organs. Residence times are the absorbed doses with 90Y radiolabeled ana-
input to software that uses the Medical Internal logues are higher than those obtained with 177Lu
4  Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors 55

radiolabeled peptides, for the same injected 68


Ga-labeled peptides can also been used for
activity. Issues affecting dosimetry studies are diagnostic purposes. However, 68Ga has a rela-
also different for different nuclides. tively short half-life (68  min) so that derivation
177
Lu, in addition to beta particles, emits two of the late part of tissue TAC is not possible.
distinct gamma photons (Table  4.2). Thus, for Besides it is possible that 68Ga peptides have dif-
177
Lu-labeled peptides, dosimetry and therapy ferent pharmacokinetics in comparison to 90Y- or
may be performed at the same time (Fig. 4.2). In 177
Lu-labeled compounds [96].
contrast 90Y is a pure beta emitter and alternative Another option for performing 90Y dosimetry
strategies need to be adopted for external imaging is using Bremsstrahlung imaging [98]. The sec-
such as the use of 111In as surrogate [97]. Owing ond modality developed relates to the use of time-
to the large availability, [111In-DTPA0]-octreotide of-flight PET/CT. The decay of 90Y has a minor
has been used as a surrogate of 90Y-DOTATOC branch to the 0+ excited state, followed by an
[92]. However, due to the different kinetics of internal e+ e− creation and consequently photon
the different radiolabeled conjugates chelators annihilation. Using this approach the distribution
(DTPA vs. DOTA), the use of [111In-DTPA0]- of radioactivity following 90Y-radioembolization
octreotide does not accurately reflect the distri- was quantified. However, this approach is tech-
bution of 90Y-DOTATOC [53]. nologically challenging [99].

a b

Fig. 4.2  Post-therapeutic planar whole body scan (panel a) evidence of high specific uptake in the known liver metas-
and SPECT/CT (panel b) of the same patient that is pre- tases corresponding well with the axial slice presented in
sented in Fig. 4.1. The scans were acquired 24 h after the Fig. 4.1. Only faint uptake can be seen in the soft tissue
first injection of 7400  MBq 177Lu-DOTATOC.  There is metastases (panel c)
56 F. Forrer

4.6.11 Side Effects and Toxicity ing to a considerable radiation to the kidneys


[101–103]. The receptor involved in the renal
Generally PRRT can be regarded as a relatively uptake of radioactive peptides binds various
safe treatment and severe side effects are rare. structurally different proteins, including albu-
Potential side effects may be predicted by the min and β2-­microglobulin. The localization of
physiological distribution of radioactivity in the radiopeptide in the kidney is not homoge-
PET/CT using DOTAT peptides. Physiological neous, but it occurs predominantly in the cortex
binding occurs in organs expressing SST2 where it follows a striped pattern, with most of
receptors, such as the pituitary gland, the thy- the radioactivity centered in the inner cortical
roid, the spleen, the adrenals, the kidneys, and zone [104]. This pattern of uptake results in dif-
the liver. In addition, the amount of radioactiv- ferent activity distributions for different radio-
ity in the plasma is a significant source of expo- nuclides [105].
sure to bone marrow [100]. The side effects in Bodei et  al. assessed the role of clinical risk
PRRT can be divided into acute side effects factors for the development of kidney toxicity in
and more delayed effects caused by radiation 28 patients receiving 90Y-DOTATOC (n = 23) and
toxicity. 177Lu-DOTATOC (n = 5) studied with a median
The acute effects occurring at the time of follow-up of 28  months. Risk factors included
injection up to a few days after therapy include hypertension, diabetes, renal morphological
nausea, vomiting, and increased pain at tumor abnormalities, the use of radiological contrast
sites, symptoms that were reported after treat- medium and previous chemotherapy with neph-
ments with all radionuclides [58, 67, 74]. These rotoxic agents. The cumulative BED was higher
side effects are generally mild, and can be pre- in patients without risk factors (40  Gy) than in
vented or reduced by anti-emetic treatment or patients with risk factors (28  Gy). Risk factors
steroids. The NETTER-1 trial reported nausea were significantly more frequent in patients that
and vomiting in up to 59% in the radiopeptide developed increased creatinine levels in compari-
arm. Abdominal pain was reported in 26% in the son to patients that did not develop nephrotox-
radiopeptide arm. However abdominal pain in icity [106]. Other factors that may increase the
26% of the patients was found in the Sandostatin risk of nephrotoxicity are cumulative renal radia-
LAR arm as well [74]. Similar side effects are tion dose, per cycle renal activity (i.e., therapy
seen using 90Y-DOTATATE [76]. In patients fractioning), kidney volume, and increasing
treated with 177Lu-DOTATATE mild hair loss was age [92, 94, 107]. The damage to the kidney
reported in up to 60% of patients, however hair seems to be progressive and nephrotoxicity may
growth normalized at follow-up 3 to 6  months appear as times goes on. Valkema et al. reported
after the treatment [73]. a decrease in creatinine clearance of 7.3% per
Beside these minor side effects severe late year for 90Y-DOTATOC and of 3.6% per year
toxicity may occur as a result of the radiation for 177Lu-DOTATOC [107]. The increase in cre-
absorbed dose in healthy organs. The organs at atinine levels may occur even 1–2 years after the
risk are mainly the bone marrow, the kidneys, and end of the therapy [106].
to a lower extent the liver. Several strategies may be adopted to reduce
kidney toxicity. The clinically most relevant strat-
egy is to interfere with the uptake of radiolabeled
4.6.12 Renal Toxicity peptides. Basic amino acids, including arginine
and lysine, bind to megalin via their cationic
The radiopeptides are filtered by the glomeru- sites and competitively inhibit renal reabsorption
lus. Although the major part of the radiophar- of radioactive peptide used in PRRT. Therefore,
maceutical is excreted into the urine, peptides basic amino acids are recommended to be used
are partially taken up in proximal tubule cells routinely to reduce renal uptake of radiolabeled
by the multiligand scavenger receptor megalin peptides [108, 109]. The reduction in renal uptake
and subsequently trapped into lysosomes lead- induced by cationic amino acids ranges between
4  Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors 57

15% and 60% depending on the amount of amino with 177Lu-DOTATATE [117] is reported in lit-
acids being used and on the experimental design erature. However, in particular when combining
[69, 110, 111]. Amino acids are infused slowly PRRT with chemotherapy the rate might be much
over a 4–10 h period. However, amino acids have higher [118].
some disadvantages. For examples, they can Also high rate of MDS has been reported after
induce nausea and vomiting, hyperkalemia, and the therapeutic use of [111In-DTPA0]-octreotide
arrhythmias [112, 113]. with MDS rates up to 6% [56]. Beside the limited
Other strategies have been investigated pre- efficacy this is another reason why [111In-DTPA0]-
clinically such as the use of the plasma expander octreotide should not be used anymore for PRRT.
gelofusine [114] or the use of the radioprotective The MDS rate in the NETTER-1 trial, after
drug amifostine [115]. However, the benefit for the previously mentioned median follow-up of
patients during PRRT remains to be proven and 14 months, was found to be 0.9%. However, as
studies in patients are lacking. the typical time point of MDS onset is approxi-
In general, renal toxicity following PRRT mately 2 years, a somewhat higher rate must be
seems to be a problem when using 90Y as the expected [74].
therapeutic radionuclide. While in studies using Essentially all studies investigating PRRT
90
Y-DOTATOC the rate of severe and irreversible report transient hematological toxicity. It appears
kidney toxicity (grade 4 & 5) was reported to be that the absorbed radiation dose to the bone mar-
up to 9.2% after a median follow-up of 23 month row is mainly caused by the circulation of the
[116], no grade 4 or 5 toxicity was reported in radioactivity in the blood. The most commonly
the NETTER-1 study after a median follow-up of adopted approach for calculation of bone mar-
14 months [74]. row dosimetry is represented by the blood based
Also no renal toxicity was reported after approach, whereby it is assumed that there is no
the therapeutic use of very high activities of specific binding of the radiopeptide in the bone
[111In-DTPA0]octreotide [56]. These differences marrow and the unique source of radiation expo-
in renal toxicity occur although dosimetric analy- sure is represented by the blood [100].
sis shows comparable absorbed doses to the kid- Severe hematological toxicity (grade 3 or 4
ney. The reason is most likely the heterogeneous for hemoglobin, white blood cells and plate-
dose distribution with significant differences lets) is reported in approximately 10–12% of the
between the various radionuclides [101]. The patients treated [73, 116, 117]. The NETTER-1
physical characteristics of the radionuclide have study reports transient lymphopenia grade 3 or
a significant impact on renal toxicity, i.e., Auger 4  in 9% of the patients in the PRRT arm [74].
electrons emitted by 111In and low-energy elec- In contrast to renal toxicity which seems to be
trons emitted by 177Lu have a short spatial range somewhat more pronounced when using 90Y, no
and do not reach the radiosensitive glomerulus. relevant difference between 90Y and 177Lu was
For future calculations of the absorbed dose to found for hematological toxicity.
normal organs and tumors these micro-­dosimetric The likelihood of a severe toxicity increases
aspects are crucial to be taken into consideration. with repeated cycles [44, 119].
In general, the decrease in blood count is
transient. Blood transfusions were needed only
4.6.13 Hematological Toxicity occasionally and patients recovered fully. Bone
marrow has been regarded as the dose-limiting
With regard to hematological toxicity one needs organ in approximately 70% of patients treated
to differentiate between early, transient toxicity with 177Lu-DOTATATE [120].
and severe irreversible long-term toxicity such as With regard to dosimetric aspects it is gener-
a myelo-dysplastic syndrome (MDS). As MDS ally accepted that in order to avoid bone marrow
is typically late toxicity the reports are inconsis- hypoplasia a maximum absorbed dose of 2  Gy
tent. A range between 0.2% after therapy with should not be exceeded [44, 111]. Already back
90
Y-DOTATOC [116] and 1.4% after treatment in 1962, in thyroid cancer patients treated with
58 F. Forrer

radioiodine, an absorbed dose of 2 Gy to the bone activity of (13.3  GBq of 90Y-DOTATOC with
marrow resulted in a probability for developing only a small chance of developing mild acute or
leukemia of approximately 2% [121]. This seems subacute hepatic injury.
to be very well in line with the results after PRRT. In the group of patients treated with
Generally, the cause for myelodysplastic syn- 177
Lu-DOTATATE, significantly increased liver
drome cases is difficult to be defined as many function parameters (grade 4 liver toxicity)
patients that are included into PRRT trials were were evident in two patients after the first cycle
pretreated with either chemotherapy or external of treatment [124]. A study focusing on hepatic
beam radiation. In summary hematological tox- toxicity found a relative risk of hepatotoxicity
icity following PRRT is frequent but generally related to PRRT exposure in metastatic GEP-
mild and transient. Myelodysplastic syndrome NET in 1.94% [125].
may occur, even though the risk is low especially No hepatic toxicity is reported in the
in the absence of previous chemotherapy and NETTER-1 trial.
radiotherapy. In summary, liver toxicity is rare and if it
occurs it is mostly mild and reversible. However,
extensive liver metastases seem to be a risk factor
4.6.14 Liver Toxicity for liver impairment after PRRT. In these patients
it may be difficult to distinguish between real
Beside the fact that most patients who are treated toxicity caused by radiation from effects by the
with PRRT suffer from liver metastases, physi- metastases themselves.
ological uptake in normal liver tissue also occurs
after administration of radiolabeled SST ana-
logues. The sum of this physiological uptake and 4.6.15 Endocrine Toxicity
the dose to the normal liver deriving from the
specific uptake in liver metastases can result in a SST receptors are expressed by several glands,
considerable radiation absorbed dose to the liver including the pituitary gland, thyroid, endocrine
[122]. However, since the tumor load in the liver pancreas, and adrenal medullas. Thus, it is of
shows high inter-patient variability, it is difficult interest to investigate whether PRRT is associ-
to generalize about the radiation absorbed doses ated with significant endocrine toxicity. Teunissen
to the liver. et al. addressed this issue in 35 men and 21 females
A significant increase in liver enzymes after treated with 22.2–29.6  GBq of 177Lu-octreotate
the administration of radiopeptides was reported in 3–4  cycles with 6–9  weeks interval and fol-
in several studies. Valkema et  al. reported lowed up for up to 24 months [126]. In 35 men,
one transient grade 3 toxicity in a group of 60 mean serum levels of inhibin B that is produced
patients treated with 90Y-DOTATOC in a phase by the Sertoli cells of the testis were decreased
I study [43]. In another study, 15 patients with at 3 months post-therapy and follicle-stimulating
known liver metastases (of whom 12 had exten- hormone (FSH) levels increased. These levels
sive liver involvement, defined as 25% or more) returned to near baseline levels after 24 months.
from NETs were treated with three cycles of Total testosterone and sex hormone binding glob-
4.4 GBq each [123]. In four of these 15 patients, ulin levels decreased. An increase of luteinizing
one or more of the three liver enzymes that were hormone (LH) levels was found at 3  months of
measured (serum aspartate aminotransferase, ala- follow-up returning to baseline levels thereafter.
nine aminotransferase and alkaline phosphatase) In 21 postmenopausal women, a decrease in lev-
increased. Increase was defined as at least one els of FSH and LH was found. Of 66 patients, 2
grade, according to the WHO criteria, from base- developed persistent primary hypothyroidism.
line to final follow-up measurement (4–6 weeks Before and after therapy adrenocorticotropic
post cycle 3). It was concluded that patients with hormone stimulation test showed an adequate
diffuse SST-positive hepatic metastases could response of serum cortisol. Five patients devel-
be treated with up to a cumulative administered oped elevated Hemoglobin A1C.  These results
4  Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors 59

indicate that 177Lu-octreotate therapy induced FDG-positive disease is found approximately


transient inhibitory effects on spermatogenesis. in 40% of G1 patients and 70% of G2 patients
In the long term, gonadotropin levels decreased [130]. In the same work the group found that
significantly in postmenopausal women. Overall, FDG-uptake has a very high prognostic value
PRRT with 177Lu-octreotate can be regarded as a in patients with NET.  For prediction of OS of
safe treatment modality with respect to short- and patients with NET the hazard ratio between
long-term endocrine function [126]. patients with positive 18F-FDG PET and negative
The NETTER-1 study as well as most of all 18
F-FDG PET was 10 and it exceeded the prog-
the other studies cited above do not repost endo- nostic value of traditionally used parameters,
crine toxicity. such as Ki-67, Chromogranin A level, and the
presence of liver metastases. Garin et al. showed
in a prospective study including 38 patients that
4.6.16 Factors Affecting 18
F-FDG PET/CT identifies patients who have
the Response to Therapy rapidly progressive NETs and that 18F-FDG PET
scan is an independent predictor of PFS [131].
An important issue would be to determine nega- Therefore, FDG imaging should be considered in
tive and positive prognostic factors relevant for NET patients beside the low sensitivity.
therapy response and survival. This would allow
identifying patients susceptible to benefit from
more intensive treatment schemes. 4.7 Conclusions
However, to date prognostic or predictive factors
are still not well investigated and are often mixed PRRT is an exciting, effective and safe treatment
up. For example, Brunner et al. demonstrated the modality for patients with metastatic, inoperable,
SST2 expression to be an independent prognostic neuroendocrine tumors. So far it is mainly indi-
factor for NET patients [127] although it is most cated for patients with NET G1 and NET G2. A
likely that a high SST2 expression is a predictive high expression of somatostatin receptors dem-
factor for a good response to PRRT as well [108]. onstrated by imaging is an absolute prerequisite
The subgroup analysis in the NETTER-1 study for this treatment.
showed consistent benefit for PRRT across major Toxicity, when using 177Lu labeled peptides, is
subgroups in comparison to the Sandostatin arm. mainly hematological and in an acceptable range.
This is a clear indication that the selection criteria Severe irreversible toxicity is rare.
used in this trial are when patients are useful. While two decades ago only very few cen-
The degree of liver involvement is inversely ters could offer PRRT, the availability of PRRT
related to the chance of remission [128]. Poorer will increase dramatically with the recent FDA-­
prognosis was also reported for patient having approval of 177Lu-DOTATATE (Lutathera®). This
elevated alkaline phosphatase concentrations in will allow to conduce further clinical trials who
serum [73, 129]. will help us to answer some of the many ques-
Poor performance status has been consistently tions that still remain to be answered in the con-
associated with poor response to therapy and text of NET and PRRT.
poor survival [43, 73].

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I-MIBG Therapy of Malignant
131

Neuroblastoma 5
and Pheochromocytoma

Arnoldo Piccardo, Luca Foppiani, Sergio Righi,


Alberto Garaventa, Stefania Sorrentino,
and Egesta Lopci

5.1 Neuroblastoma embryonal tumors including neuroblastoma,


ganglioneuroblastoma, and ganglioneuroma
5.1.1 Basis [2]. Peripheral neuroblastic tumors represent
6–10% of all pediatric cancers (age 0–14  yrs).
Neuroblastoma (NB) represents the most fre- The age distribution is characterized by a peak
quent extracranial tumor of pediatric age. It of incidence in the first year of life (infants),
derives from aberrant neural crest development followed by a rapid decline in the following
and presents as an abdominal, thoracic, or neck years. After the age of 6, it becomes rare and
masses originating in the adrenal medulla or exceptional among adolescents and adults. NB
paraspinal sympathetic ganglia [1]. A primary occurs at slightly higher rates in males than in
tumor is not found in approximately 1% of females (M/F ratio 1.1–1.2) and its mean annual
patients, in whom the disease becomes appar- incidence is 7–12 cases per million children in
ent only through signs of metastatic spread. Western countries [3].
Peripheral neuroblastic tumors is the correct More than 90% of NB excrete catecholamines,
term to identify the group of neural crest-derived which, together with their metabolites, are used
for diagnostic and follow-up purposes [2].
A familial history of neuroblastoma is
A. Piccardo (*)
Department of Nuclear Medicine and PET/CT observed in approximately 1% of patients with an
Centre, Oncology Institute of Southern Switzerland, estimated penetrance of 11% in hereditary cases.
Bellinzona, Switzerland Two main neural crest-derived developmental
Department of Nuclear Medicine, E.O. Ospedali disorders are associated with an increased risk
Galliera, Genoa, Italy to develop neuroblastoma: (1) Hirschsprung’s
e-mail: arnoldo.piccardo@galliera.it disease, characterized by an absence of ganglion
L. Foppiani cells in the distal colon resulting in functional
Internal Medicine, Galliera Hospital, Genoa, Italy obstruction and (2) Ondine’s curse, also named
S. Righi congenital central hypoventilation syndrome, a
Medical Physics Department, E.O. Galliera Hospital, disorder characterized by a failure of the auto-
Genoa, Italy
nomic control of ventilation during sleep. Both
A. Garaventa · S. Sorrentino diseases are frequently associated with each
Unit of Pediatric Oncology, Gaslini Hospital,
Genoa, Italy other, and most cases are linked to mutation of
the PHOX2B gene [4].
E. Lopci
Department of Nuclear Medicine, Humanitas Recently, the anaplastic lymphoma kinase (ALK)
Research Hospital, Milan, Italy gene was identified as a second neuroblastoma

© Springer Nature Switzerland AG 2019 65


L. Giovanella (ed.), Nuclear Medicine Therapy, https://doi.org/10.1007/978-3-030-17494-1_5
66 A. Piccardo et al.

predisposition gene. ALK mutations are present Table 5.2 International neuroblastoma risk group
(INRG) staging system [1]
in around 9% of primary NB tumors and approxi-
mately 14% of high-risk setting [5]. Stage Description
Although neuroblastomas may occur in famil- L1 Localized tumor not involving vital structures
and confined to one body compartment
ial and syndromic contexts, most cases occur
L2 Loco-regional tumor with presence of one or
sporadically. However, also in this context, more image-defined risk-factors
the amplification of oncogenes, as MYCN, is M Distant metastatic disease (except stage MS)
clinically relevant because it is associated with MS Metastatic disease in children younger than
advanced stage disease and rapid tumor progres- 18 months with metastases confined to skin,
liver, and/or bone marrow
sion, and the MYCN oncogene status is routinely
used in clinical practice to assign therapeutic
intensity. More recently, the INRG Task Force also
The clinical presentation of NB is heteroge- released the consensus recommendations on
neous, ranging from asymptomatic incidental molecular techniques, on the criteria of minimal
tumors to spontaneously regressing metastatic residual disease, on neuroblastoma response cri-
tumors in infancy or to widespread metastatic teria, and on radiographic techniques [6–10].
disease progressing to death despite intensive The high-risk phenotype, which affects nearly
therapy. At diagnosis, patients with metastatic 50% of newly diagnosed patients and is related
neuroblastic tumors usually present constitu- to poor long-term survival, is characterized by
tional symptoms such as pain, fever, and decay age >18  months on diagnosis, widespread dis-
of the overall health status. The main metastatic ease dissemination, and MYCN amplification.
sites are regional lymph nodes, bone, and bone Conversely, patients with a low-risk phenotype
marrow. (no MYCN amplification and age <18  months)
Due to the heterogeneous profile of the dis- have an excellent long-term survival [11–13].
ease, prognosis of NB patients is linked to several Localized unresectable neuroblastoma in chil-
clinical and biological factors. In this setting the dren >12  months and no MYCN amplification
International Neuroblastoma Risk Group (INRG) constitute an intermediate risk group [14].
task force established criteria for an internation- Since risk group stratification is an essential
ally risk group stratification system based on step to select the most appropriate treatment
clinical factors as age, tumor stage (Table  5.1 option, diagnostic imaging is determinant in the
and 5.2), and genetic determinants (MYCN gene initial assessment of disease extension.
amplification, chromosome 1p36 abnormalities) In this setting, nuclear medicine procedures,
(Table 5.3) [1, 6]. by using meta-iodobenzylguanidine (mIBG)
imaging, have been reported to be very effective
especially in evaluating bone and bone marrow
Table 5.1  International neuroblastoma staging system
(INSS) [19] NB involvement at the time of diagnosis and dur-
ing treatment [15].
NB Tumor Resection Lymph node
Stage 1 Localized Complete Ipsilateral
mIBG is a noradrenaline analogue developed
and negative in the late 1970s as diagnostic agent for imag-
Stage 2A Localized Incomplete Ipsilateral ing of adrenal medulla [16]. MIBG is chemi-
and negative cally related to norepinephrine and its uptake in
Stage 2B Localized Complete or Ipsilateral the cytoplasm of NB cells is associated to the
incomplete and positive
amine type-1 uptake mechanism. Indeed, mIBG
Stage 3 Localized Unresectable With or
across the without and norepinephrine share similar specific active
midline involvement uptake mechanism [17].
Stage 4 Any Any Distant 123
I-mIBG scintigraphy and 131I-mIBG scin-
metastases tigraphy have been extensively used in research
5  I-MIBG Therapy of Malignant Neuroblastoma and Pheochromocytoma
131
67

Table 5.3  International neuroblastoma risk groups consensus pretreatment classification schema [6]
INRG Age Histological Grade of tumor 11q Pretreatment
stage (months) classification differentiation MYCN Aberration Ploidy risk group
L1/ Any GN maturing Very Low
L2 GNB intermixed
L1 Any Any except GN NA Very Low
maturing or Amp High
GNB intermixed
L2 <18 Any except GN NA No Low
maturing or Yes Intermediate
GNB intermixed
≥18 GNB nodular; Differentiating NA No Low
neuroblastoma Yes Intermediate
Poorly differentiating NA
or undifferentiating
M < 18 NA Hyperdiploid Low
<12 NA Diploid Intermediate
12 to <18 NA Diploid Intermediate
< 18 Amp High
≥ 18 High
MS < 18 NA No Very Low
Yes High
Amp High
GN ganglioneuroma, GNB ganglioneuroblastoma, Amp amplified, NA not amplified

and clinical imaging of NB and are both well-­ 5.1.2 Therapeutic Context,
established diagnostic methods in the diagnosis, Indication, and Results
staging, and restaging of NB. Indeed, 123I-MIBG of 131I-mIBG Therapy
scintigraphy has been recognized as the func-
tional imaging of choice in NB assessment and The majority (>80%) of patients with high-risk
has been widely used in clinical practice for the NB are >18 months of age with INRG stage M
past 25 years. disease, as well as children 12–18 months of age
Owing to the high specificity and sensitivity with INRG stage M disease, whose tumors have
in detecting primary NB and distant metasta- unfavorable biological features (MYCN ampli-
ses, mIBG imaging is recommended as standard fication, unfavorable pathology and/or diploid)
modality to assess disease extent at diagnosis and [24]. The current approach for high-risk NB
to identify the risk of the each patient accord- incorporates induction chemotherapy (to reduce
ing to International Neuroblastoma Risk Group tumor burden by shrinking the primary tumor and
(INRG) guidance [18]. reducing metastases) using a combination che-
Worthy to remember, in INRG recommenda- motherapy regimen, followed by delayed surgery
tions the presence of a single, unequivocal mIBG-­ to remove the primary tumor and subsequent
positive lesion at a distant site is sufficient to myeloablative chemotherapy associated to autol-
define metastatic disease [5]. Consequently, since ogous hematopoietic stem cell transplantation
1996 mIBG scan has been utilized to create a risk- (AHSCT) [24]. Myeloablative chemotherapy
factor scoring system focusing on the extent and is followed by maintenance therapy for mini-
treatment response of bone disease [19–23]. mal residual disease with anti-GD2 monoclonal
Moreover, the presence of a positive 123I-mIBG antibody and cytokine immune therapy, in addi-
scan establishes the basis for the use of a targeted tion to differentiating therapy with isotretinoin
radionuclide therapy with 131I-mIBG. (Fig. 5.1) [24].
68 A. Piccardo et al.

Surgery RT

Consolidation therapy
Induction Therapy Maintenance Therapy
and AHSCT

Fig. 5.1  Treatment of high-risk neuroblastoma. Induction (AHSCT) is useful to eliminate remaining disease.
therapy includes combination chemotherapy) and a Radiotherapy to the primary tumor bed and maintenance
peripheral blood stem cell harvest. Surgery approach is therapy for minimal residual disease by using anti-GD2
attempted after chemotherapy. A high-dose chemotherapy antibody and isotretinoin are introduced at the end of the
with autologous hematopoietic stem cell transplantation therapeutic iter [24]

Although some studies evaluated the role of cumulative activity of 131I-mIBG and the asso-
mIBG therapeutic approach at the time of the first ciation between chemotherapy and mIBG both
induction [25, 26] or at the time of consolidation parameters were found positively associated to
[27], the main indication for 131I-mIBG therapy treatment response [28].
is in high-risk NB patients with evidence of per- The median overall survival reported only
sistence of mIBG avid metastatic disease at the in seven [30–36] of the 27 studies ranged from
end of the long therapeutic “iter” described above 6  months to 48  months. Among these 27 stud-
(Fig. 5.2). ies only four had controls arms [31, 33, 37,
No strict inclusion or exclusion criteria are 38]. Survival outcomes were similar between
reported in literature but an adequate life expec- patients treated with mIBG therapy and controls
tancy of at least 3 months and a preserved renal in three of these four studies, with median sur-
function should be required. In addition, hema- vival around 6 months. On the other hand, Miano
topoietic parameters (WBC > 3000/μL, Platelets and colleagues reported that patients treated with
>100  K/μL) should also be considered before 131
I-mIBG had a longer event-free survival (EFS)
131
I-mIBG therapy, especially when stem cells (18 vs. 3 months) [37].
are not available [28]. In the presence of normal The largest mIBG therapy study conducted on
renal function there is no limitation in treating 164 refractory or relapsed NB patients in 2007
previously nephrectomized patients for large by Matthay and colleagues, by using an activ-
adrenal masses. ity of 12–18  mCi/Kg, showed that the overall
No prospective, randomized and controlled response rate (including only complete and par-
trials have been conducted to identify the correct tial response) was 36% [32]. Indeed, the response
indication for mIBG therapy. Indeed, at least 27 rate for the 12-mCi/Kg cohort was 25%, and the
studies, treating 911 relapsing or refractory NB 18-mCi/Kg cohort was 37%.
patients with 131I-mIBG, have been analyzed in They found, at multivariate level, that the
a recent systematic review by Wilson and col- principal parameters influencing the response
leagues [29]. They found that the overall mean to treatment, were age (patients with more than
tumor response rate was 32% although a wide 6  years had a significantly higher likelihood of
range of proportions for each study has been response and longer EFS than younger patients),
reported [29]. In this context, tumor response was disease limited to either soft tissue or to bone
39% in patients who had also concomitant che- and bone marrow only, and less prior treatment
motherapy compared to 32% for those patients (less than 3 previous regimens). In addition, the
treated with 131I-mIBG alone. No difference was authors found that a longer time from diagnosis
observed when refractory and relapse patients to mIBG therapy, often related to a less aggres-
were compared (response rate 37% vs. 38%) sive disease, is another parameter positively asso-
(Figs.  5.3 and 5.4). When was considered the ciated to treatment response.
5  131
I-MIBG Therapy of Malignant Neuroblastoma and Pheochromocytoma 69

a b c

Fig. 5.2 Five years old male affected by stage IV one metastasis of the left lung and the unresectable pri-
NB. Patient showed persistence of disease after NB AR 01 mary tumor (arrows). Three months later, 123I-mIBG
protocol on 123I-mIBG whole body scintigraphy (a). whole-body scintigraphy (c) demonstrated optimal meta-
Patients underwent 131I mIBG therapy (15  mCi/Kg) and bolic response to treatment
post-therapeutic whole body scintigraphy (b) confirmed

5.1.3 Risk and Complications proper premedication with antiemetic drugs should


of the Procedure, Side Effects be performed. These simple precautions may at
the same time increase the urinary excretion of the
131
I-mIBG infusion is a safe therapeutic adminis- tracer (i.e., reduction of bladder radiation expo-
tration and few peri-procedural complications have sure) and improve the tolerability to mIBG induced
been reported. However, some precautions should actinic gastritis. In order to limit the early 131I-mIBG
be considered before administering mIBG therapy. loss due to deiodination, 131I-mIBG infusion should
First an adequate hydration of the patient and a be fast, not more than an hour, even in the event of
70 A. Piccardo et al.

a b

Fig. 5.3  Seven years old female affected by stage IV therapeutic whole body scintigraphy (a) confirmed the
NB. Patient, after NB AR 01 protocol, showed persistence sites of disease. Three months later, 123I-mIBG whole
of disease involving the left lung and pleura. Patient body scintigraphy (b) demonstrated optimal metabolic
underwent 131I mIBG therapy (300  mCi) and post-­ response to treatment

a b

Fig. 5.4 Three years old male affected by stage IV Patient underwent 131I mIBG therapy (15  mCi/Kg) but
NB. Patient, after NB AR 01 protocol, showed persistence 3 months later a diagnostic 123I-mIBG whole body scintigra-
of disease on 123I-mIBG whole body scintigraphy (a). phy (b) did not show any significant response to treatment
5  I-MIBG Therapy of Malignant Neuroblastoma and Pheochromocytoma
131
71

Table 5.4  Principal side effects and toxicities in NB patients treated with mIBG therapy
Impact Acute Early Late
Frequent Nausea Thrombocytopenia Hypothyroidism
Less Frequent Anorexia Leukopenia Papillary Thyroid Cancer
Infrequent Vomiting Neutropenia Other second malignancies

very high activities injected [39]. Close 131I-mIBG paper by Clement and colleagues reported at a
cycles have been proposed and the principal limita- median follow-up of 9.0  years after 131I-mIBG
tion of this approach is related to the total amount treatment the presence of thyroid disorders in
of activity administered. However, repeated treat- 50% patients and TSH elevation in 37% [45].
ments are well tolerated and stunning effect reduc- Papillary thyroid cancers may occur with a rather
ing the mIBG uptake has never been reported. high frequency and in the same recent paper one
Acute toxicity, occurring within the first hours out of the 24 NB patients survived developed a
after the infusion, consists of nausea, anorexia, papillary thyroid cancer [45].
and vomiting. Transient tachycardia and hyper- Apart from thyroid cancers, second malig-
tension are rare and reported in less than 10% of nancies are rare and arise in less than 5% [46].
the patients [40] (Table 5.4). Garaventa and colleagues reported two cases of
Early hematological toxicity is the major issue leukemia, one angiomatoid fibrous histiocytoma,
but often the entity is not severe and is activity/ one schwannoma, and one rhabdomyosarcoma
weight related. Usually it appears 2–4  weeks in 119 NB patients after 131I-mIBG therapy [47].
after infusion but the nadir occurs 2–3  weeks Nevertheless, in children heavily treated with a
later and the spontaneous recovery can be very chemotherapy multimodality therapy, it is dif-
slow after 4–6  weeks. As reported by Matthay ficult to distinguish the risk of developing sec-
and colleagues an activity higher than 444 MBq/ ondary malignancies derived from 131I-mIBG
Kg may be considered, the limit behind which radiation effects and the risk derived from the
significant hematological events may occur [41]. alkylator-based chemotherapies [40].
From this point of view, in these cases, a stem
cell support is required.
Among hematological toxicities, the most fre- 5.2 Pheocromocytoma
quent and severe is persistent thrombocytopenia
[30, 42]. However in a recent paper by Bleeker 5.2.1 Basis
and colleagues was pointed out that grade IV
thrombocytopenia occurs in only 1% of patients Pheochromocytomas (PCCs) and paraganglio-
and no episodes of major bleeding has been mas (PPGs) are rare neuroendocrine tumors
observed [43]. originating in the adrenal medulla and in the
Some studies have found a correlation between extra-adrenal ganglia, respectively. Their preva-
bone-bone marrow involvement and hematologi- lence ranges from 1:2500 to 1:6500  in Western
cal toxicity. This finding was more recently con- countries, and occur in less than 1% of hyperten-
firmed by Bleeker [43] reporting that the patients sive patients [48, 49].
with more severe toxicity (grade IV anemia, leu- The vast majority of PCCs are benign and
kocytopenia, or thrombocytopenia) all had dis- malignancy occurs in ~10% of patients; by
seminated bone marrow disease. contrast 20–40% of PPGs are malignant. These
Although the thyroid block is a corner stone tumors are considered malignant only when
in the preparation of patients for mIBG ther- metastasis is present, since there are no reliable
apy, hypothyroidism is a major late side effect, histological features or molecular markers able
despite the recent introduction of intense of pro- to differentiate a benign from a malignant tumor.
tocol using the combination potassium iodide, Metastases occur most frequently in lymph nodes
methimazole, and L-thyroxine [44]. One recent (70–80%), bone (50–70%), liver (50%), and
72 A. Piccardo et al.

lungs (30–50%) and can appear up to 20  years anesthesia, surgery, or angiography should raise
after initial presentation [50, 51]. Notably, the suspicion of PCC.  However up to 10% of
patients presenting with only bone metastasis patients are normotensive [48, 49].
have longer overall survival compared with those Finally, orthostatic hypotension due to
with liver and/or lung metastases [52]. catecholamine-­ induced intravascular volume
The most important molecular predictor depletion can be an uncommon presenting fea-
of malignancy is the presence of inactivating ture of these tumors. No significant clinical dif-
germline mutations of the mitochondrial suc- ference occurs between benign and malignant
cinate dehydrogenase subunit B (SDHB). This disease.
mutations result in a hypermethylation pheno- Up to 60% of malignant PCCs and PPGs
type with abnormal activation of epithelial-to-­ patients have tumor burden- and hormone-related
mesenchymal transition, and a more aggressive manifestations (e.g., pain and hypertension);
phenotype [52]. Besides the genotype of the pri- most of these tumors produce noradrenaline and/
mary tumor (i.e., carrier of SDHB mutations), or dopamine [51].
other factors such as the size and the location Three types of complications significantly
(adrenal or extra-adrenal) predict the onset of affect clinical outcomes and therapeutic choices
metastases and overall survival. In particular, in metastatic PCCs and PPGs patients: cardiovas-
PCCs larger than 5 cm and PPGs are at high risk cular disease, gastrointestinal dysfunction (severe
to develop metastases [51]. constipation, obstruction, ulceration, perforation,
The natural history of malignant PCCS and and/or bacterial translocation), and skeletal-­
PGGs is heterogeneous. In fact, several patients related events (SREs) [52]. SREs include pain,
have indolent disease irrespective of the pres- pathological fractures, and/or cord compres-
ence of distant metastases, which remain stable sion; although metastases are usually lytic these
over time; these patients may survive for several patients rarely develop hypercalcemia.
years with good quality of life and minimal or With regard to cardiovascular disease, patients
no therapeutic intervention. On the other hand, with catecholamine secreting tumors are at risk
some patients show very aggressive disease with of congestive heart failure, stroke, arrhythmias,
huge metastases, no response to systemic therapy, and cardiomyopathy.
and hence short life expectancy. However, most In addition, chemotherapy, molecular tar-
patients exhibit intermediate outcomes with pro- geted therapies, and radiopharmaceutical agents
gressive disease that will require medical/surgi- used to treat these tumors destroy tumoral cells,
cal management over time [52]. Overall, patients thus predisposing patients to hypertensive cri-
with metastatic PCC/PGL have a 50% 5-year sis. Consequently, these patients require proper
overall survival [48]. α- and β-adrenergic blockade. Not-competitive
These tumors, mostly PCCs, are frequently α1-adrenergic blockers such as doxazosin and
characterized by an excessive and often paroxystic terazosin are commonly used. β-Adrenergic
secretion of catecholamines which cause symp- agents (e.g., propranolol, atenolol) should be
toms such as palpitations, throbbing headaches, instituted after the α-adrenergic blockade has
and sweating. Although typical when present, been optimized. For bone metastases, a com-
this clinical triad is uncommonly encountered in bined approach including analgesics, antiresorp-
most patients. In addition, since these symptoms tive agents (bisphosphonates or RANK ligand
are not specific, the diagnosis of these tumors is antagonists), steroids, surgery, or radiotherapy is
frequently overlooked. By contrast, hyperten- recommended [51].
sion, particularly if resistant or paroxysmal, must In malignant PCCs and PGGs surgical resec-
alert the clinicians to the possibility of a pheo- tion of the primary tumor, albeit not curative, can
chromocytoma. In addition, severe hypertension have a positive impact on clinical outcomes since
or hypertensive crises following procedures as it causes a reduction of the catecholamine release
5  I-MIBG Therapy of Malignant Neuroblastoma and Pheochromocytoma
131
73

thus improving cardiovascular and gastrointes- are patients with significant tumor burden, slowly
tinal manifestations and may prevent anatomical progressive disease, adequate mIBG uptake on
complications [52]. Although tumor progression is diagnostic imaging, acceptable blood tests [49,
the most frequent cause of death from metastatic 50]. Responses to therapy are generally better in
PCCs and PGGs, up to 30% of the deaths are due patients with limited disease or soft-tissue metas-
to hypertension and intestinal occlusion [51]. tases than in patients with bone metastases.
The diagnosis of pheochromocytoma is con-
firmed with high sensitivity (>90%) by elevated
catecholamine metabolites (metanephrines) in 5.2.2 Indications
plasma and, more commonly, by raised 24-h
urinary excretion of fractionated metanephrines. According to the EANM procedure guidelines
However, plasma metanephrines have higher [54], 131I-mIBG therapy is indicated in all cases
specificity compared with 24-h urine tests with inoperable PPCs and PPGs. Patients with
(ranging from 79% to 98% vs. 69% to 95%, metastatic disease, in course of progression and/
respectively) [48, 49]. Many drugs can interfere or intractable pain, can be considered eligible
with the testing of plasma/urine metanephrines for mIBG therapy [55–57]. Although nowa-
leading to false-positive results and include days, with the advent of peptide receptor radio-
acetaminophen, selective serotonin reuptake nuclide therapy (PRRNT), there might be some
inhibitors, tricyclic antidepressants, monoamine competition due to overlapping indications [58,
oxidase inhibitors, and certain β-adrenergic 59], 131I-mIBG therapy remains the most studied
and α-adrenergic blockers. These medications radionuclide therapy for these type of neuroendo-
should be stopped for 10–14 days before testing crine tumors (Table 5.5).
if possible [48, 49]. If the medications cannot be 131
I-mIBG therapy relies on the expression of
stopped and the plasma/urine metanephrine lev- norepinephrine transporters and vesicular mono-
els are increased it is advised to perform imag- amine transporters (VMAT) in tumors of neural
ing procedures [48]. crest origin [60–62]. Already after the initial
Computed tomography or magnetic reso- imaging application in the 80s, it was clear that
nance imaging have a high sensitivity (90–95%) the majority of PPC/PPG concentrate 131I-mIBG
for detecting primary tumors and metastatic [63], which can be applied at higher doses for
and extra-adrenal lesions larger than 1  cm. therapeutic purposes. However, not all forms of
18
F-fluorodeoxyglucose positron emission PPC/PPG concentrate mIBG.  In case of malig-
tomography (FDG-PET) is the most sensitive nant transformation or tumor dedifferentiation,
scintigraphic method for assessing metastatic in succinate dehydrogenase subunit B mutation
PCCS and PGGs [51]. In addition, functional (SDHB), von Hippel–Lindau syndrome, and in
scintigraphy with 123I-mIBG can be used to deter- patients with dopamine-secreting forms, PPCs
mine whether patients are candidates for targeted and PPGs can be mIBG-negative [64–66], hence
radiotherapy with 131I-mIBG [48, 49, 51]. Given the need for a baseline pre-radionuclide therapy
its high structural similarity with noradrenaline, assessment.
mIBG is taken up by tumoral cells and causes Therefore, the prerequisite for performing
radiation-induced cell death. 123I-mIBG is supe- mIBG therapy is, in the first place, the docu-
rior to 131I-mIBG for imaging in terms of physical mented mIBG-positivity of the lesions candidate
properties, quality of images, and sensitivity (83– to treatment as demonstrated on mIBG scan [54,
100%) and specificity (95–100%) [53]. Based 67]. The scintigraphy can be performed with
on mIBG uptake on diagnostic imaging, around either 123I- or 131I-mIBG, documenting an over-
50–60% patients with malignant PCCs and PGG all sensitivity and specificity of the modality in
are suitable for 131I-mIBG therapy. The ideal can- PPCs/PPGs between 83–100% and 95–100%,
didates for mIBG therapy as a first-line therapy respectively [68, 69]. Tumors eligible for mIBG
74 A. Piccardo et al.

Table 5.5  Summary of the studies investigating 131I-mIBG therapy in pheochromocytoma (PCC) and paraganglioma
(PPG)
Patients Tumor [131]I-mIBG Cycles Objective Biochemical
Authors (year) (no.) type activity (mCi) (no.) response response Outcome
Shapiro et al. 28 PCC 97–301 1–6 7% 18% Median PFS
(1991) 18 months
Krempf et al. 15 PCC 78.4–250 1–11 33% 35% Median TTP
(1991) 36 months
Fischer et al. (1991) 14 PCC 64–210 1–6 14% / //
Lumborso et al. 11 PCC 100–200 1–6 15% 15% Median OS 16 months
(1991)
Schumberger et al. 20 PCC 100–200 1–6 15% 15% Median OS 16 months
(1992)
Bomanji et al. 5 2 PCC 83.7–300 1–7 60% 60% Median OS
(1993) 2 PPG >50 months
Loh et al. (1997)a 116 PCC 96–300 1-11 30% 45% Relapse rate 45% in
responder patients
Mukherjee et al. 15 8 PCC 100–300 1–7 40% 47% 5-year survival 85%
(2001) 7 PPG
Rose et al. (2003) 12 6 PCC 386–866 1–3 33% 42% Median response
6 PPG duration 34 months
Safford et al. (2003) 33 22 PCC 391+/−131 1–6 38% 60% Median survival
11 PPG 4.7 years; 5-year
survival 45%
Buskombe et al. 3 3 PCC 90–142 4–11 33% / Mean PFS 7.7 months
(2005) 1 PPG
Sisson et al. (2006) 21 PCC 137–349 1–6 30% / 5-year survival 70.5%
Fitzgerald et al. 30 11 PCC 557–1185 / 63% / Calculated 5-year
(2006) 19 PPG survival 75%
Gedik et al. (2008) 19 12 PCC 100–700 1–10 47% 67% Median PFS
7 PPG 24 months
Gonias et al. (2009) 50 15 PCC 492–1160 1–3 22% 66–74% 5-year survival 64%;
34 PPG 5-year EFS 47%
Shilkrut et al. 10 7 PCC 145.5 1–4 30% 50% Median PFS
(2010) 3 PPG 17.5 months
Navalkissor et al. 4 3 PCC 148.6–200 2–6 25% / Mean PFS 22 months
(2010) 1 PPG
Castellani et al. Group 1 4 PCC 124–149 7 33% 56% Median response
(2010) (12/28) 8 PPG duration 1.9 years
Group 2 11 PCC 200–350 2 31% 71.4% Median response
(16/28) 5 PPG duration 3 years
Rachh et al. (2011) 12 8 PCC / 1–5 8% 50% Mean stability
4 PPG 29 months
Sze et al. (2013) 14 7 PCC 195 2 / / 5-year survival 68%
7 PPG
Wakabayashi et al. 26 18 PCC 200 1–6 0% 35% 5-year survival 50%
(2013) 8 PPG
Yoshinaga et al. 48 37 PCC 100–300 1–4 2% 0% /
(2014) 11 PPG
Rutherford et al. 22 10 PCC 135–305 1–5 19% 10% Median survival after
(2015) 12 PPG treatment start
11.1 years
Noto et al. (2018) 21 10 PCC 181–196 6 19% 80% 1-year survival 85.7%
11 PPG 2-year survival 61.9%
EFS event-free survival, OS overall survival, PFS progression-free survival, TTP time-to-progression
a
This is a review article collecting data from 116 patients, 3 from the authors’ own center and 113 reported in the litera-
ture from 1983 to 1996
5  I-MIBG Therapy of Malignant Neuroblastoma and Pheochromocytoma
131
75

therapy require a tumor uptake clearly above the 5.2.4 Radiopharmaceutical


background activity (visual) or with a lesion-to-­ Preparation
background ratio >2 (semiquantitative) [55, 70].
Pretreatment scanning can be used in addition For radionuclide therapy, mIBG is labelled
as an aid to calculate the dose and predict the with iodine-131. This isotope has a long half-
level of uptake and retention of 131I-mIBG during life (8.02  days) and presents a high-to-medium
radionuclide therapy [56, 57, 71]. energy beta emission (89.6% 0.606  MeV; 7.2%
0.333 MeV, 2% 0.247 MeV) [75], which allows
for its therapeutic usage. The radionuclide is
5.2.3 Patient Selection commercially supplied frozen in aqueous or
and Preparation glucose solutions, which has to be radiola-
belled with iodine-131, up to a specific activity
Once the inoperable/metastatic condition is of 30–50  mCi/mg [70, 74]. This conventional
determined and tumor lesions are documented to method of preparation guarantees only one
have an increased mIBG uptake, patients can be out of 2000 molecules of mIBG labelled with
screened and prepared for radionuclide therapy. iodine-131. On counterpart, new ways for radio-
Patients eligible for mIBG therapy are prefer- labelling, also called no-­carrier-­added or carrier-
ably fit, with an acceptable performance status free high-specific-activity preparations [76], have
(Karnofsky >60; ECOG PS <2), a life expectancy been implemented, allowing for a higher amount
superior to 3  months, adequate hematopoietic of iodinated mIBG molecules up to a specific
parameters, adequate renal function, and good activity of 2500 mCi/mg [77, 78].
liver function [54, 55, 70]. Once prepared, 131I-mIBG should be admin-
Before radionuclide therapy, all drugs inter- istered intravenously with a very slow infusion
fering with intracellular mIBG uptake should be via a peripheral cannula or a central venous line.
discontinued. Some of the most important com- After the infusion, the line should be flushed very
petitors include tricyclic antidepressants, anti-­ slowly too to avoid hypertensive crises. Blood
arrhythmics, α- and β-blockers, β-2 stimulants, pressure and other vital signs should be moni-
some sympathomimetics, calcium channel block- tored during the infusion and the recovery fol-
ers, antihistamines, opioid analgesics, reserpine, lowing the administration [54].
etc. The list of drugs comprises several classes
of medication that are widely enumerated in the
EANM guidelines [54]. 5.2.5 Treatment Schedules
For therapeutic purpose, mIBG is labelled
with iodine-131, which can be found in the The therapeutic regimens with 131I-mIBG, com-
blood stream of the patient during treatment as prising number of doses and administered activi-
free iodine. Free iodine can accumulate in the ties, can be quite variegate. While the EANM
thyroid gland, resulting in direct damage to the guideline reports single doses ranging from
organ with an increased risk of hypothyroidism. 100 mCi to 300 mCi [54], in literature the admin-
Therefore, it is mandatory to protect the gland istered activities range from 64 mCi to 1165 mCi
by blocking iodine uptake before administer- (Table  5.5). The computation of these activities
ing therapy with specific drugs, such as Lugol’s can be performed either empirically, by using
solution, potassium iodine, or saturated solution fixed doses or fixed activities per body weight, or
of potassium iodide [72, 73]. Thyroid blockade following dosimetric estimation [74, 79]. The later
should start 24–48 h before radionuclide therapy one is to be preferred, since it is more reproducible
and be continued for 10–15 days after. Potassium and can maintain the amount of activity within
perchlorate can also be used in combination the dose constrain levels. Along with dose levels,
with stable iodine to allow the wash out of the also the number of doses/cycles of radionuclide
iodine-131 from the thyroid [74]. therapy is variable. Most treatment schedules
76 A. Piccardo et al.

consider multiple doses of 131I-mIBG (range since published data report quite low rates, rang-
1–11), administered every 3–6  months [79]. The ing from 0% to 18% [74, 79]. Hence, objective
regimen chosen for the treatment should have in and biochemical responses are more commonly
all cases the intent to give a sufficient amount of considered when assessing the efficacy of mIBG
dose to the tumor lesions to obtain a biochemical therapy. Depending on the administered activity
or objective response. According to the reported and the number of doses, objective response var-
data, an estimated dose of 150 Gy can be consid- ies from 0% to 63% [80, 81] (Fig. 5.5) with the
ered as advisable for this purpose [79]. majority of the studies reporting responses below
50% [79] (Table 5.5). mIBG therapy has instead
a more robust impact on symptom relief and pal-
5.2.6 Results liation related to catecholamine excretion. In this
context, particularly in multiple-dose schedules,
Based on the indications, the majority of patients the benefit from 131I-mIBG is around 50% to 85%
with PPC/PPG candidate to radionuclide therapy [82, 83].
are metastatic, with either progressive or symp- The introduction of high-dose regimens and
tomatic disease. Hence, one of the most desirable with the advent of high-specific-activity 131I-mIBG,
effects required from MIBG therapy is tumor the objective and biochemical response rates are
reduction, with biochemical response and clinical expected to increase. In case of high-dose therapy,
release of the symptoms. A complete response to objective response rates are reported in up to 30%
therapy, however, is less frequent than imagined of the patients, symptomatic responses can reach

a b c

Fig. 5.5  Sixty-four years female affected by unresectable the abdominal sites of disease. Seven months later, a diag-
abdominal metastases by PCC able to concentrate mIBG nostic 123I-mIBG whole body scintigraphy (c) demon-
(a) Patients underwent 131I-mIBG therapy (300 mCi) and strated partial metabolic response to treatment. NB
post-therapeutic whole body scintigraphy (b) confirmed neuroblastoma, PCC pheochromocytoma
5  I-MIBG Therapy of Malignant Neuroblastoma and Pheochromocytoma
131
77

92%, while biochemical responses can be seen in of thyroid blockade [54, 74]. With the introduc-
up to 74% of the patients [84, 85]. Recently, the tion of high-specific-activity mIBG, allowing for
results of a Phase I clinical trial on high-specific- a better targeting of the tumor lesions, it might
activity mIBG therapy, have been reported by be possible to reduce the amount of side effects
Noto et  al. [86]. In this study, when applying a and toxicities. Although we need more data, we
maximal tolerable activity of 296  MBq/Kg, the have already evidence of lower incidence for
best biochemical responses were observed in some side effects, such as nausea, vomiting, and
80% and 64% of patients for chromogranin A and hypertension [79].
metanephrines, respectively. Whereas objective
response was documented on RECIST (Response
Evaluation Criteria in Solid Tumors) criteria as 5.3 Dosimetric Approach
partial tumor regression in 19 patients (21% of to Neuroblastoma
the cases). and Pheocromocytoma
The responses obtained with the different reg- to Improve Safety
imens mentioned above can have quite variable and Effectiveness
duration. Median duration of response is reported
between 1.9 and 3  years [87], with a median In the 131I-mIBG treatments of NB and PCCs,
progression-­free survival reported between 17.5 bone marrow toxicity limits the amount of admin-
and 24  months [83, 88]. The survival benefit is istered activity and the therapeutic tumor dose.
more difficult to determine, although there are Since the dose to the bone marrow is a measure
data suggesting a longer OS for patients treated of hematologic toxicity, ideally bone marrow
with higher single doses (400 mCi) and in patients dosimetry for a specific patient should be per-
showing a symptomatic response and biochemi- formed prior to therapy, so that the total admin-
cal improvement after therapy [79]. Reported istered activity can be prescribed accordingly. To
overall survival ranges from 16 months to more calculate the bone marrow absorbed dose it is
than 50  months [89–91], with a 5-year survival necessary to carry out a series of blood samples
rate ranging from 45% to 85% [82, 85]. and of whole body counts. Therefore, calculating
the bone marrow absorbed dose can be difficult,
especially in pediatric patients. In practice, the
5.2.7 Side Effects whole body is introduced as a surrogate for bone
and Complications marrow, and then, the whole body dosimetry,
more easily feasible, is used instead of bone mar-
131
I-mIBG therapy can be associated with early row dosimetry. Indeed, Matthay et al. [92] demon-
and delayed side effects and toxicities. Some of strated in 42 patients with neuroblastoma that the
them can be temporary and of limited clinical absorbed bone marrow correlates with the whole
relevance, such as asthenia, nausea and vomit- body absorbed dose. Furthermore, Buckley et al.
ing, transitory myelosuppression or hematologic [93] showed that whole body absorbed dose is a
toxicities, salivary gland tenderness and short- most accurate predictor of hematological toxic-
term salivary dysfunction, pulmonary adverse ity in NB patients treated with 131I-mIBG therapy.
effects, hypertensive crises, etc. Others can be Then the prescription of administered activity
more dramatic or leave long-term consequences, based on whole-body absorbed dose allows per-
comprising bone marrow depression, deteriora- sonalized treatment according to an individual’s
tion of renal function, ARDS (acute respiratory hematologic toxicity.
distress syndrome) and bronchiolitis obliterans, George et  al. [94] calculated in 25 children
myelodysplasia, up to sparse secondary tumors affected by NB a mean whole body absorbed
or leukemia. Within the delayed toxicities, we dose per unit activity equal to 0.22  Gy/GBq.
can find also hypothyroidism and hypogonadism, Therefore, for an administered activity of
the former depending principally on the quality 11.1  GBq (300  mCi) the whole body dose is
78 A. Piccardo et al.

2.4  Gy. This value is in good agreement with tion would include both whole body and tumor
other studies on this issue. Matthay et  al. [95] dosimetry. To calculate the whole body absorbed
in 15 patients, Gaze et al. [96] in 8 patients, and dose before therapy it is necessary to evaluate
Bolster et al. [97] in 7 patients calculated mean the clearance of 131I-mIBG tracer making mea-
values of 0.23, 0.26, and 0.25 Gy/GBq, respec- surements over time using a whole body coun-
tively. By contrast, higher values have been ter. Instead, for tumor dosimetry the 123I-mIBG
evaluated in children affected by NB by other is most suitable, since it allows to obtain better
authors: Fielding et al. [98] in 25 patients calcu- scintigraphic images compared to 131I-mIBG, that
lated a mean whole body absorbed of 0.33 Gy/ is because the energy of the γ-ray emission of 123I
GBq, while Sudbrock et  al. [99] in 14 patients (159 keV) is close to the ideal for imaging using
and Monsieurs et  al. [100] in 6 patients values gamma cameras.
equal to 0.31 and 0.37 Gy/GBq, respectively. The The few studies that calculated the tumor
differences between the whole body absorbed absorbed dose in NB and PCC showed that it
dose values in NB patients reported in these ­varies widely. This is due to the large variability
studies could be related to the different residual between tumors, also within the same typology
tumor burden. Indeed, the whole body kinetics is of disease, regarding uptake and effective half-­
heavily influenced by that of the tumor. life. Sudbrock et al. [99] calculated in 24 tumors
Different studies conducted in adults affected (16 neuroblastoma and 8 pheochromocytoma) a
by PPC showed comparable body-absorbed dose mean tumor absorbed dose of 3.0 Gy/GBq (range
values. Tristam et al. [101] in 12 patients calcu- 1.1–5.8  Gy/GBq), while Tristam et  al. [101] in
lated a mean value of 0.12  Gy/GBq, similarly 20 tumors (4 NB and 16 PCC) calculated a mean
Sudbrock et al. [99] and Ertl et al. [102] in 4 and tumor absorbed dose of 2.2  Gy/GBq (range
3 patients, calculated a mean value equal to 0.14 0.04–20.0 Gy/GBq). Fielding et al. [98] in 7 NB
and 0.11  Gy/GBq, respectively. The significant tumors in children evaluated an absorbed dose
difference between the whole body absorbed value of 5.4 Gy/GBq (range 0.2–16.6 Gy/GBq),
dose values in NB and in PPC is related to the whereas Koral et  al. [105] in 7 pheochromocy-
different mass of the patients studied. In NB stud- toma tumors in adults a value of 9.2  Gy/GBq
ies, all patients were children, while in those with (range 2.2–21.6 Gy/GBq).
PPCs all patients included were adults. Therefore, for an administered activity equal
Buckley et  al. [103] demonstrated in NB to 11.1 GBq the tumor absorbed dose can range
patients that there is no correlation between the widely from few to hundreds of Grays.
absorbed dose by the whole body and that by the Since 131I-mIBG is cleared through the urine,
tumor. Indeed, tumor burden varies significantly the bladder could receive during treatment a high
and whole body absorbed dose is largely deter- radiation exposure such as to limit the adminis-
mined by kidney function. Moreover, Matthay tered activity. Fielding et  al. [98] in 5 children
et al. [92] in a large number of patients affected affected by NB without bladder catheters calcu-
by NB demonstrated the existence of a correla- lated a mean bladder wall absorbed dose equal
tion between the tumor absorbed dose for values to 3.1 Gy/GBq, and in 23 children a mean bone
>10 Gy and the tumor volume decrease. In this marrow absorbed dose of 0.34 Gy/GBq. Bolster
context, tumor dosimetry appears to be the most et al. [97] in 7 children affected by NB without
important index able to predict the outcome after bladder catheters calculated a much lower mean
131
I-mIBG therapy. Furthermore the knowledge bladder wall absorbed dose compared to Fielding
of the absorbed dose by the tumor as well as by et al. [98] equal to 0.76 Gy/GBq. This huge dif-
organs would also allow to combine 131I-mIBG ference is due to the fact that the wall bladder
therapy with external beam radiotherapy [104] in absorbed dose during treatment with 131I-mIBG is
order to obtain higher value of tumor absorbed strongly dependent on hydration and renal func-
dose not achievable with 131I-mIBG alone. Thus, tion of the patient. Koral et al. [106] and Matthay
an ideal scenario for a pretreatment investiga- et al. [95] in 7 and 15 children with NB evaluated
5  I-MIBG Therapy of Malignant Neuroblastoma and Pheochromocytoma
131
79

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Risk Group project. Radiology. 2011;261:243–57.
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In conclusion, a personalized dosimetry, Engl J Med. 2010;362:2202–11.
scheduled before 131I-mIBG, able to predict the 12. Pinto NR, Applebaum MA, Volchenboum SL,
dose to the bone marrow and to the tumor, seems Matthay KK, London WB, Ambros PF, et  al.
Advances in risk classification and treatment-
to be an important starting point to both select the strategies for neuroblastoma. J Clin Oncol.
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A, Munzer C, et  al. Poor survival for infants with
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Radiometabolic Therapy
of Bone Metastases 6
Gaetano Paone and Egbert U. Nitzsche

6.1 Radiometabolic Therapy toxic effects that are independent of the oxygen
of Bone Metastases— concentration, and the relative biological effec-
Targeted Alpha-Particle tiveness. Alpha-particles deposit their energy in
70–100  μm long tracks (less than 10 cell diam-
6.1.1 B
 asis of Alpha Emitter eters) with limited damage to the surrounding
Treatment normal tissue [3]. Another important advantage is
that α-particles are more likely than other types
Systemic targeted alpha-particle (α-particle) of radiation to cause double-strand breaks to
therapy represents an in-development approach DNA molecules, which is one of several effective
of targeted radionuclide therapy for specific causes of cell death. However, α-emitters are more
cancer diseases. A radionuclide is used, which toxic towards single cells compared to β-emitters
undergoes alpha-decay in order to treat cancer and whether there exists a relationship between a
lesions at close proximity. For example, cancer larger skeletal tumor burden and the efficacy of
lesions originating from bony metastatic disease Ra-223 remains to be clarified. Because of the
of castration-­
resistant prostatic cancer, glioma, short range of action, with its inherent overall
leukemia, lymphoma, melanoma, metastatic low hematological toxicity, it is not clear, whether
prostate cancer presenting with lymph node and α-particles reach the inner marrow areas, where
visceral metastases in addition to multiple osse- frequently prostate cancer cells are detected, or
ous metastases, and peritoneal carcinomatosis the inner part of larger metastases. In addition, the
underwent α-particle therapy [1, 2]. The primary tumor microenvironment, especially the relation
advantage of α-particle emitters compared to between prostate cancer cells and bone environ-
β-emitting radionuclides is their very high linear ment, needs more established insight information.
energy transfer (80 keV/μm), which leads to cyto- Radium-223 (Ra-223) dichloride (Xofigo®)
is the first targeted systemic α-emitter therapy
approach used for targeted α-particle therapy
G. Paone (*) of bone metastases in patients suffering from
Department of Nuclear Medicine and PET/CT
Centre, Oncology Institute of Southern Switzerland, castration-­
resistant prostate cancer. Ra-223 is
Bellinzona, Switzerland an isotope of radium with an 11.4-day half-life.
e-mail: gaetano.paone@eoc.ch Ra-223 mimics calcium and forms complexes
E. U. Nitzsche with the bone mineral hydroxyapatite at areas of
Department Nuclear Medicine and Molecular increased bone turnover, such as bone metastases.
Imaging, Aarau General Cantonal Hospital, Following intravenous injection, Xofigo® is rap-
Aarau, Switzerland
e-mail: egbert.nitzsche@ksa.ch idly cleared from the blood and distributed

© Springer Nature Switzerland AG 2019 85


L. Giovanella (ed.), Nuclear Medicine Therapy, https://doi.org/10.1007/978-3-030-17494-1_6
86 G. Paone and E. U. Nitzsche

primarily into bone. Xofigo® is mainly elimi- ing, optimal timing is important. Five substances
nated by fecal excretion, while renal elimination with three different mechanisms of action are
remained very small (range 1–5%) [4, 5]. Slower currently available for the treatment of mCRPC
intestinal transit time could potentially cause patients (Table  6.1). All of them have demon-
higher intestinal radiation exposure, which in turn strated a statistically significant survival benefit
may result in increased gastrointestinal toxicity. in randomized phase 3 trials: The two chemo-
However, Xofigo® is not metabolized. Therefore, therapeutic drugs docetaxel and cabazitaxel, the
hepatic as well as renal function impairment is not α-radiator Xofigo® and the androgen receptor
expected to affect its pharmacokinetics. Regarding signaling pathway inhibitors abiraterone and
cardiac electrophysiology, no large changes in the enzalutamide [6–12]. The ultimate place for
mean QTc interval (i.e., greater than 20 ms) were the use of Xofigo® is unclear. However, the use
detected for the calcium mimic Ra-223 up to 6 h of Xofigo® as the last treatment option has not
post-dose application. proved successful. Studies are currently investi-
gating the use in first-line therapy in combina-
tion with abiraterone or enzalutamide, and initial
6.1.2 I ndications, Contraindications, results are expected by the end of 2018. The
and Practical Remarks right time window enables:
for Xofigo® Therapy of Bony
Metastatic Disease in Patients –– The opportunity to administer all 6  cycles
Presenting with Castration-­ within an individual multimodal therapy regi-
Resistant Prostate Cancer men of choice.

Xofigo® is indicated as a single agent therapy for Regarding the opportunity to administer all
the treatment of castration-resistant prostate can- 6  cycles of Xofigo®, a recent study investigated
cer (CRPC) with symptomatic skeletal metasta- the previous and concurrent mCRPC therapies
ses and no known visceral metastatic disease. It and laboratory data that are associated with the
is approved for a course of 6 cycles. number of Xofigo® doses received. The investi-
The use of additional cycles and combinatorial gators obtained the following results: Twenty-­
strategies is currently evaluated in ongoing stud- five patients (18.5%) received 1–2 radium-223
ies. Several guidelines assigned a level 1 evidence doses, 27 (20.0%) received 3–4, and 83 (61.5%)
to Xofigo® for use in CRPC patients with bone received 5–6. The most common reasons for treat-
metastases who did or did not receive taxane-­based ment discontinuation included disease progres-
chemotherapy, for example, the American Society sion (61.5%, n = 40), patient preference (15.4%,
of Oncology, European Society for Medical n  =  10), and toxicity (10.8%, n  =  7). Factors
Oncology, European Association of Urology, and associated with therapy completion in univariate
American Urological Association, whereas the analysis included previous sipuleucel-­T treatment
NCCN guidelines recommend Xofigo® after use (P  =  0.068), no previous abiraterone or enzalu-
of the first novel hormone. As greater insights tamide treatment (P = 0.007), hemoglobin ≥ lower
into specific biomarkers, such as somatic or limit of normal (LLN; P  =  0.006), white blood
germline mutations targeted by poly ADP ribose cell count ≥ LLN (P  =  0.045), absolute neutro-
polymerase (PARP) inhibitors develop, Xofigo® phil count (ANC) ≥ LLN (P = 0.049), lower alka-
is of potential interest too. Xofigo® may prove line phosphatase (P  =  0.029), and lower lactate
beneficial in patients with splice variant, such dehydrogenase levels (P  =  0.014). Factors asso-
as androgen-­receptor splice variant 7 messenger ciated with therapy completion in multivariable
RNA (AR-­V7), that might render novel oral hor- analysis included previous sipuleucel-­T treatment
monal agents less advantageous. (P = 0.009), hemoglobin ≥ LLN (P = 0.037), and
Since multimodality therapy, e.g., the right ANC  ≥  LLN (P  =  0.029). Therefore, it appears
therapeutic for the right patient at the right time that several clinical parameters are associated
for individualized cancer therapy is progress- with Xofigo® therapy completion. Overall, these
6  Radiometabolic Therapy of Bone Metastases 87

Table 6.1  Flowchart to choose a first-line treatment in CRPC with symptomatic bone metastases, no visceral lesion

CRPC patients with symptomatic bone metastases,


without visceral lesions

Unfit for CHT


Fit for CHT

Taxane-based chemotherapy
[docetaxel and cabazitaxel] Xofigo Androgen receptor signaling pathway
inhibitors [abiraterone and enzalutamide]

Xofigo Androgen receptor signaling pathway


inhibitors [abiraterone and enzalutamide]

parameters potentially reflect earlier disease stage analysis. There were no significant associations
and require prospective testing [13]. between hematologic toxicities and number of
A recent multivariate analyses of data from Xofigo® injections received (4–6 vs. 1–3). This
ALSYMPCA trial patients carried out by means that hematotoxicity is not cumulative.
Vogelzang et  al. [14] identified baseline factors Of note, blood count follow-up of eryth-
that may increase hematologic toxicity risk with rocytes at least over the last 3  months without
Xofigo® such as extent of disease and degree of continuous decrease, which signalizes prob-
prostate-specific antigen elevation, which were able early discontinuation of Xofigo® therapy, is
predictive of grade 2–4 anemia; prior docetaxel, important in order to enable the patient to receive
and decreased hemoglobin and platelets, both most likely all six treatment cycles. Moreover, in
were predictive of grade 2–4 thrombocytopenia. that way the major goals of Xofigo® treatment,
Patients with these factors require close monitor- e.g., prolongation of overall survival, delay of
ing during Xofigo® therapy. Further, grade 3/4 skeletal-­related adverse events, pain relief, and
thrombocytopenia was more common in Xofigo® subsequently improvement of the quality of life
versus placebo patients (6% vs. 2%). Logistic may be achieved best.
regression analyses identified significant base- However, some current contraindications such
line predictors for grade 2–4 hematologic tox- as jaw osteonecrosis, spinal cord compression,
icities related to Xofigo® treatment: extent of recent fractures, and inflammatory bowel disease
disease (6–20 vs. < 6 bone metastases; odds ratio (for example, Crohn’s disease and ulcerative coli-
[OR]  =  2.76; P  =  0.022) and elevated prostate-­ tis) may be specifically investigated in the future.
specific antigen (OR = 1.65; P = 0.006) for ane- Data about pain should be collected based
mia; prior docetaxel (OR  =  2.16; P  =  0.035), on a structured interview: Pain localization and
decreased hemoglobin (OR  =  1.35; P  =  0.008), score (based on a visual analog pain scale), num-
and decreased platelets (OR = 1.44; P = 0.030) ber and type of analgetic treatment. The bone
for thrombocytopenia. Neutropenia events were metastasis osteoblastic activity must be con-
too few in placebo patients for a comparative firmed by functional bone imaging [bone scan
88 G. Paone and E. U. Nitzsche

(Figs. 6.1 and 6.2) or sodium fluoride positron 6.1.3 Results of Xofigo® Therapy
emission tomography/computed tomography]. of Bony Metastatic Disease
Before starting the Xofigo® treatment, patients in Patients Presenting
need to have platelet count ≥100*109/L, hemo- with Castration-Resistant
globin level  ≥  10  g/dL, and absolute neutro- Prostate Cancer
phil count ≥1.5*109/L.  Patients can undergo
Xofigo® treatment and follow-up as outpa- 6.1.3.1 Overall Survival
tients, because the estimated radiation dose Based on the ALSYMPCA trial, Xofigo® proved
to caregivers and household members is very effective regarding the improvement of over-
low, 2  μSv  h  −  1  MBq  −  1 on contact and all survival [14.9  months vs. 11.3  months; haz-
0.02  μSv  h  −  1  MBq  −  1 at 1  m immediately ard ratio (HR)  =  0.70, 95% confidence interval
after administration [15]. (CI) = 0.58−0.83; p = 0.00185)] [7].

R V L L D R R V L L D R

Three months post


Pre Xofigo® therapy
6 cycles Xofigo® therapy

Fig. 6.1  Bone scan response in a 55-year-old patient pre- within the scapula, ribs, and pelvis bilaterally as well as
senting with castration-resistant metastatic prostate can- the vertebral column, while the follow-up bone scan three
cer and multiple bone metastases prior to Xofigo® therapy months after completion of Xofigo® therapy demonstrates
and regressed metastatic bone disease 3  months after markedly reduced osteoblastic activity in the reference
completion of six therapy cycles. Legend: There are mul- lesions of the right scapula, vertebra TH 6, and ribs 6/7
tiple findings of increased osteoblastic activity represent- right anterolateral, whereas multiple smaller lesions
ing metastatic spread of prostate cancer into the skeleton within the ribs and pelvic skeleton disappeared
6  Radiometabolic Therapy of Bone Metastases 89

R V L L D R R V L L D R

Three months post


Pre Xofigo® therapy
6 cycles Xofigo® therapy

Fig. 6.2  Bone scan representing progressive bony meta- prostate cancer into the skeleton within the pelvis bilater-
static disease in a 62-year-old patient presenting with ally as well as one rib lesion in the fourth rib dorsal right
castration-resistant metastatic prostate cancer and multi- sided. Three months after completion of Xofigo® therapy
ple bone metastases prior to Xofigo® therapy and progres- the follow-up bone scan demonstrates despite the known
sive disease 3  months after completion of six therapy metastatic lesion in the pelvic bone new metastatic bone
cycles. Legend: There are multiple findings of increased lesions outside the pelvic skeleton representing progres-
osteoblastic activity representing metastatic spread of sive bony metastatic disease

6.1.3.2 Delay of Skeletal-Related randomization was investigated. Significantly


Adverse Events fewer Xofigo® (218/589; 37.0%) vs. placebo
The time until the onset of skeletal events was patients (133/292; 45.5%) had at least one hos-
prolonged (15.6 vs. 9.8 months; HR = 0.66, 95% pitalization event (P  =  0.016). However, mean
CI = 0.52−0.83; p < 0.001) [16]. number of hospitalization events per patient
was similar (Xofigo® 0.69 vs. placebo 0.79,
6.1.3.3 Improvement of the Quality P  =  0.226), likely due to the significantly lon-
of Life ger follow-up time for Xofigo® (7.82 months vs.
The quality of life was improved (p  =  0.02) 6.92 months for placebo) [17].
and deterioration in ECOG-PS of two or more
points was significantly lower in the Xofigo® 6.1.3.4 Treatment Monitoring
treated group (HR = 0.62, 95% CI = 0.46−0.85; Regularly, six Xofigo® iv injections are given
p  =  0.003). In addition, healthcare resource in 4-week treatment intervals over six months.
use (HCRU), including hospitalization events Whenever possible, the Xofigo® treatment should
and days, were prospectively collected in be a tandem care provided by (uro)oncology/
the ALSYMPCA trial. Subsequently health- nuclear medicine physicians according to the
care resource use for the first 12  months post-­ multiple eyes watching principle in an optimized
90 G. Paone and E. U. Nitzsche

therapeutic setting. Standard hematologic blood were infrequent [19, 20]. Nadir of myelotox-
tests prior to each treatment with Xofigo® are icity occurred at 2–4  weeks after treatment
mandatory as well as proper restaging of disease and recovery was observed within 24  weeks
prior to initiation of Xofigo® therapy. [21]. In any case, myelosuppression was dose-
Circulating biomarkers like alkaline phospha- related and reversible. However, more common
tase (ALP) and prostate-specific antigen (PSA) no-­hematological toxicities, such as diarrhea,
are indicators of overall response. Unfortunately, nausea, vomiting, and fatigue, were more fre-
both are indirect markers and do not provide quent than with other novel therapies, such as
information about individual sites of involve- abiraterone and enzalutamide, although easily
ment. Therefore, laboratory measurement of ALP manageable [22].
and PSA is regularly recommended prior to and
3 months after completion of Xofigo® treatment. 6.1.5.2 Xofigo® Re-Treatment
In case of a clinical worsening of the patient with As indicated from initial results published recently,
suspected progressive tumor disease or recur- Xofigo® re-treatment was well tolerated in a highly
rence of symptoms, especially on the skeleton, selected population, with minimal hematologic
an intermediate check should be performed toxicity, and provided continued control of disease
using available on-site morphological and func- progression in bone [23].
tional imaging approaches (evaluation of skeletal
metastases, new and/or progressive lymph node 6.1.5.3 Carcinogenesis, Mutagenesis,
metastases, new-onset of visceral metastases) Impairment of Fertility
and supplementary ALP and PSA check. Animal studies have not been conducted to eval-
uate the carcinogenic potential of Radium-223
dichloride. However, in repeat-dose toxicity
6.1.4 Methodology studies in rats, osteosarcomas, a known effect
of the Treatment of bone-seeking radionuclides, were observed at
clinically relevant doses 7–12  months after the
European expert recommendations sharing best start of treatment. The presence of other neoplas-
practice and experience to optimize Xofigo® tic changes, including lymphoma and mammary
treatment service provision and improvement of gland carcinoma, was also reported in 12- to
patient care have been published recently by Du 15-month repeat-dose toxicity studies in rats.
Y and coworkers [18]. Key points such as: Genetic toxicology studies have not been con-
ducted with Radium-223 dichloride. However,
–– center organization, preparation including
the mechanism of action of Xofigo® treatment
staff training and patient referral,
–– Xofigo® ordering, preparation, and disposal, involves induction of double-strand DNA breaks,
which is a known and in this case desired effect
–– Xofigo® treatment delivery including initial
of radiation.
consultation, required blood tests, and admin-
Animal studies have not been conducted
istration of the agent with a suggestion for
to evaluate the effects of Xofigo® treatment on
follow-up consultation, and finally
male or female fertility or reproductive function.
–– patient experience with regard to comfort, sat-
Xofigo® may impair fertility and reproductive
isfaction, and proper information are explained.
function in humans based on its mechanism of
action.
6.1.5 Risks and Complications The safety and efficacy of concomitant che-
of the Procedure, Side Effects motherapy with Xofigo® have not been estab-
(Immediate/Long-Term) lished. Outside of a clinical trial, concomitant
use with chemotherapy is not recommended due
6.1.5.1 Safety and Side Effects to the potential for additive myelosuppression. If
chemotherapy, other systemic radioisotopes, or
The safety for Xofigo® therapy was demon- hemibody external radiotherapy is administered
strated, since grade 3 and 4 myelotoxicity during the treatment period, Xofigo® should be
6  Radiometabolic Therapy of Bone Metastases 91

discontinued. This also applies to ongoing corti-quent. Six Xofigo® iv injections are given in
sone therapy due to the risk of bone fracture. 4-week treatment intervals over six months.
Whenever possible, the Xofigo® treatment
6.1.5.4 Secondary Malignant should be a tandem care provided by (uro)
Neoplasms oncology/nuclear medicine physicians accord-
Xofigo contributes to a patient’s overall long-­ ing to the multiple eyes watching principle in an
®

term cumulative radiation exposure. Long-term optimized therapeutic setting. Standard blood
cumulative radiation exposure may be associated tests prior to each treatment with Xofigo® are
with an increased risk of cancer and hereditary mandatory as well as proper restaging of dis-
defects. Due to its mechanism of action and ease prior to initiation of Xofigo® therapy. The
neoplastic changes, including osteosarcomas in right time window (yet to be defined more pre-
rats, Xofigo® may increase the risk of osteosar- cisely) enables the opportunity to administer all
coma or other secondary malignant neoplasms. 6  cycles within an individual multimodal ther-
However, the overall incidence of new malig- apy regimen (Table 6.2).
nancies in the randomized trial was lower on In the future Xofigo® may not be administered
the Xofigo arm compared to placebo (<1% vs. in castration-resistant prostate cancer patients
®

2%; respectively). The expected latency period with symptomatic bone metastases only, but also
for the development of secondary malignancies in patients presenting with metastatic high-risk
exceeded the duration of follow-up for patients osteosarcoma and metastatic bone disease in
in the trial. Moreover, a recent updated final hormone-­ refractory breast cancer as indicated
long-term safety follow-up ALSYMPCA analy- from ongoing trials [26, 27].
sis shows that Xofigo® is well tolerated in CRPC
patients with symptomatic bone metastases, with
minimal nonhematologic adverse events, a low Table 6.2  Xofigo quick use-guide
incidence of myelosuppression with long-term Indication CRPC with symptomatic skeletal
metastases and no known visceral
preservation of hematopoietic function, and no metastatic disease
new safety issues [24]. Administration Six Xofigo® iv injections are given
in 4-week treatment intervals over
6.1.5.5 Interactions with Other Drugs 6 months
Concurrently Used Blood test Plt count ≥100*109/L, Hb level
pre-therapy ≥ 10 g/dL, ANC count ≥1.5*109/L.
Subgroup analyses indicated that the concur-
Treatment Standard blood tests prior to each
rent use of bisphosphonates or calcium channel monitoring treatment are mandatory
blockers did not affect the safety and efficacy Hematological Grade 3/4 myelotoxicity
of Xofigo® in the randomized clinical trial. side effect (Infrequent). Nadir at 2–4 weeks
Regardless of baseline opioid use, a favorable after treatment and recovery within
24 weeks.
safety profile in castration-resistant prostate can-
Non-­ Diarrhea, nausea, vomiting, and
cer patients with symptomatic bone metastases hematological fatigue
was observed [25]. side effect
Concomitant Concomitant chemotherapy or
therapy EBRT with Xofigo® have not been
established and is not
6.1.6 Summary recommended. If chemotherapy,
other systemic radioisotopes or
To date it is established that Xofigo® improves hemibody external radiotherapy are
survival and the quality of life in patients suf- administered during the treatment
period, Xofigo® should be
fering from castration-resistant prostate cancer
discontinued
with symptomatic bone metastases. It prolongs Interactions Concurrent use of bisphosphonates
the time until the onset of skeletal events. The with other drugs or calcium channel blockers did not
safety for Xofigo® therapy was demonstrated, affect the safety and efficacy of
since grade 3 and 4 myelotoxicity were infre- Xofigo®
92 G. Paone and E. U. Nitzsche

6.2 Radiometabolic Therapy specific affinity for bone remodeling sites and are
of Bone Metastases— classified as osteotropic drug [31–34].
Targeted Beta-Particle Multiple β-emitting radionuclides had been
evaluated and used clinically prior to the develop-
6.2.1 B
 asis of Beta Emitter ment of radium-223 (Table 6.4). The most widely
Treatment studied are strontium-89 (89-Sr), samarium-­153
(153-Sm), Phosphorus-32, and Rhenium-186.
Radionuclide therapy with beta-particle In clinical application the most widely used are:
(β-particle) plays a crucial role in the pallia- 89-Sr (Metastron), 153-Sm EDTMP (Quadramet).
tive regimen of metastatic bone pain, represent- 89-Sr is an alkaline-earth metal, belongs to the
ing a valid alternative and support in the drugs same periodic family as calcium, able to bind to
sequence to treat cancer-induced bone pain. the bone without a carrier. It is marketed as chlo-
The ideal radionuclide for the treatment of bone ride (89SrCl2), rapidly eliminated by urinary tract
metastases presents the following characteristics: while 50% of the administered dose binds bone
selective uptake by bone metastases, rapid clear- structure. 153Sm-EDTMP is a chelated complex
ance from soft tissues and healthy bone, energy of a radioisotope (Samarium with EDTMP) that
emission between 0.8 and 2 MeV, bio-­distribution exhibits similar binding properties to the diphos-
similar to that of diphosphonates, limited irradia- phonates used for bone scintigraphy. It is rapidly
tion of the bone marrow, prompt availability, and removed from the bloodstream with the urine and
reasonable costs [28–30]. has a binding of 60% of the administered dose
Beta-emitting radionuclides, compared to [35–37].
α-particles, deposit their energy in 50–10.000 μm
long tracks with relative limited damage to the
6.2.2 I ndications, Contraindications,
surrounding normal tissue causing a single-
and Practical Remarks
strand breaks to DNA molecules, generally easy
for Beta-Emitters Therapy
to repair with less likely to introduce cellular
of Bony Metastatic Disease
death. As previously described these radionu-
clides exploiting their high LET (even if lower
Radiometabolic therapy with β-emitters is a tar-
than the α-particles, Table  6.3) directly on the
geted and selective treatment of metastatic bone
neoplastic cells (magic bullet), regulating in par-
localizations and is performed for analgesic
ticular the surrounding inflammatory reaction,
purposes. Further indication could be primary
thus temporarily reducing the pain, with a mod-
est amount of side effects. The therapeutic effect
Table 6.4  Radionuclide (β-emitters) characteristics
is mainly due to a lower release of pain modu-
latory agents, as cytokines and interferon, from T½ Eβ(MeV) Range Dose
Radionuclide (d) med/max (mm) max (mCi)
tumor microenvironment, reduced activation of
89-Sr (SrCl2) 50.5 0.58/1.46 6.8 4
periosteum nociceptors, edema and inflamma- 153-Sm 1.9 0.35/0.80 3.3 0.5–1/
tory reaction with associated decrease of inter- (EDTMP) Kg
stitial pressure and algogenic substances release. 32-P (Phosphate) 14.2 0.69/1.7 8.0 3–12
These bone-­seeking radiopharmaceuticals have a 186-Re (HEDP) 3.7 0.36/1.07 4.7 25–35

Table 6.3 Comparison of absorbed doses for red bone marrow and bone surface for selected osteotropic
radiotherapeutics
89-Sr 153-Sm 223-Ra
Radiation Beta Beta Alpha
Administered dose (MBq) 148 2590 21
Absorbed dose rBm (Gy) 1.628 3.988 1.50
Absorbed dose BSF (Gy) 2.516 17.508 16
6  Radiometabolic Therapy of Bone Metastases 93

ity of life, performance status, estimated life


expectancy, patient compliance) and generally
require a stepwise approach to pain management
led by variety of therapeutic options available.
Chemotherapy, targeted therapies, and hormone
therapy may contribute to pain relief by reducing
tumor bulk and/or by modulating pain-signaling
pathways. In the late stage of disease few drugs
are effective, making necessary other therapeu-
tic approach as radiation therapy and recently
bisphosphonate in addition to the analgesic
strategy. Bone-targeted radionuclide therapy, for
its effectiveness and safety profile, fits into this
scenario as a valid option for pain palliation in
diffuse bony disease and are generally reserved
for individuals with persistent or recurrent multi-
focal bone pain after EBRT and/or other forms of
therapy. Generally 153-Sm is approved for pain
palliation in patients with confirmed osteoblastic
bone lesions that enhance on radionuclide bone
scan, while 89-Sr is approved for the relief of
bone pain in patients with painful skeletal metas-
tases [39].
Fig. 6.3  Bone scan evaluation pre-radionuclide therapy
with 153-Sm in a 66-year-old patient presenting with 6.2.2.1 Contraindications of Bone-­
CRPC. Legend: Positive bone scan with multiple findings Targeted Radiopharmaceutical
of increased osteoblastic activity representing metastatic Therapy
spread of prostate cancer into the skeleton in patient with Absolute contraindications are: pregnancy,
diffuse bone pain
breastfeeding, acute or chronic renal failure
­(creatinine >1.8 mg/mL and or glomerular filtra-
painful bone tumors when confirmed by areas of tion rate  <  30  mL/min), acute spinal cord com-
intense uptake on bone scintigraphy; however, pression and myelosuppression (PLT < 60 × 109,
this indication is not yet approved. leukocytes less than 2.5  ×  109/L), a life expec-
Prerequisite for bone-targeted radionuclide tancy <1 month.
treatment is a positive bone scan and associ- Relative contraindications are: predominant
ated diffuse bone pain (Fig.  6.3). Contextual extra-skeletal metastatic involvement, diffuse
general condition are: refractory bone pain to medullary involvement defined as “superscan”
minor analgesic therapy or opioid therapy in on bone scintigraphy (Fig. 6.4) with higher risk
increasing doses, life expectancy >3  months, of myelotoxicity, chemotherapy and/or radio-
no cytotoxic chemotherapy and/or radiation therapy performed in the previous 6 weeks,
therapy a few weeks (6  weeks) prior to treat- disseminated intravascular coagulation (DIC)
ment and preserved bone marrow reserve with associated risk factor for severe throm-
(BCC: Hb  >  90  g/L; WCC  >  3.5  ×  109/L, bocytopenia, myelosuppression (PLT < 100
PLT  >  100  ×  109/L) and renal function × 109/L), pathological fracture (therapy fea-
(Creatinine 0.5–1.5 mg/mL) [38]. sible only in association with prosthesis and/
The most appropriate treatment choice may or external RT and evidence of other metastatic
be complex, influenced by multiple factors (qual- sites) [40, 41].
94 G. Paone and E. U. Nitzsche

6.2.3 Results of Beta-Emitters The main advantage is represented by rapidly,


Therapy of Bony Metastatic selectively, and simultaneously targeting of all
Disease bone lesions.
Several clinical trials confirm that β-emitters
The main objectives in the management of patient can achieve bone pain relief with response rate
with bone metastases are: optimization of pain between 50 and 95%, including a complete relief
control, preservation and restoration of function, in about 15–30% of patients [42–44]. Single
stabilization of the skeleton, reduction of risk of treatment can achieve pain relief in about 70% of
skeletal-related events (SRE), quality of life and patient for 89-Sr and 153-Sm, otherwise combi-
improvement of local tumor control. The wide- nation with other therapies is slightly more effec-
spread and constant bone pain remains the most tive with pain palliation in 74% of patients with
disabling symptom and is not easily managed. prostate or breast cancer [45].
153-Sm was compared with placebo in two
6.2.3.1 Pain Palliation randomized phase III trials. Both found that treat-
Bone-targeted radioisotope therapy offers a ben- ment with β-emitter was more effective than pla-
eficial effect on pain control in patients with cebo in providing pain relief [46, 47].
osteoblastic or mixed pattern (osteoblastic/osteo- The effects of bone-targeted radiopharmaceu-
clastic) metastases [33, 34]. tical therapy in breast cancer was underlined in a
systematic review that confirm a moderate bone
pain palliation with low evidence in terms of sup-
porting the clinical effect in relieving pain [48].
Pain palliation has a latency period from the
administration time taking up to one to four
weeks and that is usually shorter for the 153-Sm
than 89-Sr. The palliative effect lasts 2–4 months
after the administration of the 153-Sm and from
3 to 6  months after administration of 89-Sr
(Table  6.5). Generally lithic bone metastases
showed a worse response (42%) than osteoblastic
(62.50%) or mixed pattern (60%) [49, 50].

6.2.3.2 Quality of Life and Survival


Radionuclide treatment proved effective regard-
ing the improvement of quality of life in patients
with osteoblastic or mixed pattern metastases
[51, 52].
Few results highlighted survival benefits after
radionuclide therapy with β-emitters, particularly
a phase II study in prostate cancer showed a sur-
vival benefit if chemotherapy was added to 89-Sr
(27.7 vs. 16.8 months) [53].
R ANT L L POST R
6.2.3.3 Combination of Radionuclide
Fig. 6.4  Bone scan evaluation in a 73-year-old patient Therapy and Other Treatments
presenting with CRPC. diffuse medullary involvement Bone-targeted radionuclide therapy, in patients
defined as “superscan” on bone scintigraphy. Legend:
Positive bone scan with diffuse medullary involvement
with multiple sites of symptomatic bone metas-
defined as “superscan” and considered as relative contra- tases, offers a similar degree of pain relief than
indication for radionuclide therapy with β-emitters external hemi-body radiation and may be asso-
6  Radiometabolic Therapy of Bone Metastases 95

Table 6.5  Effect on pain palliation and myelotoxicity of β-emitters


Radionuclide % reduction pain % complete relief Duration (m) Latency (w) Myelotoxicity
89-Sr 50–75 15–30 3–6 <2 w Moderate
153-Sm 65–75 30 2–4 1–3 w Low

ciated with less myelotoxicity. External beam Mandatory procedures to be performed before
radiotherapy (EBRT) represents the treatment of treatment are: medical history, life expectancy
choice if the bone scan is negative and in cases of estimation, radiological imaging, bone scan,
imminent pathological fracture. Combination of complete blood count, renal function evaluation,
EBRT and radionuclide therapy should be evalu- and pregnancy test. In the absence of contraindi-
ated only in selected patients [54]. cation, there are not specific patient preparation to
No evidence-based data support concomitant implement before the treatment. Patients should
or sequential use of radionuclide therapy and be informed about the risk of a possible initial
chemotherapy due to the possible myelotoxic- increase in bone pain (pain flare phenomenon)
ity. Normally it is preferable to avoid long-act- and that its reduction occurs within 2–4  weeks
ing myelosuppressive chemotherapy 4–6  weeks after therapy.
prior to the β-emitter administration. After Center organization, trained and certified
bone-­seeking radionuclide treatment (indiffer- staff, radionuclide ordering, preparation, and
ently 89-Sr, 153-Sm), systemic chemotherapy disposal are key points to administer radionu-
should be avoided for about 12  weeks. Among clide therapy.
the few data reported in literature certainly the Bone-seeking radionuclide should be admin-
TRAPEZE trial reports interesting result, in a istered intravenously slowly over 1–2  min,
cohort of 757 patients, suggesting improved clin- using appropriate precautions for handling
ical progression-­free survival after 89-Sr com- and disposal, followed by 0.9% saline flush. If
bined with docetaxel without evident benefits in ­extravasation occurs it is necessary to stop infu-
terms of OS and SRE free-interval [55]. sion. It is mandatory to measure with a prop-
Different studies support, instead, concomi- erly calibrated active meter radio-drug activity.
tant or sequential use of radionuclide therapy and Generally recommended doses are 37  MBq/Kg
bisphosphonates despite previous data under- for 153-Sm and 150 MBq (4 millicurie [mCi] or
lined the possible reduced uptake of bone-target 1.5–2.2 MBq/Kg) for 89-Sr. (Table 6.4).
radionuclide. In particular, recent studies indicate Re-treatment, in case of pain recurrence,
absence of competition between bisphosphonates should be based on individual response, symp-
and 153-Sm or 89-Sr [56–58]. toms, and blood counts and are generally
not recommended at intervals <90  days (10–
12 weeks for 153-Sm and 12 weeks for 89-Sr)
6.2.4 Methodology [38, 59, 60].
of the Treatment

EANM guideline published recently by 6.2.5 Risks and Complications


Handkiewicz-Junak et al. shared best practice and of the Procedure, Side Effects
experience to optimize radionuclide treatment in (Immediate/Long-Term)
patient with bone metastases suggesting, when-
ever possible, a multidisciplinary approach pro- Adverse reactions are very rare and frequency
vided by nuclear medicine physician, a medical not defined. A flushing sensation has been
oncologist, and a radiation oncologist according reported following rapid (<30  s) injection. No
to the multiple eyes watching principle in an opti- suspected/dangerous interactions with other
mized therapeutic setting. drug were found.
96 G. Paone and E. U. Nitzsche

6.2.5.1 Immediate Side Effects radiopharmaceutical excretion during the first


Pain-flair phenomenon is a transient increase in 24–48  h after injection. Patients must comply
bone-pain. It usually occurs in about 5–15% of rigorous hygiene rules to avoid contamination
cases and generally within 72 h after administra- using the same toilet facility. Inpatient treatment
tion. This symptom is temporary and responding required rigorous radiation safety instructions
to a common analgesic therapy. It represents an for nursing personnel; urinary catheterization is
“inflammatory” reaction caused by irradiation necessary for incontinent patients (to minimize
and is considered a positive-response indicator radioactive contamination of clothing, bedding,
to the treatment associated with a good clinical and/or environment) [38, 39].
response.
Nausea and vomiting are very rare, par-
ticularly observed in patients with diffuse bone 6.2.6 Summary
involvement [39, 61].
Radionuclide therapy with β-emitters is purely
6.2.5.2 Long-Term Side Effects palliative in case of symptomatic bone metas-
Frequent moderate transient myelotoxicity is tases refractory to analgesics/opioid therapy.
observed, predominantly affecting thrombocyte Key clinical aspects are life expectancy superior
and leukocyte. Nadir and recovery times are >3  months, no cytotoxic chemotherapy and/or
usually related to the individual condition and radiation therapy a few weeks (6  weeks) prior
radioactivity. Generally bone marrow depres- to treatment and conserved bone marrow reserve
sion begins after 2  weeks, nadir at 3–5  weeks (Table  6.6). To date it is established that bone-­
(153 Sm) or 12–16 weeks (89-Sr) with complete targeted radionuclide therapy offers a beneficial
or partial recovery within 3–6 months. effect on pain control and improvement of qual-
Myelosuppression with grade 3 or 4 toxicity is ity of life in patients with osteoblastic or mixed
strictly related to previous therapy, bone marrow pattern (osteoblastic/osteoclastic) metastases.
reserve and may be exacerbated by bone marrow The main advantage is represented by rapidly,
replacement in case of extensive bone involve- selectively, and simultaneously targeting of all
ment. Use is not recommended in patients with bone lesions. No evident data were highlighted in
severely impaired bone marrow function by prior terms of survival and concomitant or sequential
therapies or diffuse disease infiltration (unless use of β-emitters therapy with EBRT and chemo-
potential benefit outweighs risks). therapy. Contrarily the concomitant/sequential
Monitor blood-count may be useful for up use with bisphosphonates is indicate in clinical
to 6  weeks after treatment with 153-Sm. After routine. Life expectancy estimation, bone scan
89-Sr administration longer follow-up is required and radiological imaging, complete blood count,
because of prolonged and more evident myelo- renal function evaluation, pregnancy test are man-
toxicity (12–16 weeks) [38, 62]. datory prior to initiation of therapy. The safety
was demonstrated with moderate myelotoxicity,
6.2.5.3 Radiation Safety Procedure exacerbated by bone marrow replacement in case
Pregnancy should be avoided for at least of extensive bone involvement. Use is not recom-
6–8 months following treatment. In case of treat- mended in patients with severely impaired bone
ment on an outpatient basis, patients remain in marrow function by prior therapies or diffuse
the nuclear medicine department for 4–6 h after bone infiltration. Monitor blood-­count is useful
administration to assess any early side effects. after treatment (for up to 6 weeks with 153-Sm
Particular precaution is necessary for urinary and 12–16 weeks after 89-Sr).
6  Radiometabolic Therapy of Bone Metastases 97

Table 6.6  β-Emitters quick use-guide 4. Bruland OS, Larsen RH.  Radium revisited. In:
Bruland OS, Flagstad T, editors. Targeted cancer
Indication Palliative treatment in symptomatic
therapies: an odyssey. Ravnetrykk No. 29: University
bony metastatic disease refractory to
Library of Tromso; 2003. p. 195–202.
analgesics/opioid therapy
5. “Preparation and use of radium-223 to target calcified
Administration β-emitters radionuclide should be tissues for pain palliation, bone cancer therapy, and
administered intravenously slowly bone surface conditioning” US 6635234 http://patft.
over 1–2 min uspto.gov
Blood test Hb > 90 g/L; WCC > 3.5 × 109/L, 6. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska
pre-therapy PLT > 100 × 109/L A, Chi KN, et al. Docetaxel plus prednisone or mito-
Re-treatment Based on individual response, xantrone plus prednisone for advanced prostate can-
symptoms, blood counts and generally cer. N Engl J Med. 2004;351(15):1502–12.
not recommended at intervals 7. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan
<90 days JM, Fossa SD, et  al. Alpha emitter radium-223 and
Hematological Transient myelotoxicity predominantly survival in metastatic prostate cancer. N Engl J Med.
side effect affecting thrombocyte and leukocyte. 2013;369(3):213–23.
Nadir at 3–5 weeks (153 Sm) or 8. de Bono JS, Oudard S, Ozguroglu M, Hansen S,
12–16 weeks (89-Sr) with complete or Machiels JP, Kocak I, et  al. Prednisone plus caba-
partial recovery within 3–6 months. zitaxel or mitoxantrone for metastatic castration-­
Non-­ Pain-flair phenomenon (transient resistant prostate cancer progressing after docetaxel
hematological increase in bone-pain). Nausea and treatment: a randomised open-label trial. Lancet.
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Interactions Concomitant or sequential use of
Cotogna PM, Steinberger AE, et  al. Radium-223
with other radionuclide therapy and
use in clinical practice and variables associated
drugs bisphosphonates did not affect the
with completion of therapy. Clin Genitourin Cancer.
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2016;15(2):e289–98.
14. Vogelzang NJ, Coleman RE, Michalski JM, Nilsson
S, O’Sullivan JM, Parker C, et al. Hematologic safety
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Amato RJ, Pagliaro LC, et  al. Bone-targeted ther-
Selective Internal Radiotherapy
(SIRT) of Primary Hepatic 7
Carcinoma and Liver Metastases

Niklaus Schaefer

7.1 Introduction embolic agents to induce ischemia. The trans-­


arterial chemotherapy (TACE) consists of a che-
SIRT (selective internal radiation therapy) is a motherapeutic agent mixed with an embolic
form of internal radiation given to a selective site. material. This combination allows a very high
In Nuclear Medicine the term “SIRT” is usually concentration of chemotherapy in the respective
used in the context of internal radiation of liver metastases. A third relatively widely used ther-
metastases and primary liver tumors as apy option is the trans-arterial radioembolization.
HCC. Other terms for this form of treatment are Contrary to TAE and TACE it deposits radiation
liver radioembolization or trans-arterial radioem- in the tumor bed and can be used in patients who
bolization (TARE). develop chemo-resistant metastases. Furthermore
All forms of intra-arterial treatments of liver it is in contrary to TAE and TACE not embolic.
tumors have a distinctive mode of action. The TARE therefore has less complication, is overall
liver is perfused by the liver arteries and the por- better tolerated by the patients, and can be used in
tal vein. In physiological condition the liver is larger tumor burden in the liver. In the following
perfused around 90% by the portal vein, and chapter we overview technical aspects, the
around 10% by the hepatic arteries. In contrast, dosimetry, clinical data, side effects, and how to
intrahepatic tumors are normally perfused only follow up patients after TARE.
by the arterial vessels and therefore restricted
from the portal venous flow (Fig. 7.1). Therefore,
catheterizing the arterial blood flow is of specific 7.2 Technical Procedure
interest since different forms of payload can be
transported in the tumoral capillary bed. Several A TARE procedure consists of two major techni-
forms of intra-arterial liver-directed treatments cal sessions, which are performed, by a radiolo-
exist. The trans-arterial embolization (TAE) is gist and nuclear physician in consensus. It needs
used to obliterate the arterial supply of liver pri- to be underlined that the nuclear physician needs
mary tumors or liver metastases. TAE or bland a profound understanding of the liver anatomy to
embolization of intrahepatic arteries aims to understand angiography images and possible pit-
block the hepatic arterial flow using different falls, as well as the radiologist needs the knowl-
edge about the nuclear medicine procedure and
interpretation of the functional images. It is also
N. Schaefer (*) mandated that the NM physician and the radiolo-
Department of Nuclear Medicine, University Hospital gist both perform a pre-interventional visit to dis-
of Lausanne, Lausanne, Switzerland
e-mail: Niklaus.Schaefer@chuv.ch cuss the indication and possible contraindications

© Springer Nature Switzerland AG 2019 101


L. Giovanella (ed.), Nuclear Medicine Therapy, https://doi.org/10.1007/978-3-030-17494-1_7
102 N. Schaefer

Venous Blood Flow Arterial Blood Flow


Arterial Blood Flow Venous Blood Flow

Fig. 7.1  General principle of hepatic blood flow in a normal liver and a liver with tumor metastases or primary tumors

Table 7.1  Contraindication for Liver TARE sis of the arterial perfusion of the liver, an injec-
• Ascites or other clinical signs of liver failure on tion of Tc99m macro-albumins (MAA) is
physical exam [absolute] performed at the respective site where the thera-
•  Pregnancy [absolute] peutic injection is anticipated. The dose of Tc99m
• Previous radiation therapy to the liver (not MAA might be prescribed between 60 MBq for a
stereotactic, gamma/cyberknife)
single left lobe and 180 MBq for an injection of
• Excessive tumor burden with limited hepatic
reserve (>66%) the total liver.
• Capecitabine within previous or subsequent After successful injection of Tc99m MAA,
2 months the patient should be transferred with not too
• Abnormal organ or bone marrow function as much delay in the Nuclear Medicine unit to per-
determined by:
form scintigraphy to avoid free technetium-99m
 – Total bilirubin level > 2.0 mg/dL (>34 μmol/L)
in absence of reversible cause
in the diagnostic images. Usually the diagnostic
 –  Serum albumin <3.0 g/dL scintigraphy scan aims to calculate the liver-­
 – AST (SGOT)/ALT (SGPT) >5 × institutional versus-­lung ratio to calculate a possible shunting
ULN of the MAA product in liver veins and subse-
 –  Creatinine >2.5 mg/dL quently in the lung. A shunt up to 10% needs no
 – Platelets <60,000/μL; leukocytes <2500/μL; therapy adaption, if shunt is between 10% and
absolute neutrophil <1500/μL
20% a dose reduction is anticipated and a shunt
Following work-up procedure:
>20% needs either replanning of the angiography
• Pre-treatment scan showing >20% Lung Shunting
[absolute] to exclude the shunting liver volume or the patient
•  Non-correctable shunting to the GI tract [absolute] cannot be treated by TARE. After planar liver /
thorax imaging, usually a single photon com-
puted tomography (SPECT) of the liver region
(Table 7.1) of the patient and discuss all cases in needs to be performed. The SPECT identifies
the multidisciplinary tumor board to evaluate all visually and computationally the ratio between
possible therapy option for the patient. malignant liver tumors and normal liver tissue
After decision to perform a TARE and which needs to be spared from internal radiation.
obtained consensus of the patient two principal As general rule the radiation applied to the nor-
interventional session need to be planned mal liver should not exceed 40 Gy to avoid liver
(Fig. 7.2). A first session is purely diagnostic and fibrosis. However this limit has been set using
establishes the principle knowledge about the external beam radiation and is the limit to induce
anatomic properties of the arterial perfusion liver fibrosis of the normal liver. Newer data rec-
using the angiography. In this first session possi- ommend doses for the normal liver up to 70 Gy.
ble interfering arteries, for example, gastric or Further careful evaluation needs to be performed
duodenal arteries, might need coiling by the radi- on intestinal shunting, for example, in the duode-
ologist to avoid misplacement of the radioactive nal/pyloric region, the gastric wall, and the
beads in the therapy session. After careful analy- ­pancreas. After evaluating the above parameter, a
Diagnostic Angiography Dosimetric Angiography Post-Intervnetional
Patient Selection Diagnostic
Arterial Coiling Calculations Y90 TARE Treatment Bremsstahlung Scan
Tumorboard MAA Scintigraphy
Tc99m MAA Injection

Diagnostic Phase Therapy Planning Therapeutic Phase

Fig. 7.2  Workflow of a TARE procedure


7  Selective Internal Radiotherapy (SIRT) of Primary Hepatic Carcinoma and Liver Metastases
103
104 N. Schaefer

dosimetry to optimize the given dose is recom- further side effects. Imaging control is recom-
mended and the patient is planned for the thera- mended usually after three months and will be
peutic procedure. This second intervention discussed later in the text.
usually is planned at a different day after per-
forming dose calculation or dosimetry. The prin-
ciple of dose calculation and dosimetry is 7.3 Dose Calculation
described in the next section. and Dosimetry
The therapeutic procedure needs again careful
investigation of the liver arterial anatomy. Due to The dose calculation relies on the simple princi-
coiling of relevant arteries the arterial perfusion, ple not to harm the normal liver tissue caused by
for example, of the duodenum, via a supra-­ off target treatment and lung tissue caused by
duodenal artery or any other intestinal organs arteriovenous shunting of the radioactive spheres.
might change. After careful investigation the cath- It has been shown in the past that patients receiv-
eter is placed at the respective site of the prepara- ing more than 40 Gy on the normal liver by exter-
tion scan and the infusion of the radioactive, nal beam radiation develop radiation-induced
therapeutic beads is performed by the radiologist liver fibrosis (REILD). REILD is a subacute form
and nuclear physician in consensus. There are two of liver injury and develops usually after 4 weeks
general therapeutic products used for the TARE or later. The symptoms of a REILD are usually
procedure (Table 7.2) which both are based on the fatigue and right upper quadrant pain. Physician
Y90 isotope. Y90 is a relatively strong radiating examination can resemble a Budd-Chiari syn-
isotope (T1/2 64.10 h; β− energy 2282 MeV). It is drome with ascites and jaundice. A radiation-­
therefore very important that the staff is securely induced lung disease might develop in patients
protected at all tasks and the procedure is super- receiving over 20  Gy external beam radiation.
vised by personnel trained in radiation safety. There are several methods to calculate a dose for
Furthermore the angiography room needs to be patients receiving a selective internal radiother-
approved for open unsealed radioactive sources. apy. Most simple is a body surface method, which
After infusions of the Y90 beads, the patient is takes the affected liver versus normal liver into
transferred to the nuclear medicine unit to per- account. This method is called the BSA model
form a bremsstrahlung scan using SPECT imag- (body surface area). It is a validated method to
ing or an Y90 PET/CT to confirm the distribution prescribe a dose; however, due to a calculation
of the internal radiation (Fig.  7.3). The patient using a ratio this model is sensitive for overtreat-
furthermore needs carful clinical investigation to ment in small livers with small tumors and under
exclude short-term significant side effects treatment in large livers with large tumors.
(Table 7.2). A control by the referring physician
is recommended in the first two weeks to exclude
7.3.1 BSA Formula
Table 7.2  Products used for Liver TARE
DOSE ( GBq ) = BSA ( m 2 )
Glass Resin (SIR
(TheraSphere) Spheres) æ Volume Tumor ö
- 0.2 + ç ÷
Size 20–30 μm 20–60 μm è Volume Tumor + Volume Liver ø
Isotope Yttrium-90 in Yttrium-90 on
glass matrix resin surface The BSA formula has been mainly developed
Specific gravity High Low for SIR Spheres treatment and is still currently
Activity/sphere 2500 Bq 50 Bq used by many centers. The calculation for the
(at calibration)
# of dose sizes 6 (3, 5, 7, 10, 1 (3 GBq)
Therasphere product is different. The recom-
15, 20 GBq) mended dose by the producer is between 80 Gy
# spheres/dose 1.2–8 Million 40–80 Million and 150 Gy. The amount of radioactivity required
# spheres/3GBq 1.2 Million 40–80 Million to deliver the desired dose to the liver may be cal-
dose culated using the following formula:
7  Selective Internal Radiotherapy (SIRT) of Primary Hepatic Carcinoma and Liver Metastases 105

a b

Partition Model Dosimetry. RTF = 7:1


c 450

Dturn
400 Dnon turn

350

300
Dose [Gy]

250

200

150

100

50

0
0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6 2.8
Aadmin-[GBq]

d e

Fig. 7.3 (a) Angiography of a patient with well-differentiated tumoral liver. Predicting a dose of 40 Gy to the normal left
NET, post right hemi-hepatectomy showing multiple liver liver and 270 Gy on the metastatic NET lesions using a dose
lesions in the remaining left lobe. (b) SPECT/CT after injec- of 1.8 GBq of Y90 TARE. (d) SPECT/CT after 1.8 GBq of
tion of 60  MBq of 99mTc loaded macroalbumines. (c) Y90 TARE. (e) Follow-up MRI showing a very favorable
Partition model dose estimation: (blue) normal liver, (red) response
106 N. Schaefer

Mass of Targeted Liverkg


Activity ( GBq ) = ( Desired DoseGy ) *
50 * (1-
- Lung Shunt Fraction )

It is highly recommended that TARE dosing is 4.5–6.7) [2]. A multicenter study by Sangro et al.
performed by a highly experienced Nuclear reported outcome of TARE in 325 HCC patients.
Medicine specialist or a dedicated physicist. The The consortium reported a median overall sur-
compartment partition model is the most accurate vival of 12.8  months in the overall population.
means to determine the dose administered to the Divided in subgroups according to BCLC stages,
liver tumor, the normal parenchyma, and the lung outcome by disease stage (BCLC A 24.4 months;
and is based on uptake ratios, liver tumor volum- BCLC B 16.9  month; BCLC C 10.0  months)
etry, normal liver volumetry, and lung uptake [1]. [95% CI, 7.7–10.9 months]. Reported prognostic
factors in this study were ECOG status, hepatic
function (Child-Pugh class, ascites, and baseline
7.4 Clinical Data total bilirubin), tumor burden (number of nod-
ules, alpha-­fetoprotein), and presence of extrahe-
7.4.1 Hepatocellular Carcinoma patic disease [3]. Very recent prospective and
(HCC) randomized studies compare the efficacy of
TARE versus systemic treatment. A large
HCC is a primary carcinoma of the liver and European study showed no difference in overall
therefore is very suitable for liver-directed treat- survival of TARE versus Sorafenib (Beyer
ments. However, especially in limited disease Pharma, Berlin Germany). In brief, overall 467
many options exist and the indication to either patients were investigated and randomized into
operate, radiofrequency, TACE (trans-arterial the TARE or Sorafenib group. Median overall
chemoembolization) or SIRT versus systemic survival was 8.0 months in the TARE group ver-
treatment options have to be discussed carefully sus 9.9 months in the Sorafenib group (p = 0·18)
in a dedicated tumor board together with hepa- [4]. However, patients undergoing a single TARE
tologists, surgeons, interventional radiologists, intervention had significant less toxicities than
oncologists and nuclear physicians. Guidance patients in the Sorafenib group. This trial was
can be given via different staging systems, how- paired by a HCC trial in the Asia-Pacific region.
ever in HCC the Barcelona criteria (BCLC) are of Patients coming from this region have a distinct
use for treatment guidance. TARE has been tested different survival due to much more underlying
in early BCLC A to advanced stages (BCLC C). viral hepatitis as disease driver. Overall, this trial
Importantly, TARE has been shown to be safe in compared the safety and efficacy of Asian
patients with portal venous thrombosis (PVT). patients receiving either Sorafenib or
The efficacy of TARE in HCC is highly depen- TARE.  Median OS was 8.8–10.0  months with
dent on a number of factors regarding liver function, TARE and Sorafenib, respectively (hazard ratio,
patient performance status, and tumor extension 1.1; 95% CI, 0.9–1.4; p  =  0.36) and therefore
(BCLC, UNOS, Child-Pugh). First series pub- revealed no significant difference. However,
lished by the Northwestern group reported in 291 TARE was significantly better tolerated [5].
patients and 526 TARE treatments and overall There are several ongoing trials to prospectively
time to progression of 7.9 months and an overall investigate the role of SIRT in advanced HCC
survival differed between patients with Child- patients. A very prominent study is the STOP
Pugh A and B disease (A, 17.2  months; B, HCC trial by the Northwestern group, which
7.7 months; p = 0.002). Patients with Child-Pugh might be the largest multicenter study looking
B disease who had portal vein thrombosis (PVT) again at the question of Sorafenib and TARE as
survived 5.6  months (95% confidence interval, first line in HCC patients [6].
7  Selective Internal Radiotherapy (SIRT) of Primary Hepatic Carcinoma and Liver Metastases 107

Another important questions is to bridge since we speak, in contrast to HCC, of metasta-


patients to liver transplantation has been recently sized disease once liver tumor occur.
investigated. This might be a very useful concept Early randomized data compared TARE in
since patients usually wait long term to receive a combination with floxuridine versus floxuridine
donor liver. A recent combined series of 178 only. Progression-free survival was significantly
patients revealed promising data for patients linger in patients receiving TARE (15.9 vs.
with HCC waiting for liver transplant [7]. Further 9.7 months, p = 0.001) and toxicity was reported
concept involves liver TARE prior to hemihepa- to be very low without grade 3 or 4 toxicity. A
tectomy to induce liver growth in the future liver phase III study by Flamen et al. tested TARE in
remnant (FLR). It has been shown that FLR combination with 5 fluorouracil (5-FU) vs. 5-FU
growth after TARE reaches around 50% after only. Median time to progression was signifi-
nine months [8]. Other studies investigate the cantly longer in the TARE group (2.1 vs.
efficacy of TARE against TACE in HCC. Among 5.5  months; p  =  0.003) and median overall sur-
somewhat heterogeneous study results, large vival was 7.3 vs. 10.0 months in the TARE group
centers have shown that partial response rates [11]. A phase I study by Sharma et al. evaluated
favor TARE-Y90 versus TACE (61% vs. 37%) the combination of TARE with a modern FOLFOX
and downstaging to UNOS T2 was achieved in (5-FU, Oxaliplatin) regime. In this study 20
58% of the TARE patients compared to 31% of patients were enrolled and 18 of 20 patients
TACE patients [9]. Further studies investigated showed a partial response in the further evalua-
the role of surgery in HCC post-TARE.  Very tion. Median progression-free survival was
recent studies show the safety and efficacy of 9.3 months, and median time to progression in the
combining TARE and surgery [10]. liver was 12.3 months. The dose-limiting toxicity
Overall TARE in HCC seems to be a very use- was neutropenia but the combination was in gen-
ful therapy option. However, prospective studies eral well tolerated [12]. The promising results of
in a rather unselected patient population have not this phase I study led to the design of a large phase
shown superiority of TARE versus Sorafenib. III study to test TARE combined with FOLFOX
This underlines the importance how to choose versus FOLFOX alone. In a large patient popula-
correctly the patients and the necessity that all tion the median PFS at any site was 10.2 vs.
patients need to be performed at large center and 10.7  months in TARE plus FOLFOX versus
have to be evaluated by a dedicated tumor board. FOLFOX alone (p  =  0.43). However, the liver
only PFS revealed a significant longer local PFS
of 20.5 vs. 12.6 months (p = 0.002). Higher grade
7.4.2 M
 etastatic Colon Cancer adverse events were reported in 73.4–85.4% of
(mCRC) patients in FOLFOX versus the combined group
[13]. This data has been pooled with the FOXFIRE
The liver is a predominant site of distant metasta- trial [14] and global results were reported in over
ses in patients with advanced colon cancer. In the 1000 patients. Although higher numbers in
last twenty years, the evolution of systemic che- patients, the addition of SIRT to first-­ line
motherapy combined with antibody treatment in FOLFOX chemotherapy for patients with liver-
selected patients did yield high response rates and only and liver-dominant metastatic colorectal
prolonged overall survival. In this rapidly evolv- cancer did not improve overall survival compared
ing therapeutic armamentarium TARE treatment with that for FOLFOX alone [15]. Altogether,
needs to be chosen with care. In general, the same SIRT in combination with FOLFOX cannot be
rule as for HCC applies. All patients need to be recommended in early treatment lines. A current
seen in a dedicated colorectal tumor board with study (EPOCH, TS-102 study) is currently evalu-
all respective specialists. Especially the oncolo- ating TARE in combination with standard of care
gists need to exclude useful systemic therapies chemotherapy in second line [16]. Overlooking
prior to set an indication for TARE in mCRC, the current evidence how to implement TARE in
108 N. Schaefer

the treatment of mCRC it is recommended to options. Furthermore, these patients were some-
evaluate all validated systemic therapy in a tumor times under chemotherapy and anti-hormonal
board setting prior to treat with TARE. Currently therapy for many years. Therefore the liver reserve
TARE is well accepted as salvage treatment in might be limited and the patients have to be treated
patients with liver-dominant disease. with special care and possible dose reduction.
There is no prospective TARE data in mBCa
patients. An early study by Salem et al. investi-
7.4.3 Metastatic Neuroendocrine gated 27 patients with complete and partial
Tumors (mNET) response in 39.1% patients (in nine patients),
stable disease in 52.1% patients, and progressive
NET are a variety of tumors with endocrine fea- disease in 8.8% patients. Despite this response
tures originating from the neural crest. In gen- rates, the median survival was only several
eral, NET are divided in foregut, midgut, hindgut, months [19]. This trial shows exemplary that
and pancreatic neuroendocrine tumors. Although mBCa has to be seen as systemic disease and the
well differentiated in many cases, NET tend to role of locoregional treatments needs to be fur-
metastasize in lymph nodes, bone, and liver and ther explored. In the recent years larger retro-
are due to their slow progression identified usu- spective studies have been published. A study by
ally at a later stage. In the case of metastasized Fendler et al. reported a response rate of 52% in
NET, many options exist and are dependent on FDG—PET after TARE, leading to a median
the primary site and the mitotic level (Ki-67) of overall survival of 35 weeks [20].
the tumor. Therefore all NET patients need to be
discussed in a dedicated neuroendocrine tumor
board with NET specialists and only in very spe- 7.4.5 Melanoma
cific cases TARE might be an option.
Many phase II studies have already been pub- Melanoma has to be divided into ocular mela-
lished. The largest series by Kennedy showed noma (OM) which has a strong liver tropism and
stable disease in 22.7%, partial response in therefore is a suitable target for TARE versus a
60.5%, complete in 2.7%, and progressive dis- melanoma originating from the skin leading to
ease in 4.9% of the NET patients. In the treated metastases at many different sites. Currently
patient population no radiation liver failure many new therapy options, especially in the field
occurred and the median survival was reported to of immunotherapy, evolve. Therefore these
be 70 months [17]. A more recent study by Peker patients have to be discussed in the respective
et  al. demonstrated the safety and effectiveness tumor board prior to any locoregional procedure.
for the treatment of unresectable liver NETs with A recent study of TARE in OM showed a hepatic
one- and two-year survival rates of 71% and progression-free survival of 5.9  months and an
45%, respectively [18]. A meta-analysis revealed overall survival of 12.3 months. The median overall
an objective response of 50% and a weighted survival after diagnosis of liver metastases was
average DCR of 86%. This large meta-analysis 23.9 months [21]. In this salvage patient population
considered TARE as effective treatment option these numbers seem encouraging. A very recent
for patients with hepatic metastatic NET with report of a nationwide analysis of TARE in OM
high response rates and survival. showed tumor control in overall 61% of the patients.
The median overall survival was 18.7 months [22].

7.4.4 M
 etastatic Breast Cancer
(mBCa) 7.4.6 Intrahepatic
Cholangiocarcinoma (iCC)
Metastatic breast cancer patients have many sys-
temic therapy options. Prior to any locoregional ICC is a primary liver tumor evolving from the
therapy they have to be carefully evaluated at the small bile ducts. In contrast to HCC these tumors
dedicated tumor board to exclude useful systemic are usually less arterialized and therefore less
7  Selective Internal Radiotherapy (SIRT) of Primary Hepatic Carcinoma and Liver Metastases 109

suitable for intra-arterial therapies. Nevertheless, advanced response criteria (PERCIST) have been
several studies have been published to investigate evaluated to assess response in TARE patients.
TARE in this patient population. Change in SUVpeak and total lesions glycolysis
Earlier studies by Lewandowski et al. showed predicted overall survival (p = 0.039; hazard ratio
partial response in 25%, stable disease in 73%, [HR], 0.24; 95% confidence interval [CI], 0.06–
and progressive disease in 2% of the patients 0.93), progression-free survival (p  =  0.016; HR,
[23]. A very recent study reported a median over- 0.15; 95% CI, 0.03–0.69), and time to intrahepatic
all survival of 21.4 months after initial diagnosis progression (p = 0.010; HR, 0.16; 95% CI, 0.04–
and 12.0 months after TARE. Especially patients 0.65). Interestingly, in the same study summed
with solitary tumors have good outcome with an baseline CT diameter of less than 8 cm for the 2
overall survival of 25  months after performing largest liver metastases predicted time to intrahe-
TARE [24]. Overlooking current data, TARE patic progression (p  =  0.013; HR, 0.21; 95% CI,
might be an interesting therapy option for patients 0.06–0.72) but did not predict overall or
with iCC, who have normally limited therapy progression-­free survival [31]. Overall, the body of
options. evidence supports that a reduction of FDG avidity
in early PET (4 weeks) might be useful to predict
further outcome of the patients. Not many early
7.5 Follow-Up Imaging studies investigated the role of MRI in the follow-
up after TARE.  Enhancement around a treated
Follow-up imaging after liver-directed radioembo- lesion after TARE is a finding often observed in
lization (TARE) is always a challenge. Main prob- MRI, corresponding to the inflammation area of
lems are the inflammatory changes after high-dose the hepatic parenchyma and sometimes misunder-
radiation and generally delayed anatomic response stood as tumor viability or tumor progression. A
to TARE.  Early literature compared anatomical recent comparison of FDG—PET and DWI—MRI
imaging by computed tomography (CT) against before and 6 weeks after TARE showed a higher
metabolic imaging by FDG—PET. A reduction in positive predictive and a higher negative predictive
metabolic activity measured by SUVmax precedes value for DWI—MRI versus FDG—PET (96% vs.
the anatomical size reduction [25] in metastatic 88%; 96% vs. 56%). Overall, the detection for
colorectal cancer (mCRC). Other series in mixed response was higher for DWI—MRI than for
histologies confirmed this finding where FDG— FDG—PET/CT (96%; 22/23 vs. 65%; 15/23)
PET detected responders 6 weeks after intervention (p < 0.02) [32]. Overall, more recent studies show
[26] where only 13% of these patients did show the value of DWI—MRI and the paradigm that
reduction in size (PR) in the anatomical imaging. early FDG—PET best detects outcome might be
More recent studies confirmed the prognostic role questioned. As pointed out, early studies showed
of early FDG—PET in mCRC after TARE. Four the superiority of functional PET imaging to
weeks after the intervention, a reduction of CT. One major problem is certainly, that in general,
SUVmax of at least 50% predicted a difference in RECIST criteria are not suitable for modern treat-
survival of 10 months versus 4 months in mCRC ments. This problem was already identified in
[27]. Identical results were published in HCC, patients undergoing anti-angiogenesis treatment,
where metabolic responders survived 10  months as, for example, SORAFENIB in HCC [33]. A
versus non-responders who did survive only recent study investigating different criteria found
5 months [28]. Further studies supported the evi- that RECIST 1.1 after TARE is not suitable to
dence in metastatic breast cancer, where post-treat- assess response in these patients. However, the
ment FDG—PET three months after TARE was same study found Choi criteria and difference in
the only independent predictor of the survival out- tumor attenuation well predicts outcome in TARE
come (65  weeks vs 43  weeks; p  <  0.05) [29]. In mCRC patients and has the same predictive power
patients with intrahepatic cholangiocarcinoma, a as the EORTC PET response criteria [34]. Overall,
reduction of FDG avidity predicted outcome where the paradigm that CT might not be an imaging of
responders had a survival of 114  weeks versus choice has to be re-challenged in the light of new
19  weeks in non-­responders [30]. More recently, response criteria and more advanced protocols as
110 N. Schaefer

arterial perfusion protocols. An interesting 3. Sangro B, Carpanese L, Cianni R, Golfieri R, Gasparini


D, Ezziddin S, et  al. Survival after yttrium-90 resin
approach is to predict survival outcome by measur- microsphere radioembolization of hepatocellular car-
ing relative or absolute radiation dose targeted to cinoma across Barcelona clinic liver cancer stages: a
the tumor lesions by Bremsstrahlung SPECT/CT European evaluation. Hepatology. 2011;54(3):868–
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the TARE procedure [35]. microspheres compared with sorafenib in  locally
advanced and inoperable hepatocellular carcinoma
(SARAH): an open-label randomised controlled
phase 3 trial. Lancet Oncol. 2017;18(12):1624–36.
7.6 Outlook in the Future https://doi.org/10.1016/s1470-2045(17)30683-6.
5. Chow PKH, Gandhi M, Tan S-B, Khin MW,
Currently TARE is performed using Y90 bound Khasbazar A, Ong J, et  al. SIRveNIB: Selective
internal radiation therapy versus sorafenib in Asia-
resin or glass micropsheres. Future compounds pacific patients with hepatocellular carcinoma.
might use other isotopes as Holmium-166 J Clin Oncol. 2018;36(19):1913–21. https://doi.
(Quirem Microspheres, Quirem Medical BV, The org/10.1200/jco.2017.76.0892.
Netherlands). The advantage of this procedure is 6. Chauhan N, Bukovcan J, Boucher E, Cosgrove D,
Edeline J, Hamilton B, Salem R, et  al. Intra-arterial
the visibility of Holmuim-166  in the MRI scan therasphere yttrium-90 glass microspheres in the
[36]. This might facilitate therapy planning. treatment of patients with unresectable hepatocel-
However, further prospective trials have to inves- lular carcinoma: protocol for the STOP-HCC phase
tigate the role of Holmium-166 Spheres versus 3 randomized controlled trial. JMIR Res Protoc.
2018;7(8):e11234. https://doi.org/10.2196/11234.
Glass and Resin Y90 based microspheres. 7. Levi Sandri GB, Ettorre GM, Giannelli V, Colasanti
M, Sciuto R, Pizzi G, Lucatelli P, et al. Trans-arterial
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7.7 Conclusion with hepatocellular cancer to access liver trans-
plantation, a world review. Transl Gastroenterol
Hepatol. 2017;2(11):98. https://doi.org/10.21037/
TARE is a highly effective and safe procedure; tgh.2017.11.11.
however, it has to be used in the right patient at 8. Vouche M, Lewandowski RJ, Atassi R, Memon K,
the right time. Most recent data have disappointed Gates VL, Ryu RK, Salem R, et al. Radiation lobec-
tomy: time-dependent analysis of future liver remnant
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that we further investigate the role of TARE in analysis of transarterial downstaging for hepatocellu-
different indication to explore the right use of this lar carcinoma: chemoembolization versus radioembo-
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doi.org/10.1111/j.1600-6143.2009.02695.x.
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Radioimmunotherapy
of Lymphomas 8
Clément Bailly, Caroline Bodet-Milin,
François Guerard, Nicolas Chouin, Joelle Gaschet,
Michel Cherel, François Davodeau,
Alain Faivre-­Chauvet, Françoise Kraeber-Bodéré,
and Mickaël Bourgeois

8.1 Introduction lymphoid, histiocytic, and dendritic neoplasms


differentiate lymphomas into mature B-cell neo-
Malignant lymphoma is a generic name describ- plasms, mature T and NK neoplasms, Hodgkin
ing a wide group of hematological cancers lymphoma, posttransplant lymphoproliferative
derived from white blood cells or lymphocytes. disorder (PTLD), and histiocytic and dendritic
This group of pathologies presents a great variety cell neoplasms [1]. Each of these lymphoma sub-
of distinct diseases with heterogeneous histologic types can be divided into histological subtypes as
aspects, immunophenotypes, genetic abnormali- well as be separated according to their aggressive
ties, and finally clinical outcomes for patients. or indolent nature. In terms of frequencies, B-cell
The current 2016 WHO classification of mature lymphoma is the most common at approximately

C. Bailly · C. Bodet-Milin · A. Faivre-Chauvet


F. Kraeber-Bodéré (*)
INSERM UMR1232—CNRS UMR6299—Centre AMaROC Research Group, ONIRIS (Nantes-Atlantic
de Recherche en Cancérologie de Nantes-Angers National College of Veterinary Medicine, Food
(Equipe 13), Institut de Recherche en Santé de Science and Engineering), Nantes, France
l’Université de Nantes, Nantes, France e-mail: nicolas.chouin@oniris-nantes.fr
Department of Nuclear Medicine, University M. Cherel
Hospital, CHU de Nantes, Nantes, France INSERM UMR1232—CNRS UMR6299—Centre
e-mail: clement.bailly@chu-nantes.fr; de Recherche en Cancérologie de Nantes-Angers
caroline.milin@chu-nantes.fr; (Equipe 13), Institut de Recherche en Santé de
alain.faivre-chauvet@univ-nantes.fr; l’Université de Nantes, Nantes, France
francoise.bodere@chu-nantes.fr
Department of Nuclear Medicine, ICO-René
F. Guerard · J. Gaschet · F. Davodeau Gauducheau, Boulevard Jacques Monod,
INSERM UMR1232—CNRS UMR6299—Centre Saint-Herblain, France
de Recherche en Cancérologie de Nantes-Angers e-mail: Michel.Cherel@univ-nantes.fr
(Equipe 13), Institut de Recherche en Santé de
M. Bourgeois
l’Université de Nantes, Nantes, France
INSERM UMR1232—CNRS UMR6299—Centre
e-mail: francois.guerard@univ-nantes.fr;
de Recherche en Cancérologie de Nantes-Angers
joelle.gaschet@univ-nantes.fr;
(Equipe 13), Institut de Recherche en Santé de
francois.davodeau@univ-nantes.fr
l’Université de Nantes, Nantes, France
N. Chouin
Department of Nuclear Medicine, University
INSERM UMR1232—CNRS UMR6299—Centre
Hospital, CHU de Nantes, Nantes, France
de Recherche en Cancérologie de Nantes-Angers
(Equipe 13), Institut de Recherche en Santé de GIP Arronax, Saint-Herblain, France
l’Université de Nantes, Nantes, France e-mail: mickael.bourgeois@univ-nantes.fr

© Springer Nature Switzerland AG 2019 113


L. Giovanella (ed.), Nuclear Medicine Therapy, https://doi.org/10.1007/978-3-030-17494-1_8
114 C. Bailly et al.

80%, Hodgkin lymphoma occurs in 10% of son to conventional external beam radiotherapy:
cases, and T/NK cell lymphoma accounts for heterogeneous and continuous irradiation, and an
approximately 6% of all lymphomas. Among the exponentially decreasing low dose rate [6].
most frequent B-cell lymphomas, the clinical Currently, the mechanisms underlying this type
practice subdivides pathologies by morphologi- of radiobiological irradiation are imperfectly
cal and phenotypic aspects of B-cell like Diffuse known, and the dose-response relationship with
Large B-Cell Lymphoma (DLBCL), Burkitt lym- patient outcomes, such as cell survival, has not
phoma, Extranodal marginal zone lymphoma of yet been demonstrated. Despite these shortfalls,
mucosa-associated lymphoid tissue (MALT lym- the synergy between the immunological cytotox-
phoma), mantle cell lymphoma, or follicular icity and RIT, including bystander and abscopal
lymphoma (FL). effects, is well established with a higher efficacy
Patient outcomes have improved greatly over against the tumor [7].
the last 40 years as a result of the use of radio- The first clinical trial for chemotherapy-­
therapy in cases of localized pathology, but resistant non-Hodgkin’s lymphoma was reported
mainly by multi-agent chemotherapy, immuno- in 1988 by De Nardo et  al., and used an anti-­
therapy, and stem cell transplantation. The guide- HLA-­DR Lym-1 monoclonal antibody radiola-
line for treatment protocol choice is commonly beled with iodine-131 [8]. RIT efficacy is mainly
based on the lymphoma subtype and the molecu- dependent on the mAb and isotope choice.
lar signature for each of them. Over the last two Regarding therapeutic applications, nuclear med-
decades, improvements in the information on the icine practitioners use massive emission particles
lymphoma phenotype have allowed targeted use such as beta-negative particles, Auger electrons,
of monoclonal antibodies (mAbs) in immuno- or alpha particles. These radioactive emission
therapy in combination with classical chemother- types specifically deliver their ionizing energy
apy. While this has considerably improved the locally. The penetration distance of these radio-
patients’ prognosis and treatment, relapsed and active emissions depends on the initial energy
refractory disease remain a major treatment and should match the targeted tumor size. The
challenge. path-length penetration for Auger electrons is of
Lymphoma cells are well known to be radio- the order of a few nanometers and requires an
sensitive and consequently are ideal targets for internalization of the radiolabeled mAb to obtain
radioimmunotherapy (RIT) [2–4]. RIT is a tar- efficient irradiation. For alpha particles, irradia-
geted therapy, whereby irradiation from radionu- tion occurs up to several hundred micrometers
clides is delivered to a tumor using monoclonal around the emission point. For beta-negative par-
antibodies (MAbs) specifically directed to a ticles, irradiation extends up to a few millimeters
tumor antigen, and can therefore be effective in and results in a cross-fire effect on nearby tumor
patients who do not respond to nonradioactive cells. This cross-fire effect may result in an anti-
“cold” immunotherapy. tumor effect against cells that are not specifically
bound by the targeting mAb. Optimizing RIT
requires a good balance between the pharmacoki-
8.2 General Principles of RIT netic/biodistribution properties of the mAb and
the half-life of the radionuclides. To circumvent a
RIT is a cytotoxic approach which involves both potential mismatch, biochemists and immuno-
immunological and radiobiological processes chemists have developed a number of immuno-
[5]. The RIT methodology relies on a radionu- conjugates which are derived from antibody
clide vectorization, or targeting, that is driven by molecules such as F(ab) and F(ab’)2 fragments or
the mAb specificity to a particular tumor antigen, synthetic proteins (e.g., minibodies or single
with an irradiation of healthy tissues as low as chain variable fragments) [7].
reasonable. The internal irradiation generated by Today, the efficacy of RIT for the treatment of
RIT presents the following benefits in compari- hematological cancers like lymphomas has been
8  Radioimmunotherapy of Lymphomas 115

demonstrated and found to be beneficial for classically 14.8  MBq/kg (0.4  mCi/kg) and
relapsed or refractory lymphomas or as 11.1 MBq/kg (0.3 mCi/kg) with a platelet count
consolidation after immunochemotherapy [9].
­ of 100,000–149,000/mm3 [17].
Despite evidence of clinical efficacy, RIT treat- Clinical results showed that Zevalin® and
ment remains limited in routine lymphoma ther- Bexxar® had a significant efficacy, but moderate
apy. The contrast between efficiency and current response duration as monotherapy in rituximab-­
clinical use is probably due to the competition refractory recurrence of FL. RIT with anti-CD20
with other nonradioactive therapies and the neces- mAbs could be integrated into clinical practice
sity for RIT phase III randomized clinical trials to using non-ablative doses for treatment of patients
convince the oncohematologist community. with relapsed or refractory FL, or as consolida-
tion after induction chemotherapy. A meta-­
analysis of four clinical trials involving relapsing
8.3 Efficacy of RIT in Lymphomas B-cell lymphoma patients treated by Zevalin®
demonstrated a long-term response (time pro-
As outlined above, the proof of concept study for gression >12  months) in 37% of patients. The
RIT in non-Hodgkin’s B-cell lymphoma used an estimated 5 year overall survival (OS) was 53%
anti-HLA-DR Lym-1 antibody radiolabeled with for all patients treated with Zevalin® and 81% for
iodine-131 [8]. Because of the very large pheno- long-term responders.
typic variability in the lymphoma subtypes, RIT Recent studies have shown an increased effi-
approaches have mainly focused on identifying cacy where RIT was administered in combina-
and targeting the overexpressed antigen specific tion with chemotherapy to obtain a myeloablative
for each pathology subtype [10]. state. These approaches require autologous or
allogeneic SCT. A recent prospective multicenter
study consisting of Zevalin® administration
8.3.1 Anti-CD20 RIT (14.8  MBq/kg) in association with BEAM
polychemotherapy (Carmustine/Etoposide/
CD20 is an activated-glycosylated phosphopro- Cytarabine/Melphalan) demonstrated safety and
tein expressed on normal B-cells, and is overex- efficacy in comparison with the BEAM protocol
pressed in many B-cell lymphoma subtypes. Two alone as a conditioning regimen for stem cell
radioimmunoconjugates targeting the CD20 anti- transplantation (SCT) in 43 patients with
gen have been approved: 131I-tositumomab relapsed/refractory non-Hodgkin lymphoma. An
(Bexxar®; GlaxoSmithkline) which was subse- international and randomized phase III clinical
quently discontinued for commercial reasons and trial aiming to assess the benefits for RIT in first-­
90
Y-ibritumomab tiuxetan (Zevalin; Spectrum line indolent advanced follicular lymphoma (FIT
Pharmaceuticals) which continues to be used trial) [18] enrolled 414 patients with partial or
both in the USA and in Europe. The benefits of complete response after standard front-line che-
anti-CD20 90Y-ibritumomab tiuxetan in consoli- motherapy regimens. The 208 patients in the RIT
dation after induction in first-line therapy have arm (14.8  MBq/kg) of this large broad clinical
been shown for follicular lymphoma, mantle cell trial showed a conversion rate of 77% from par-
lymphoma, and DLBCL patients [11–16]. tial to complete response. After 3.5 years of fol-
Zevalin®, the only commercially available low-­up, the median progression-free survival was
anti-CD20 RIT drug, is classically administered significantly improved from 13.3 to 36.5 months.
6–8 days after a pre-dose of cold anti-CD20 mAb Patients in the RIT arm presented a greater than
(2  ×  250  mg of rituximab), which targets the 5 year improvement in the time to next treatment.
same antigen as the RIT, in order to improve the A long-term follow-up of these patients included
biodistribution of the radioactive mAb. The in the FIT trial [19] confirmed these patient out-
posology of Zevalin® is based on patient body comes in terms of treatment consolidation with
weight and platelet count. The therapeutic dose is durable 19% progression-free survival advantage
116 C. Bailly et al.

at 8 years and an improvement of the time to next unconfirmed complete response at higher dose
treatment of 5.1 years for patients with advanced (>1.11  GBq/m2). Grade 3–4 hematological tox-
follicular lymphoma. icities were observed and were manageable with
Hematological toxicity is the major side support for patients with <25% bone marrow
effect of RIT and depends on the extent of bone involvement.
marrow involvement and prior treatment. Non-­ An alternative to increasing the total adminis-
hematological toxicity is generally low. tered dose without any additional hematological
Secondary myelodysplastic syndrome (MDS) or toxicity consists of a dose fractionation approach
acute myelogenous leukemia (AML) are rare (see dose fractionation in RIT optimization part)
symptoms and were reported in 1–3% of cases [21, 22]. Using this approach, efficacy was demon-
[11, 12, 15, 16]. In the FIT trial, MDS or AML strated in a multicenter phase I/II study where
was reported for seven patients in the RIT arm patients with documented B-cell NHL received
which enrolled 208 patients (3.4%) compared to 92.5–1110 MBq/m2 per injection repeated twice at
one MDS in the control arm. Cytogenetic testing 2–3 weeks intervals in a dose escalation protocol.
revealed chromosomal abnormalities typical of For the highest doses the total dose administered
therapy-induced MDS/AML and confirmed the was higher than in the classical single dose proto-
known risk increment in patients previously col. The adverse effects remained manageable
treated by several lines of chemotherapy or (mainly grade 1–2 hematologic toxicity for low
radiotherapy. Finally, the FIT trial didn’t show doses and frequently grade 3–4 for doses
additional long-term toxicities or congenital >740 MBq/m2) and no abnormal pattern of changes
malformations [19]. occurred in standard serum chemistry. A fraction-
ated approach for anti-CD22 RIT provides a high
rate of durable complete response in relapsed/
8.3.2 Anti-CD22 RIT refractory NHL, and 740 MBq/m2 injected twice at
2 week intervals seems to be a good efficacy/safety
CD22 is a transmembrane glycoprotein expressed compromise [23]. More recently, the efficacy of
on mature B-cells but not on stem cells or plasma RIT fractionation with CD22 targeting was con-
cells. CD22 is expressed highly on a number of firmed for post-­chemotherapy adjuvant treatment
malignant B-cell lymphomas. It is also a relevant in diffuse large B-cell lymphoma (DLBCL) where
alternative target for B cell lymphomas which do patients were treated with two doses at 7 day inter-
not express the CD20 antigen or for patients with vals of 555 MBq/m2 of 90Y-epratuzumab tetraxetan
no response to cold anti-CD20 immunotherapy. (anti-­CD22 mAb) [24].
The anti-CD22 mAb epratuzumab is a human- This methodology demonstrated efficacy (no
ized mAb that has been extensively tested in progression of the disease after standard chemo-
RIT. It is internalized by the target cells and can therapy) without acute toxicity (only grade 3–4
be administered without the requirement for cold thrombocytopenia and neutropenia) [23].
dose antibody pre-treatment such Zevalin® or
Bexxar® [20].
90
Y-epratuzumab RIT has been developed as a 8.3.3 Anti-CD37 RIT
repeat injection therapeutic. A multicenter study
enrolled 64 patients with different B-cell lym- CD37 is an internalizing transmembrane antigen
phoma histologies. These patients were injected overexpressed in most B-cell malignancies. The
with activities ranging from 0.185 to 1.665 GBq/ anti-CD37 mAb lilotomab has recently been
m2 over several doses. The objective response used to treat indolent non-Hodgkin B-cell lym-
rate was 62% (48% complete response/uncon- phoma (NHL) by RIT. For this application, lilo-
firmed complete response). For FL subtype tomab is pre-activated with a chelating agent
patients without SCT, response increased with (DOTA  =  satetraxetan) and radiolabeled with a
total injected activity to 92% complete response/ bêta emitter such 177Lu.
8  Radioimmunotherapy of Lymphomas 117

A phase I clinical trial with four arms [25] was one patient showed a complete response, one
designed to test pre-dosing regimens (one ritux- patient showed partial response, and five had dis-
imab dose and two doses of cold lilotomab) to ease stabilization. For non-Hodgkin lymphoma,
improve the safety and efficacy profile. In this one patient showed a complete remission and one
study, patients with relapsed incurable NHL of a partial remission.
follicular grade I–IIIA, marginal zone, mantle For Hodgkin lymphoma indication, only one
cell, lymphocytoplasmic, and small lymphocytic patient developed grade IV thrombocytopenia
subtypes (all patient have platelet counts and leukocytopenia. All other patients had hema-
>150 × 109/L) were eligible for inclusion. A total tological toxicity of grade III or lower. For non-­
of 36 patients were enrolled. The overall tumor Hodgkin lymphoma, one patient which received
response rate observed in 23 patients evaluable 1.48 GBq developed hematological toxicity that
for efficacy was 57%, comprising 30% complete required stem cell infusion
responses, 26% partial responses, 22% stable dis-
ease, and 22% with progressive disease.
Furthermore, one patient is still in remission 8.3.5 O
 ther Antigens Under
more than 3  years after treatment, and two Preclinical Development
patients are still in remission more than 2 years
after treatment. The advances in lymphoma phenotypic discrimi-
Hematological toxicity is the most common for nation and the knowledge and success of anti-
all dose-limiting toxicities. Observed thrombocy- ­CD20 immunotherapy have led to a large effort
topenia and neutropenia are reversible and man- in identifying and exploring alternative molecu-
ageable. A pre-dosing injection of nonradioactive lar targets.
lilotomab at a dose of 40 mg/m2 reduces the inci- The CD74 antigen is the gamma chain of the
dence of hematological side effects for 15 MBq/kg MHC class II invariant chain, also known as Li
of 177Lu-lilotomab satetraxetan. A 100 mg/m2 pre- fragment, and is expressed classically on the
dosing injection of non-radioactive lilotomab fur- B-cell surface. CD74 is expressed at low levels
ther reduces the red-marrow absorbed dose and to but is rapidly internalized. This important turn-­
an increment of tumor/red-marrow ratio [26]. The over of CD74 molecules conduces to an impor-
dosimetry of 177Lu-lilotomab satetraxetan for other tant accumulation of anti-CD74 mAb in the
critical organs (liver, spleen, and kidneys) was B-cell lymphoma which will be used in RIT to
found to be modest in comparison to assumed tol- accumulate intracellularly large amount of radio-
erance limits [27, 28] activity. In this way anti-CD74 RIT with beta-­
negative or Auger electron emitters in Burkitt’s
lymphoma in vitro cultured cells showed specific
8.3.4 Anti-Tenascin RIT and effective cytotoxicity [32].
The cell surface receptor CD30, also known
Tenascin is a hexameric glycoprotein localized in as tumor necrosis factor receptor superfamily 8
the extracellular matrix. The tenascin-C variant is (TNFRSF8), is physiologically expressed in
involved in tumor processes and in particular in activated T- and B-cells and is pathologically
the lymph nodes of B-cell NHL and HL [29, 30] overexpressed in both T- and B-cell lymphomas.
but also in T-cell NHL [31]. An anti-CD30 mAb, HeFi-1 conjugated to
A phase I/II clinical trial with 2.05  GBq/m2 yttrium-90 appeared very promising in a B-cell
injection of 131I-81C6 (anti-tenascin antibody) in lymphoma murine model, with tumor growth
eight refractory Hodgkin lymphoma patients was significantly inhibited compared to the control
designed [29]. For refractory NHL, a phase I trial group [33]. More recently, CD30 was targeted
study enrolled nine patients with a dose regimen using a 89Zr radiolabeled antibody for pheno-
of 1.11 GBq or 1.48 GBq [30]. typic imaging and showed specific accumulation
For Hodgkin lymphoma indication, at the first of the mAb in a murine xenograft model of T-cell
response assessment (4–6  weeks after therapy), non-­Hodgkin’s lymphoma [34, 35].
118 C. Bailly et al.

CD38 is a transmembrane glycoprotein over- because it allows healthy bone marrow regenera-
expressed in multiple myeloma and other B-cell tion to occur faster than tumor cell growth. This
malignancies. Green and colleagues used a pre- differential phenomenon in repair kinetics
targeting strategy (see Sect. 4.1 pretargeting between healthy and cancerous tissues is well
approach) to study a murine model of NHL, and known in conventional external beam radiother-
used a bispecific antibody directed against both apy. For this purpose, a rationale for using frac-
CD38 and 90Y-biotin [36]. This CD38 bispecific tionated doses with a total dose augmentation
pretargeted RIT approach resulted in 75–80% was reported in 2002 [38]. The first confirmation
complete remission at day 12 with minimal of this dose fractionation efficacy was reported
toxicity. using 90Y-ibritumomab tiuxetan (Zevalin®) in 74
CD19 is a transmembrane glycoprotein anti- patients treated for FL (international phase II
gen belonging to the immunoglobulin family and study—FIZZ study). The patients in this study
is expressed on all B-cells except for plasma and received two doses of 11.1 MBq/kg at 8–12 week
follicular dendritic cells. An in  vivo study of a intervals for a 48% higher total dose compared to
Burkitt’s lymphoma xenograft murine model the classical single dose protocol [39, 40]. The
showed an antitumor activity for a single anti- results of this study demonstrated an improve-
­CD19 mAb dose of 11.1  MBq, and most mice ment in overall response (94% vs. 87% for the
survived over 119  days with no evidence of single dose protocol) with a similar toxicity pro-
tumors [37]. file. Thus, the fractionation approach was clini-
cally validated with a progression-free survival
of 40  months versus 26  months for single dose
8.4 RIT Optimization treatment.

8.4.1 Pretargeting Approach


8.4.3 Other Isotopes
The key requirement for success of RIT relies on
the ability to deliver the maximum radioisotope Despite the great number of radioisotopes that
emission to the tumor while exposing healthy tis- could be used in clinical RIT practice, only a few
sues to as little irradiation as possible. The pretar- of them are currently used, the beta emitters
geting approach consists of a two-step procedure. iodine-131 and yttrium-90. The recent produc-
First, a bispecific cold (nonradioactive) mAb is tion and development of new isotopes raises the
administered; this mAb binds directly to the opportunity of delivering ionizing energy directly
tumor target. The second injection delivers a low-­ within tumors. Thus, for beta particle emitters,
molecular-­weight radioactive hapten with a high new isotopes such as lutetium-177 or copper-67
affinity for the bispecific mAb which is bound to exhibit good irradiation parameters and promise
the tumor. The small size of the radioactive hap- improved benefits for patient outcomes [41–44].
ten allows both rapid tumor penetration and fast On the other hand, alpha particle emitters such
elimination of the unbound radioactivity from the astatine-211 or actinium-225 deliver a high pro-
body by renal clearance. The proof of concept for portion of their energy inside the targeted cells
this strategy was first shown in a preclinical leading to highly efficient killing. Radiobiologic
murine NHL model in 2018 [36]. studies have demonstrated that 1–20 cell nuclei
traversals by alpha particles are sufficient to inac-
tivate a cell, compared to thousands or tens of
8.4.2 Dose Fractionation thousands of beta-negative particles required to
obtain the same effect. These physical radiobio-
As described previously, the major limitation of logic properties are particularly well suited for
RIT treatment for lymphomas is hematological the purpose of treating hematological diseases
toxicity. Dose fractionation in RIT is of interest such as lymphomas.
8  Radioimmunotherapy of Lymphomas 119

8.4.4 Diagnostic and Dosimetry multimodality strategy requires dedicated treat-


Approach by Phenotypic ment for a poor-prognosis cancer that is resistant
Imaging to conventional therapies. After a proof of con-
cept phase in the 1990s and 2000s and many
While mAbs play a pivotal role in RIT, they are recent advances, it is now time for the oncohema-
also critical in the modern era of in vivo whole tology community as a whole, to assess the effi-
body phenotypic imaging. This complementary cacy of RIT using randomized and stratified
information can be acquired using Positron clinical trials and to adopt new protocols (new
Emission Tomography (PET) technology where lymphoma antigens, fractionation, and pretarget-
the mAb is radiolabeled with a beta-positive ing approaches), new isotopes (alpha- or beta-­
emitter [45]. A number of radioimmunoconju- negative emitters), and improved pathology
gates developed for PET imaging have been knowledge and phenotypic imaging.
described, and these permit a precise phenotypic
diagnosis and a dosimetric evaluation for RIT Acknowledgments  This work has been supported by the
[46–48]. French National Agency for Research called
Investissements d’Avenir via grants Labex IRON n ANR-­
Radiation dosimetry studies using 89Zr, a posi- 11-­
LABX-0018-01 and Equipex Arronax plus n
tron emitter, coupled to an anti-CD20 mAb such ANR-11-EQPX-0004.
as rituximab [49] or the newly FDA approved
obinutuzumab and ofatumumab [50] have dem-
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