Radiopharmaceuticals for Therapy

  • Federica OrsiniEmail author
  • Sara Mazzarri
  • Erinda Puta
  • Federica Guidoccio
  • Alice Lorenzoni
  • Giuliano Mariani
Living reference work entry


Common radionuclides used for radiometabolic therapy include 131I, 153Sm, 89Sr, 223Ra, and 90Y. In this chapter we will focus on therapeutic radiopharmaceuticals are employed for therapy of differentiated follicular thyroid carcinomas,for therapy of pheochromocytoma/paraganglioma/neuroblastomas, for bone pain palliation, for radioimmunotherapy of lymphomas, for peptide radioreceptor therapy of neuroendocrine tumors, and for intra-arterial radioembolization of hypervascularized tumors of the liver.


Radiopharmaceuticals Radionuclides Nuclear oncology Radiometabolic therapy Radioimmunotherapy Peptide receptor radionuclide therapy Transarterial radioembolization 



153Sm-ethylenediamine tetramethylene phosphoric acid


188Re-hydro-ethylidene diphosphate






1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (macrocyclic coupling agent to label compounds of biological interest with metal radionuclides)








Glucagon-like peptide-1


Gastrin-releasing peptide


Gray unit (ionizing radiation dose in the International System of Units, corresponding to the absorption of one joule of radiation energy per kilogram of matter)


Human anti-chimeric antibody


Human anti-human antibody


Human anti-mouse antibody


Potassium iodide


Linear energy transfer






Neuroendocrine tumor


Non-Hodgkin’s lymphoma


Sodium-iodide symporter


Peptide receptor radionuclide therapy


Tripeptide composed of L-arginine, glycine, and L-aspartic acid




Somatostatin receptors






Thyroid stimulating hormone


A radiopharmaceutical is a compound containing a radionuclide, which is employed clinically for the detection, characterization, or treatment of disease. While diagnostic radiopharmaceuticals are γ or β+ emitters, therapeutic radiopharmaceuticals exert their action through the emission of electrically charged particles (β or α++ particles) that deposit their energy within a relatively limited range in the tissue, thus causing radiation damage to the site of localization, the desired radiobiological effect resulting in cell death. Depending on their energy, the β particles emitted by radionuclides utilized for therapeutic radiopharmaceuticals typically travel a few millimeters from their emission point (or even few micrometers, as in the case of the very low-energy Auger electrons); on the other hand, α++ particles typically travel few tens of micrometers in tissues. In addition to particle emission causing a cytocidal radiobiological effect, some therapeutic radiopharmaceuticals also emit γ-rays, which can be detected with a conventional gamma camera and thus can provide information on their distribution in the body. This information is useful to confirm that the administered radiopharmaceutical has in fact concentrated in the target tissue of interest (usually tumor lesions) and to allow a posteriori calculation of the radiation dose to the target lesion(s) and to normal tissues/organs.

Therapeutic radiopharmaceuticals can be administered systemically through the i.v. route or orally, intracavitary, or even via the intra-arterial route. Although the focus of this chapter is on radionuclide therapy employed for treatment of various forms of cancer with either curative or palliation purposes, in some instances radionuclide therapy is utilized to reduce an organ’s function (e.g., for hyperthyroidism).

Table 1 lists the most widely used radionuclides for labeling currently approved radiopharmaceuticals to be used in nuclear oncology and their main physical properties. Radiopharmaceuticals can be classified based on physical characteristics of the radionuclide (type and energy of the characteristic emissions, physical half-life) or else on their physicochemical properties of the molecule (size, hydro- or lipophilicity, positive, negative, or neutral electrical charge) and mechanism of localization (Table 2).
Table 1

Most widely used radionuclides and their main physical properties for approved therapeutic radiopharmaceuticals in oncology


T 1/2

Emax/Emean (MeV)

Emissions (main)

Max penetration in water (mm)


14.3 days





50.5 days





64.1 h





8.02 day







45.6 h







6.71 days




0.113, 0.208



16.8 h







11.4 days




Table 2

Main mechanisms of distribution/localization of radiopharmaceuticals used for therapeutic purpose.




Mechanical trapping (capillary blockade)

The regional distribution of perfusion in an organ can be assessed by administering in the afferent blood vessel radiolabeled particles that, because of their large size (tens of μm), cause microembolization in the precapillary bed of an organ

90Y-microspheres for treatment of liver tumors (intra-arterial)

Membrane transport: simple, facilitated, and active transport

Active, energy-dependent transmembrane transport of molecules against a concentration gradient: sodium-iodide symporter

131I-ioide for the treatment of malignant or benign thyroid disease

Accumulation in intracellular, neurosecretory vesicles

ATPase-linked energy-dependent process physiologically utilized for the intracellular accumulation of noradrenaline

[131I]MIBG for the treatment of neural-crest-derived neuroendocrine tumors

Non-receptor-mediated binding

Radiolabeled antibodies (whole antibodies or engineered minibodies) targeting specific antigen sites on the surface of tumor cells

90Y-Ibritumomab tiuxetan (anti-CD20) for radioimmunotherapy of non-Hodgkin’s lymphoma (NHL)

Receptor-mediated probes

The radiopharmaceutical competes with the physiologic ligands for binding with the target receptor

Somatostatin analogs used for neuroendocrine tumors as vehicles to guide radioactivity to tissues expressing somatostatin receptors

Ion exchange (chemisorption)

Exchange of ions between two electrolytes or between an electrolyte solution and a complex (binding to hydroxyapatite crystals or to amorphous calcium phosphate)

Bone-seeking, bisphosphonate-based radiopharmaceuticals for the treatment of metastatic bone disease

Selection of the most appropriate radionuclide for any given therapeutic application should take into account the nature of the particulate radiations and their energies, physical half-life, and chemistry in relation to the carrier molecule (see also chapter “Principles of Molecular Targeting for Radionuclide Therapy”). The possibility of deriving pretreatment dosimetric estimates is also very important. The ionizing radiations with therapeutic potential involve β particle emitters, α-particle emitters, and emitters of Auger electrons. These radionuclides are linked to carrier molecules capable of (selectively) transporting the radiotracers to the target tissue. The main target for the biologic effects of ionizing radiation is DNA. Biologic response to ionizing radiation depends on many factors: cell radiosensitivity, localization of the radiopharmaceutical, and physical properties such as absorbed dose and linear energy transfer (LET) of the emitted radiation (see also chapter “Radiobiology and Radiation Dosimetry in Nuclear Medicine” of this book). The latter parameter, expressed in keV/μm, reflects energy deposition and, therefore, ionization density along the track of a charged particle. Any γ-emission possibly associated to the particle emission does not contribute to the effectiveness of therapy and may even lead to an increase of irradiation to nontarget tissues. Nevertheless, this emission can be exploited to obtain sequential scintigraphic images, therefore to determine the time course of in vivo localization of the radiopharmaceutical, to be used for radiation dosimetry calculations.

Alpha-Particle Emitters

Alpha particles are positive helium nuclei; their emission leads to a daughter nucleus with two fewer protons and two fewer neutrons than in the original radionuclide. These monoenergetic particles are usually emitted with high energy (5–8 MeV) and produce a high density of ionization along their short linear tracks of 40–100 μm, corresponding to about five to ten cell diameters. LET values of α-particles are typically in the 80–100-keV/μm range. Their biologic effect is independent of the oxygenation state or cell cycle phase, as their interaction with the cell nucleus results in single- and/or double-strand DNA breaks that are lethal per se for the cell. The tumoricidal effect is maximal if the α-particles are emitted within the cell nucleus. Despite the existence of over 100 α-emitting radionuclides, investigations on the therapeutic potential of α-particle emitters has focused mainly on five radionuclides (223Ra, 211At, 212Bi, 213Bi, and 225Ac), because either the physical or chemical characteristics of the remainders are not appropriate for therapeutic use.

Radium-223 (223Ra)

223Ra (energy 5.7 MeV, half-life 11.4 days) for medical use is normally produced by a 227Ac generator (half-life 21.8 years), with the intermediate decay step of thorium-227 (half-life 18.7 years); this system guarantees availability of the radionuclide for long periods. 223Ra ultimately provides for the emission of four α-particles per decay. There are also minor associated emissions resulting in the production of β (3.6%) and γ (1.1%) radiations with different energies and emission probabilities. Administered as a chloride salt, the 223Ra++ ion behaves in vivo as a calcium analog and has therefore bone-seeking properties that make this radionuclide useful for treating bone pain from skeletal metastases.

Auger Electron Emitters

Auger electrons are low-energy orbital electrons emitted after electron capture. Electron capture causes a vacancy, which is filled by electrons moving from an outer shell and thus initiating a cascade of electron transitions that shift the vacancy toward the outermost shell. Auger electrons have an extremely short path length in tissues (2–500 nm), with LET ranging from 4 to 26 keV/μm. Localization of the radionuclide within the cell, especially within the cell nucleus, is required to achieve cell killing, as mitochondrial or cell surface localization does not produce significant cytotoxic effects. Auger-electron emitters of radiobiologic interest include 67Ga, 75Se, 77Br, 111In, 125I, 123I, 165Er, 197Hg, 117mSn and 201Tl.

Emitters of β Particles

Radionuclide therapy is presently based almost exclusively on radioisotopes emitting β particles. These negatively charged particles have low LET (0.2 keV/μm) and a continuous spectrum of energy. After their emission, the daughter nucleus has one more proton and one less neutron than the original radionuclide. Their maximum path length in tissues ranges from 0.05 to 12 mm (at least for the radionuclides currently employed for therapy), depending on the energy of the particle (see Fig. 1). Therefore, optimal therapeutic activity requires a higher radionuclide concentration within the target tissue compared to α emitters, in order to obtain comparable radiobiologic efficacy. However, the longer path length in tissues results in the so-called crossfire effect, thus irradiating also the cells that have not directly accumulated the radionuclide (Fig. 2). This effect reduces the problems possibly caused by inadequate uptake and heterogeneous distribution of a given radiopharmaceutical within the target tissue.
Fig. 1

Correlation between maximum energy (Emax, expressed in MeV) and maximum range in water of either β+ or β particles emitted during decay of different radionuclides employed for either diagnostic purposes (β+) or therapeutic purposes (β). Most of the energy deposited by each emission is nevertheless limited within a much shorter range (about 20–25% of the maximum range). The plot demonstrates that electrical charge does not influence the path of β particles, as the only determinant factors are mass and energy

Fig. 2

Schematic representation of the so-called crossfire effect for particle-emitting radionuclides employed for therapy (assumed to be β particles for this representation). Because of delivery of energy within a certain range from the point of emission, the radiotoxic effect is not limited to the cells that specifically accumulate the radiopharmaceutical but also involves nearby cells (either they be neoplastic or tumor cells). In this representation, it is assumed that the radiopharmaceutical has accumulated at three specific locations within a tumor lesion (the uptake points are indicated by the radioactivity symbol). The red area with decreasing intensity from the center depicts the range in tissue along which the particles travel and deposit their energy, with maximum in the center and decreasing delivery of energy toward the periphery. The arrows indicate the tissue zones between the different radionuclide localization points; these are the cells exposed to the crossfire effect (From Volterrani D, Erba PA, Mariani G, eds. Fondamenti di medicina nucleare—tecniche e applicazioni. Milan (Italy): Springer; 2010, with permission)

Iodine-131 (131I)

In addition to γ-rays, the radiohalogen 131I (half-life 8.04 days) emits β particles with maximum energy of 0.61 MeV and a maximum path range of 2–4 mm in tissues (mean 0.7 mm). In the chemical form of 131I-iodide , this radionuclide is extensively employed since several decades for treating benign and malignant thyroid diseases. Other therapeutic applications involve radiolabeling with 131I of more complex molecules, such as MIBG or monoclonal antibodies. Incorporation of radioiodine is generally achieved through an oxidation reaction involving, for example, an OH radical in a tyrosine residue or a −CH3 group; within certain limits (i.e., number of radioiodine atoms per molecule not to exceed 1), the resulting molecule of biologic interest has a metabolic fate very close to that of the native, unlabeled molecule, since the steric radius of the halogen atom is very similar to that of the hydroxyl or methyl groups.

Yttrium-90 (90Y)

The radiometal 90Y (half-life 64 h) emits high-energy β particles (2.2 MeV) with a maximum path length of 11–12 mm. This radionuclide is produced by the generator system 90Sr/90Y and decays to stable 90Zr. Decay is associated with pair production of β+ particles, although in a minimal proportion (32 β+ particles per million decays). Radiolabeling of peptides and monoclonal antibodies requires the use of a bifunctional chelate, for example, DOTA or tiuxetan.

There are currently three major clinical uses of 90Y: to label a monoclonal antibody for radioimmunotherapy of lymphomas, bound to resin or glass microspheres for transarterial radioembolization of liver tumors, and to label somatostatin analogs for peptide receptor radionuclide therapy of neuroendocrine neoplasms. During radioimmunotherapy with 90Y-tiuxetan-ibritumomab, the radiolabeled antibody binds to lymphocytes expressing the CD20 antigen, resulting in death of these cells. Treatment with 90Y-tiuxetan-ibritumomab is approved for previously untreated follicular NHL that achieve a partial or complete response to first-line chemotherapy and relapsed or refractory, low-grade, or follicular B-cell NHL. Resin or glass microspheres containing 90Y are approved forms of treatment for either primary or metastatic liver tumors, to be administered during selective or super-selective catheterization of the main or the segmental branches of the hepatic artery. Effective forms of peptide receptor radionuclide therapy of neuroendocrine neoplasms expressing somatostatin receptors has initially been based solely on the use of somatostatin analogs labeled with 90Y, although more recently interest is also focusing on peptide analogs labeled with 177Lu (see below). Regarding the use of 90Y for therapy of non-tumoral diseases, 90Y-colloid can be used for radiosynoviorthesis of the large joints.

Lutetium-177 (177Lu)

The radiolanthanide 177Lu (half-life 6.7 days) decays through the emission of β and γ-radiations. The β particles emitted by 177Lu have a maximum energy of 0.49 keV and a maximum path range of 2 mm in water. The γ-emission has energy photopeaks of 113 keV (6.4%) and 208 keV (11%), which is suitable for imaging with conventional gamma cameras. Lutetium-177 is increasingly being used in patients for receptor-targeted radionuclide therapy with peptides such as DOTA0-Tyr3-octreotate. Other possible uses of 177Lu include conjugation with bisphosphonates (e.g., 177Lu-EDTMP), to produce a bone-seeking radiopharmaceutical for treatment of bone pain from skeletal metastases.

Samarium-153 (153Sm)

This radiolanthanide is produced by neutron capture using a samarium target enriched in 152Sm. Its physical decay half-life is 1.9 days, and it emits β particles with maximum energy of 0.81 MeV and maximum path range in water of approximately 3 mm. 153Sm also emits γ-rays (103-keV photo peak) suitable for gamma camera imaging. The prevalent use of 153Sm is in the chemical form of a radiolabeled diphosphonate (153Sm-EDTMP; see Fig. 3a), which is employed in the clinical routine for treating osteoblastic bone metastasis.
Fig. 3

Chemical structure of the radiolabeled bone-seeking bisphosphonates employed for palliation therapy of bone pain from skeletal metastasis. For simplicity of representation, the gray atom at the center of each 3-D structure represents the radionuclide (153Sm for 153Sm-EDTMP, 186Re for 186Re-HEDP). Other elements are represented with the following color codes: red = O, white = H, fuchsia = P, light blue = C, dark blue = N

Strontium-89 (89Sr)

This alkaline earth metal radionuclide (half-life 50.5 days) is a pure emitter of β particles with a maximum energy of 1.46 MeV (average 0.58 MeV). The maximum path length in tissues of these β particles is 6–8 mm. Its current clinical use is for treatment of osteoblastic bone metastasis, in the simple chemical form of chloride salt; the 89Sr++ behaves in vivo as a calcium analog and is therefore rapidly adsorbed on the newly formed bone mineral component, where it is retained with a physical half-life of 50.5 days.

Rhenium-186 (186Re) and Rhenium-188 (188Re)

Rhenium is a group VII metal with labeling chemistry properties similar to those of technetium; for this reason, its radioactive isotopes have attracted attention for the potential of directly translating to rhenium radionuclides the vast radiochemistry experience accumulated with 99mTc. Rhenium-186 is normally produced by direct neutron activation of metallic rhenium enriched with 185Re via the 185Re(n,γ)186Re nuclear reaction; alternative routes through the 186W(p,n)186Re and the 186W(d,2n)186Re nuclear reactions yield no-carrier-added 186Re. 186Re (half-life 3.7 days) decays with the emission of β particles (maximum energy 1.09 MeV and path range 1–2 mm) and a low abundance (9%) of γ-ray (137 keV). Although also 188Re (half-life 16.9 h) can similarly be produced in a thermal reactor through the 186W(n,γ)188Re nuclear reaction, the radionuclide for medical uses is more conveniently produced in the no-carrier-added form using a 188W/188Re generator; 188W has a half-life of 69 days, thus making use of the generator especially convenient for immediate local availability of 188Re on demand with the use of instant-labeling kits also in remote locations. 188Re has maximum energy of 2.12 MeV and decays to stable 188Os, with a γ-ray emission of 155 keV (15%).

These two radionuclides are currently used clinically for treatment of bone pain from skeletal metastases, after conjugation to diphosphonates (see Fig. 3b).

Phosphorus-32 (32P)

Phosphorus-32 is a pure emitter of β particles (physical half-life of 14.3 days) with a maximum energy of 1.71 MeV (average 0.659 MeV). The maximum path length in tissues of these β particles is 8 mm. Treatment for 32P in the chemical form of orthophosphate is indicated for palliation of bone pain from skeletal metastases, polycythemia vera, and essential thrombocythemia.

Treatment of Thyroid Disease with 131I-Iodide

Iodine-131 is commonly administered as sodium iodide for treating thyroid disorders. The radioactive I ions present in the circulation and in interstitial fluid are transported into the thyroid cells by the sodium-iodide symporter (NIS), an active transport mechanism located on the basolateral membrane of thyroid follicular cells that allows entry of iodine into the cell against a concentration gradient, based on energy from the electrochemical gradient of sodium. Similarly as for other parameters of thyroid cell function and growth, the intracellular accumulation of iodine is regulated by serum TSH. Once inside the thyroid cell, iodine is oxidized by the enzyme peroxidase; this starts the organification process that enables to incorporate iodine (either native or radioactive) into tyrosine, an amino acid contained in the thyroglobulin molecules produced by the endoplasmic reticulum and Golgi apparatus. Molecules of monoiodotyrosine (MIT) and diiodotyrosine (DIT) are thus formed. These two chemical species are then combined to produce the thyroid hormones thyroxine (T4) and triiodothyronine (T3). Thyroid hormones are finally secreted into the circulation by pinocytosis, again following stimulation by TSH.

Although with a lower efficiency level, iodine ions are taken up also by other systems, such as the salivary glands, sweat glands, gastric glands, mammary gland, and the placenta. These physiological processes can induce unwanted side effects when using 131I for high-dose therapy in patients with differentiated thyroid cancer, thus possibly causing sialoadenitis (sometimes with persistent xerostomia) and gastritis (with nausea and vomiting). 131I uptake in the placenta and mammary gland would expose the fetus or the baby, respectively, to an unacceptable radiation dose.

131I-iodide is commonly used both in benign thyroid diseases (such as hyperthyroidism in Grave’s disease or multinodular goiter or hyperfunctioning Plummer’s adenoma) and in malignant disease (differentiated thyroid carcinomas).

Although radiation safety regulations can vary from country to country, radioiodine treatment of hyperthyroidism is generally performed on an outpatient basis, after adequate preparation and dosimetric evaluations. Two methods are commonly used to select the amount of 131I-iodide activities to be administered: (1) administration of a fixed activity based on clinical experience and (2) administration of an activity personalized on the basis of dosimetric calculations according to the target volume and radioiodine uptake of the individual patient. The aim of radioiodine therapy in hyperthyroid patients is to restore euthyroidism or, more commonly, to induce permanent hypothyroidism (which will then be treated with simple thyroid hormone replacement therapy).

The initial step in the treatment of differentiated thyroid carcinoma derived from follicular epithelium (papillary and follicular carcinoma) is thyroidectomy. After surgery, an ablative dose of 131I-iodide is generally administered to patients with intermediate- to high-risk cancer, in order to eliminate any remaining thyroidal cells. Whole-body scintigraphy is then performed 4–7 days after administration of the high-dose amount of 131I-iodide, based on the consistent γ-ray emission of 131I. The images so obtained (often integrated with spot acquisitions – possibly with SPECT/CT) often enable to depict metastatic lesions not recognized at the time of surgery. In addition to ablation of the postsurgical thyroid residue, therapy with 131I-iodide is also used for the treatment of locoregional recurrences and/or distant metastases.

Since the amounts of 131I to administer for radioiodine therapy of patients with thyroid cancer vary from 1.1 to 7.4 GBq (30–200 mCi), in Europe this treatment requires hospitalization in specially equipped rooms for adequate handling of radioactive wastes. In the US, activities up to 200 mCi are usually outpatient procedures. Prior to therapeutic 131I administration, patients are counseled by radiation safety. Patients are discharged when measurements of their radioactivity emissions fall below certain limits, which can vary according to local radiation safety regulations.

Early side effects of treatment with radioiodine are generally mild and usually do not require specific treatments. They consist of pain in the anterior cervical region (caused by inflammation induced by the cytotoxic action of radioiodine), dysgeusia, anosmia, nausea, and vomiting. In 10–60% of cases, acute or chronic sialadenitis can occur, due to radioiodine accumulation in the salivary glands; it affects mainly the parotid gland, which is particularly rich in ductal cells. In order to prevent this occurrence, some precautions are recommended, such as abundant hydration and frequent stimulation of salivary flow (for instance, with lemon juice). Nausea (rarely vomiting) is the direct effect of some degree of radiation-induced gastritis, since the stomach is the first recipient of a highly concentrated amount of radioiodine; these side effects are prevented by pre-administration of metoclopramide and proton-pump inhibitors. Actinic cystitis (caused by the ionizing radiation due to the presence of urinary excretion of radioiodine in the urinary bladder) is rare and can be prevented by abundant hydration and frequent urination.

About 6 weeks after treatment, a reduction in the circulating levels of platelets and white blood cells can occur; nevertheless, this occurrence is very rare and usually transient if the absorbed dose to the bone marrow is maintained below 200 cGy. As to the long-term side effects of therapy with 131I-iodide in the amounts utilized for patients with differentiated thyroid cancer, the induced risk of a second solid cancer or leukemia is very low, approximately in the same order of magnitude as that determined by other anti-neoplastic therapeutic approaches, such as chemotherapy.

As for all therapy with radionuclides, absolute contraindications to radioiodine treatment are pregnancy and lactation. Since the specific activity of the radiopharmaceutical used for therapy is very high (typically >200 MBq/μg), the amounts of iodine contained in a therapeutic dose of 131I-iodide is considerably lower than the recommended daily dose in a normal diet. Thus, allergy to iodine is not considered a contraindication.

The administration of 131I-iodide is generally performed orally (capsules or liquid solutions), while the intravenous administration is needed only in uncooperative patients or in case of uncontrolled vomiting; to facilitate and accelerate intestinal absorption, fasting should be observed for at least 6 h prior to and for 3 h after administration.

Treatment of Neuroendocrine Neoplasms Originating from the Neural Crest with [131I]MIBG

Meta-iodobenzylguanidine (MIBG) or iobenguane is a catecholamine analog in which the iodinated benzyl group of bretylium is combined with the guanidine group of guanethidine (see Fig. 4). This molecule was developed in the early 1980s to visualize tumors of the adrenal medulla, and it can be labeled either with 123I (for diagnostic use only) or with 131I (for use either diagnostic or therapeutic applications).
Fig. 4

Tridimensional representation of the chemical structure of radioiodinated meta-iodobenzylguanidine (MIBG). The green atom represents radioiodine. Other elements are represented with the following color codes: white = H, light blue = C, dark blue = N

Due to its structural analogy with catecholamines, MIBG is taken up by chromaffin cells through a physiologic active uptake mechanism via the epinephrine transporter used for noradrenaline accumulation in neurosecretory granules. MIBG is then secreted through an exocytosis mechanism following depolarization induced by high transmembrane flux of calcium ions. This accumulation process is abundantly expressed in the sympathetic ganglia, the adrenal medulla, and in all tissues with high adrenergic innervations (myocardium, salivary glands).

Tumors that typically accumulate this radiopharmaceutical are tumors originating from the neural crest. The main clinical applications of MIBG scintigraphy are therefore detection, localization, staging, and follow-up and response to treatments of NETs and their metastases, particularly in those of the sympathoadrenal system such as pheochromocytoma, paraganglioma, and neuroblastoma, although other neuroendocrine tumors such as medullary thyroid carcinoma and carcinoids can also be visualized. Diagnostic MIBG scintigraphy is crucial when planning treatment with high activities of [131I]MIBG, to adequately select patients who will most likely benefit from such therapy.

For therapy, the radiopharmaceutical is usually administered through a slow i.v. injection (see further below). About half of the administered activity is excreted in the urine within the first day, 70–90% of the activity being cumulatively excreted within 2 days; therefore, the kidneys, the bladder, and the excretory urinary tract can be intensely visualized even in the late scans. About 3% of MIBG excretion occurs via the gastrointestinal tract.

The most important precaution in the preparation of patients for [131I]MIBG therapy includes discontinuing drugs interfering with MIBG uptake (such as labetalol, tricyclic antidepressants, reserpine, and some sympathomimetic drugs) for an appropriate period before MIBG administration. These drugs can in fact interfere with and reduce MIBG uptake. Free radioiodine produced during in vivo [131I]MIBG degradation can cause accumulation of radioactivity in thyroid and the gastrointestinal tract. Thyroid blocking using potassium iodide (KI) or lugol solution, also in combination with potassium perchlorate, is therefore necessary, generally starting 1 or 2 days prior to treatment and continuing for up to 14 days after treatment.

Administration of [131I]MIBG must be performed very slowly (over 1–4 h after dilution in 50 mL of saline), because therapy dose levels involve injecting a sizable amount of a catecholamine analog that may induce the sudden release into circulation of catecholamines previously accumulated in neurosecretory granules, with possible pharmacologic effect (such as tachycardia, arterial hypertension, nausea, vomiting). For the same reason, the specific activity of [131I]MIBG for therapy should be higher than that for diagnostic purpose (up to 1.8 GBq/mg), with the aim of reducing the incidence of pharmacologic effects.

The role of [131I]MIBG therapy has been best defined in patients with pheochromocytoma and paraganglioma. In these patients symptomatic and biochemical improvements are frequently observed after treatment, while complete response rates are low. In neuroblastoma patients, [131I]MIBG can be used with therapeutic intent, as good responses have been obtained in selected patients with advanced disease where first-line therapy failed. The response rates in these studies using single doses or large cumulative doses of [131I]MIBG were between 25% and 46%. The actual benefit of multiple treatments is still debated. There is currently no consensus on the optimal dosing strategy. In patients treated with median activities of 10 GBq versus 5.5 GBq, higher activities seem to deliver the desired dose faster with a modest increase in toxicity but similar overall response rates.

Peptide Receptor Radionuclide Therapy

The biological basis of peptide receptor radionuclide therapy (PRRT) is the receptor-mediated internalization and intracellular retention of the radiopeptide, linked in turn to the overexpression of somatostatin receptors (SSTR) in most neuroendocrine neoplasms. The rationale for such therapy is to convey radioactivity inside the tumor cells, where the sensitive targets, such as DNA, can be hit as a result of internalization of the somatostatin receptor and radiolabeled analog complex.

The somatostatin analogs (ligands) that are currently in clinical use with the most promising results include DTPA-octreotide, DOTA-d-Phe1-Tyr3-octreotide (DOTA-TOC), DOTA-d-Phe1-Tyr3-octreotate (DOTA-TATE), and DOTA-lanreotide.

The macrocyclic chelator 1,4,7,10-tetraazacyclododecane-N,N′,N″,N″-tetraacetic acid (DOTA) forms stable complexes with metallic isotopes such as 90Y and 177Lu. The DOTA-coupled somatostatin-based radiopharmaceuticals are 90Y-DOTA-Tyr3-octreotide (90Y-DOTA-TOC), 90Y-DOTA-lanreotide, and 177Lu-DOTA-Tyr3-Thre8-octreotide (177Lu-DOTA-TATE). These compounds differ in their SSTR affinity profile. In particular, the DOTA-TATE derivative exhibits the highest affinity for SSTR2, while DOTA-lanreotide has highest affinity for SSTR5. Tyr3-octreotide has similar kidney uptake (the dose-limiting organ) as Tyr3-octreotate but faster renal clearance. Advantages of 177Lu-DOTA-TATE over 90Y-DOTA-TATE include the emission of an associated γ-radiation, which makes it possible to acquire conventional scintigraphic imaging for radiation dosimetry estimates; furthermore, the shorter tissue range of the β particles emitted by 177Lu justifies the assumption that use of this radionuclide allows a higher radiation dose be delivered to smaller tumors. On the other hand, the use of 90Y (which emits β particles with higher energies and longer tissue ranges) would be more suitable for the treatment of larger tumors, in case of bulky and/or heterogeneous masses.

These radiolabeled peptides are cleared through the kidneys, where they are and reabsorbed and partially retained in the proximal tubules, causing dose-limiting nephrotoxicity. Since residence times of DOTA-TATE in tumor and kidney are longer than those of DOTA-TOC, 177Lu appears more beneficial when using DOTA-TATE for therapy, while 90Y appears more convenient to label DOTA-TOC. The administration of L-lysine and/or L-arginine in order to competitively inhibit the proximal tubular reabsorption of the radiopeptide is now part of the clinical routine, to reduce the renal dose.

Tumor candidates for PRRT are basically all the somatostatin receptor-expressing tumors; scintigraphy with 111In-pentetreotide is currently the most accurate and validated method to assess for the presence of SSTR overexpression. Nevertheless, it is likely that 68Ga-DOTA-TOC and 68Ga-DOTA-TATE will become the new standard analogs, since they mimic as closely as possible the in vivo pattern of their 90Y- or 177Lu-labeled counterparts used for PRRT.

The radiopeptide that has been most extensively evaluated for PRRT is 90Y-DOTA-TOC, with a recommended activity per cycle of about 5 GBq (cumulative activities: 13–18.5 GBq). Complete and partial remissions have been recorded especially in patients with gastrointestinal neuroendocrine tumors. Promising clinical results of PRRT with the newer radiopeptide 177Lu-DOTA-TATE have been also obtained. More recently, a combination radionuclide therapy using 177Lu- and 90Y-labeled peptides has been proposed in order to improve efficacy in patients with tumors of various sizes and nonhomogeneous receptor distribution.

Other radiopeptide analogs are in less advanced stages of clinical validation. They include cholecystokinin (CCK8) and bombesin for GRP receptors expressed in prostate, breast, lung, and pancreatic cancers (188Re(H2O)(CO)3-diaminopropionic acid-SSS-bombesin(7-14)NH2 and 177Lu-DOTA-8-Aoc-BBN[7-14]NH2), arginine-glycine-aspartate (RGD) peptides to target αvβ3 receptors upregulated on tumor cells and neovasculature, glucagon-like peptide-1 (GLP-1), and melanocortin 1 receptor for various tumors.

Bone-Seeking Radiopharmaceuticals

Bone metastases are a frequent and serious complication in advanced stages of neoplastic disease, occurring in about 70% of patients with prostatic cancer or breast cancer and in 30–50% of those with cancers of the lung, bladder, and thyroid. The major complications associated with this condition are pain (initially mild to medium intensity, then increasing), hypercalcemia, radicular compression, and/or spinal cord and pathological fractures. Treatment of patients with pain from skeletal metastases should be based on a multidisciplinary approach, since it can include (in sequence or, sometimes, in association) external beam radiation therapy, surgery, chemotherapy, hormone therapy, pain-killing medications (from simple anti-inflammatory nonsteroidal drugs to opioids), bisphosphonates, and therapy with radiopharmaceuticals.

In patients with metastatic involvement of multiple skeletal segments (therefore not amenable to external radiotherapy and/or surgery), bone-seeking radiopharmaceuticals represent an important strategy for palliation of bone pain (in some cases also with survival benefits). All these agents bind to the mineral component of bone either because they are calcium analogs or in a similar manner as any typical bisphosphonate agent labeled with 99mTc for diagnostic purposes, with increased uptake at the sites of active osteogenesis; thus primary bone tumors (osteosarcomas) as well as areas of metastatic involvement predominantly osteoblastic in nature (or of mixed type) can accumulate significantly greater concentrations of the radiopharmaceuticals than the surrounding normal bone. This treatment is therefore indicated in patients with multiple painful osteoblastic skeletal metastases exhibiting high uptake of 99mTc-labeled bisphosphonates confirmed on a conventional bone scan prior to therapy.

Besides the historical interest 32 P-sodium orthophosphate (which is nevertheless still used in some low-income countries where other agents are not available), the bone-seeking radiopharmaceuticals currently available include strontium-89 chloride (89SrCl2), samarium-153 ethylenediamine tetramethylene phosphoric acid (153Sm-EDTMP), rhenium-186 or rhenium-188 hydro-ethylidene diphosphate (186Re- or 188Re-HEDP), and radium-223 dichloride (223RaCl2). For all these agents, the dose-limiting toxicity is bone marrow suppression, which is generally reversible.

Upon administration of 89 SrCl 2 (Metastron®), the 89Sr++ ions follow the same in vivo metabolic fate as calcium, with rapid incorporation into the inorganic matrix of bone. 89Sr is quickly cleared from the blood and selectively localizes in bone mineral, with at least 50% of the injected activity localized in the skeleton within few hours post-administration. The unbound excretion pathways are two-thirds urinary and one-third through the fecal route. Urinary excretion is greatest in the first 2 days following administration. The recommended activity of 89SrCl2 is 148 MBq (4 mCi) or alternatively 1.5–2.2 MBq/kg body weight.

153 Sm-EDTMP (Quadramet®) also accumulates avidly in the skeleton, where it remains adsorbed on the surface of the newly formed hydroxyapatite crystals. Osteoblastic metastatic lesions accumulate about fivefold more 153Sm-EDTMP than does the healthy skeleton. Following i.v. administration (37 MBq/kg), 153Sm-EDTMP is cleared rapidly from the blood with a half-life of 5.5 min; less than 1% of the administered activity remains in the circulation 5 h postinjection. Up to 55–60% of injected activity remains stably bound to the skeleton and accumulates in metastatic lesions in a 5:1 ratio compared with normal bone uptake. The main excretory route is through the kidneys. The onset of pain relief is generally noted within 2 weeks of radiopharmaceutical administration, with a mean duration of pain relief of 3–4 months; since the critical organ from the radiation dosimetry point of view is the bone marrow, a minimum interval of 8 weeks should be allowed between subsequent administrations in order to allow adequate recovery of bone marrow function.

186 Re-HEDP is cleared from the circulation with a relatively long half-life (41 h), since it undergoes some binding with plasma proteins. Its uptake in bone is due to conjugation with the hydroxyapatite crystals through a hydrolysis reaction, and its mean effective biological half-life in bone is about 16 h. About 70% of the administered 186Re-HEDP (usually in a standard activity of 5 GBq) is excreted in the urine within 24 h.

As a calcium analog, 223 RaCl 2 (Xofigo®) shows a similar pattern of biodistribution as 89SrCl2, less than 1% of injected activity remaining in the circulation 24 h after administration. Nevertheless, at variance with other bone-seeking radiopharmaceuticals, a non-negligible fraction of excretion occurs through the gastrointestinal tract and constitutes the basis for the reported gastrointestinal toxicity of this radiopharmaceutical. Each treatment cycle includes four to six administrations at 4-week intervals, and it has been recognized that therapy with 223RaCl2 induces not only palliation of bone pain but also a significant benefit in survival. Since this is the latest radiopharmaceutical approved by regulatory agencies for therapy, a much more detailed discussion of the clinical observations that have led to this approval is presented in chapter “Novel Radiopharmaceuticals for Therapy” of this book.

Radioimmunotherapy for Hematologic Malignancies

The introduction of immunotherapy in the clinical routine has opened new opportunities for the treatment of some hematologic diseases. In fact, antigens expressed on the surface of neoplastic cells (usually of the B lineage) are suitable targets for the development of monoclonal antibodies used for immunotherapy. In radioimmunotherapy (RIT), the cytotoxicity caused by an ionizing radiation is conveyed to the neoplastic cells through binding to tumor-specific antigens at the molecular level, a monoclonal antibody acting as carrier of a suitable radionuclide.

Efforts in the past 20 years have focused on the so-called molecular therapy to identify possible tumor antigens against which to address the monoclonal antibody. The selection of the appropriate antigen plays a key role for the efficacy of treatment. The ideal antigen should be densely and uniformly expressed on the surface of malignant cells (but not in normal cells), it should form a stable complex with the antibody, and the antigen/antibody complex should not be internalized (although the latter property is not so crucial).

Another important issue concerns the origin and structure of these antibodies; many monoclonal antibodies were in fact initially developed from murine cells, thus being intrinsically heterologous proteins with immunogenic activity when administered to humans. This immunogenicity is much lower for the chimeric antibodies (made up of components for 60% human and 40% murine) or for those humanized (with 95% of human components, while generally only the binding site for the antigen is murine) developed through genetic engineering techniques. In fact, the formation in the patient receiving these preparations of human anti-mouse antibody (HAMA), anti-chimeric (HACA), or anti-human (HAHA) can alter the pharmacokinetic profiles of the monoclonal antibody or predispose to allergic reactions during repeated administration. The monoclonal products currently used for the preparation of radiopharmaceuticals are characterized by greatly reduced immunogenicity compared to their initial products.

The radiolabeled anti-CD20 antibody 90Y-ibritumomab tiuxetan (Zevalin®) has been approved for the treatment of relapsed or refractory, low-grade, or follicular B-cell non-Hodgkin’s lymphoma (NHL) or treatment of previously untreated follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy.

90Y is chelated to tiuxetan, which is covalently linked to the antibody via arginine and lysine. The basis for therapy with 90Y-ibritumomab tiuxetan is that CD20 antigen is expressed on the surface of normal B-lymphocytes (except pre-B cells and secretory B cells) and of more than 90% of B-cell lymphomas. Unlabeled monoclonal antibody (rituximab) is given as part of 90Y-ibritumomab tiuxetan therapy in order to block CD20 antigens on normal B cells and spleen and to facilitate deeper penetration into the tumor. The unlabeled monoclonal antibody itself induces several mechanisms of tumor cell killing.

90Y-ibritumomab tiuxetan is administered as a slow i.v. infusion over 10 min; the pharmacokinetics of 90Y-Ibritumomab tiuxetan is characterized by a plasma half-life of 28 h. The administered activity is generally 15 MBq/kg body weight (0.4 mCi/kg), with a maximum limit of 1.2 GBq (32 mCi). In patients with mild thrombocytopenia (platelet count between 100.000 and 149.0000 per mm3), the administered activity should be reduced to 11 MBq/kg (0.3 mCi/kg).

Dose-limiting toxicity for 90Y-ibritumomab tiuxetan is bone marrow suppression, which is reversible. However, no statistically significant correlation was noted between the development of hematological toxicity and pharmacokinetic parameters of the compound.

Since 90Y does not emit γ-rays (and on the other hand scintigraphic visualization of the secondary X-rays emitted by the reaction of Bremsstrahlung is not satisfactory), biodistribution can be evaluated by administering a diagnostic-level dose of the surrogate radiopharmaceutical 111In-ibritumomab tiuxetan. The early images (up to about 24 h) typically show activity in the blood pool, with significant uptake in the liver and spleen, while accumulation in the lung and bone is generally low. Dosimetric studies have demonstrated an up to 850-fold greater radiation dose to the tumor lesions than to normal organs, and cumulative urinary excretion is only 7% of administered activity at 7 days post-administration.

Another monoclonal antibody (tositumomab) labeled with 131I has been approved in the United States in 2003, with similar indications as Zevalin® in patients with non-Hodgkin’s lymphomas. 131I-tositumomab (Bexxar®) is specifically directed against a different epitope of the same CD20 surface antigen, and the reported response rate is about 70%. However, it has recently withdrawn from the market because of declining sales.

Radionuclide Therapy of Primary and Metastatic Liver Tumors

Liver tumors (both primary and metastatic) have always been considered a major cause of morbidity and mortality in oncologic patients. The treatment options are represented by surgical resection, liver transplantation, systemic chemotherapy, or locoregional treatments. The locoregional treatments consist of percutaneous ablative techniques (radiofrequency ablation, laser coagulation, cryotherapy, percutaneous ethanol injection) and transarterial methods, such as chemoembolization and radioembolization.

Early attempts at radionuclide therapy for primary or metastatic liver cancers began in the 1970s with the use of albumin colloids labeled with 32P, under the rationale that radiocolloids administered systemically accumulate in the reticuloendothelial system, which is particularly abundant in the liver. This approach was soon abandoned due to significant bone marrow toxicity.

Transarterial radioembolization of liver tumors (also defined as “selective internal radiation therapy”) can be performed using either 131I-lipiodol or microspheres containing the β emitter 90Y. 131I-lipiodol, a mixture of iodized esters of poppy seed oil fatty acid, is still employed for treatment of hepatocellular carcinoma. The rationale for using transarterial 131I-lipiodol is its entrapment and embolization in the microvessels of the tumor as well as endocytosis of this agent by the endothelial cells and the tumor cells themselves.

Nevertheless, this approach is most commonly based on the use of resin or glass microspheres containing 90Y. The advantages of this type of therapy consist in the favorable toxicity profile and in the possibility to combine it with other forms of therapy (such as systemic chemotherapy or hepatic resection) without an increase in toxicity. The rationale for this therapy is radiomicroembolization of the hypervascularized tumor lesions in the liver, which receive their blood supply primarily from the hepatic artery, whereas the normal liver parenchyma receives blood primarily via the portal vein. Thus, microspheres injected into the hepatic artery (most commonly into the right or left hepatic artery – or even more selectively into the proper segmental artery) are trapped within the tumor microvasculature and deliver radiation selectively to the tumor liver lesion. The two types of 90Y–microspheres currently available commercially (resin and glass microspheres) are biocompatible but not biodegradable nor metabolized.

90Y-resin-based microspheres (SIR-Spheres®) are an acrylic polymer in which 90Y is bound to the carboxylic group of the polymer after production of microspheres. They have a diameter size between 20 and 60 μm with a specific activity of 50 MBq per sphere. There are about 40–80 million microspheres per vial, with a total activity of 3 GBq, which can be subdivided to treat two or more patients. Because of their elevated number, resin microspheres used for this treatment may have a moderate embolic effect and must be delivered at a slow rate (no more than 5 mL/min) to avoid reflux down the hepatic artery and into other organs. The shelf-life of the device is 24 h, which restricts clinical flexibility and patient scheduling.

In the 90Y-glass spheres (TheraSphere®), 89Y is embedded in the glass matrix, to be activated to 90Y in a nuclear reactor. Their medium diameter size is 20–30 μm, and the specific activity is 2,500 Bq per sphere. The number of 90Y-glass spheres required for treatment ranges between 1.2 and 8 million, and the preparation is supplied in six sizes of activities: 3, 5, 7, 10, 15, and 20 GBq. The embolic effect linked to treatment with the glass 90Y-microspheres is limited because a lower number of microspheres is injected intra-arterially. They can be used also in patients with portal vein thrombosis. The shelf-life of the glass spheres is 15 days from the date of calibration; therefore, no physical manipulation is required to prepare the desired, patient-based activity for administration, which is obtained simply by letting a certain activity to decay to the desired level.

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Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  • Federica Orsini
    • 1
    Email author
  • Sara Mazzarri
    • 2
  • Erinda Puta
    • 1
  • Federica Guidoccio
    • 2
  • Alice Lorenzoni
    • 3
  • Giuliano Mariani
    • 2
  1. 1.Nuclear Medicine Unit“Maggiore della Carità” University HospitalNovaraItaly
  2. 2.Regional Center of Nuclear MedicineUniversity of PisaPisaItaly
  3. 3.Nuclear Medicine ServiceNational Cancer InstituteMilanItaly

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