Educational Articles

Production of 177Lu for Targeted Radionuclide Therapy: Available Options

Abstract

Background: This review provides a comprehensive summary of the production of ¹⁷⁷Lu to meet expected future research and clinical demands. Availability of options represents the cornerstone for sustainable growth for the routine production of adequate activity levels of ¹⁷⁷Lu having the required quality for preparation of a variety of ¹⁷⁷Lu-labeled radiopharmaceuticals. The tremendous prospects associated with production of ¹⁷⁷Lu for use in targeted radionuclide therapy (TRT) dictate that a holistic consideration should evaluate all governing factors that determine its success. Methods: While both “direct” and “indirect” reactor production routes offer the possibility for sustainable ¹⁷⁷Lu availability, there are several issues and challenges that must be considered to realize the full potential of these production strategies. Results: This article presents a mini review on the latest developments, current status, key challenges and possibilities for the near future. Conclusion: A broad understanding and discussion of the issues associated with ¹⁷⁷Lu production and processing approaches would not only ensure sustained growth and future expansion for the availability and use of ¹⁷⁷Lu-labeled radiopharmaceuticals, but also help future developments.

Keywords: Carrier-added (CA) ¹⁷⁷Lu, Extraction chromatography (EXC), Neutron irradiation, No carrier-added (NCA) ¹⁷⁷Lu, Radiochemical separation, Targeted radionuclide therapy (TRT)

Introduction

Over the last several years, the ¹⁷⁷Lu radionuclide has attracted considerable attention and exhibited great promise in the research, commercial and clinical communities for use in a variety of therapeutic procedures [1–8]. Despite being a late entrant, ¹⁷⁷Lu has not only consolidated its potential, but also established a strong foothold at the forefront of TRT. In a relatively short time span, ¹⁷⁷Lu has virtually pervaded all areas of in vivo radionuclide therapy and may be poised to become a key therapeutic radionuclide of choice for TRT. The growing interest in the use of ¹⁷⁷Lu in targeted molecular therapies has primarily developed from recent unprecedented advances in molecular and cell biology, which include the use of peptides targeted to cell surface receptors, which are overexpressed on the surface of tumor cells.

Lutetium-177 decays in 76 % of events (E _β(max) =0.497 MeV) to the stable ground state of ¹⁷⁷Hf with a half-life of 6.65 days and decays in 9.7 % of events (E _β(max) =0.384 MeV) and 12 % of the time (E _β(max) = 0.176 MeV) to an excited state of ¹⁷⁷Hf that lies 0.24967 MeV and 0.32132 MeV above the ground state, which de-excites to the ground state with the photon emission. During these radioactive decay events, ¹⁷⁷Lu emits β^- particles with an E _β(max) of 497 keV (78.6 %), 384 keV (9.1 %) and 176 keV (12.2 %) and low-energy gamma photons [E_γ = 113 keV (6.6 %), 208 keV (11 %)] [9, 10]. A simplified decay scheme for ¹⁷⁷Lu is shown in Fig. 1.

Fig. 1

Simplified decay scheme of ¹⁷⁷Lu

Increasing use of ¹⁷⁷Lu in nuclear medicine procedures has been impressive, and widespread applications of ¹⁷⁷Lu therapeutic agents have not only stimulated progress of TRT, but have also been responsible for stimulating the growth of these therapeutic methods. The utility of ¹⁷⁷Lu is thus continually evolving, well entrenched in the arena of targeted radionuclide therapy, and has unveiled a broad spectrum of ¹⁷⁷Lu-labeled therapeutic radiopharmaceuticals for treating a wide range of diseases. It is surmised by many that diffusion of ¹⁷⁷Lu into nuclear medicine has not only brought spectacular developments in radionuclide therapy, but has also prompted a perceptible shift of the radiotherapeutic method toward the treatment of some diseases. The remarkable prospects and impetus associated with the use of ¹⁷⁷Lu-labeled radiopharmaceuticals in TRT have been the major factors evoking excitement among researchers and capturing the imagination of the clinical community thanks to advances in molecular and cellular biology.

While myriad factors contribute to the success of ¹⁷⁷Lu-labeled radiopharmaceuticals, the cost-effective availability of sufficient activity levels of ¹⁷⁷Lu that have the required quality is a key determinant underpinning the success of using ¹⁷⁷Lu in in vivo targeted therapy. The recent surge of interest in the use of ¹⁷⁷Lu in TRT has been the motivation to provide this review on the production and processing of this emerging radionuclide. This article focuses on a discussion of the ¹⁷⁷Lu production strategies that are currently used and other approaches that may have considerable potential in the foreseeable future.

Why is ¹⁷⁷Lu Expected to Be So Important in Targeted Radionuclide Therapy?

The striking diffusion and exciting perspectives of ¹⁷⁷Lu in TRT are primarily attributed to the following.

The mean penetration range of β⁻ particles emitted by ¹⁷⁷Lu in soft tissue is 670 μm, making this radionuclide ideal for delivering energy to small volumes, including micrometastatic disease, and tumor cells near the surface of cavities. Lutetium-177 is found to be effective in localizing cytotoxic radiation in relatively small areas and proficient in destroying small tumors as well as metastatic lesions (typically less than 3 mm diameter) with less damage to surrounding normal tissue.
The emission of low-energy gamma photons enables imaging the biodistribution and excretion kinetics with the same radiolabeled preparation used for therapy and allows dosimetry to be performed before and during treatment as well. This property is important for “personalized” medicine for the development of “theranostic” agents for combined diagnostic and therapeutic use that can deliver therapy to individual cells in affected tissues.
The emission of moderate-energy beta β^- particles as well as low-energy gamma photons results in a relatively low radiation dose and therefore offers the potential to handle relatively high ¹⁷⁷Lu activity levels during radiopharmaceutical preparation and formulation of radiopharmaceuticals as well as during patient administration.
Lutetium exclusively exists in the +3 oxidation state, which precludes any solution chemistry reduction-oxidation complications and commonly forms nine coordination complexes. This property therefore provides the potential for radiolabeling a variety of molecular carriers, which include small molecules, and peptides, proteins and antibodies with the specific desired characteristics for therapy. The chemical characteristics of Lu⁺³ are suitable for peptide and protein radiolabeling by attachment of a bifunctional chelating agent (BFCA) through a metabolically resistant covalent bond.
The 6.65-day half-life of ¹⁷⁷Lu offers extended time periods, which may be required for the use of more sophisticated procedures to radiolabel and purify ¹⁷⁷Lu-labeled radiopharmaceuticals, and for performing quality control and administration. The use of a longer lived therapeutic radionuclide such as ¹⁷⁷Lu is particularly well suited for the radiolabeling of antibodies that have slow targeting kinetics.
The relatively long 6.65-day physical half-life of ¹⁷⁷Lu not only minimizes decay loss, which may be encountered during the transportation and distribution to users, but also provides excellent logistical advantages for shipment to sites distant from the reactor production facility as well as radionuclide-processing facilities.

A wide range of ¹⁷⁷Lu radiopharmaceuticals has been successfully developed and evaluated. The in vivo applications of key ¹⁷⁷Lu radiopharmaceuticals for a variety of therapeutic procedures include peptide receptor radionuclide therapy [11–26], bone pain palliation [27–33], radiation synovectomy [34–39] and radioimmonutherapy [40–46]. There is a steadily expanding list of ¹⁷⁷Lu-labeled radiopharmaceuticals that is currently being evaluated at the preclinical research or at product development stages; these may potentially be used in vivo in humans for evaluation for radionuclide therapy [1–3]. A summary of key ¹⁷⁷Lu-labeled radiopharmaceuticals currently used in TRT is depicted in Table 1.

Table 1

Key examples of current ¹⁷⁷Lu-labeled radiopharmaceuticals

Application	Chemical form	Usual administered activity	References
Peptide receptorradionuclide therapy (PRRT)	[DOTA⁰,Tyr³]octreotate DOTA-TATE,DOTA-TOC, DOTA-NOC	7.4 GBq (200 mCi) per course. It is bound to 180 to 300 μg of the peptide with the chelator DOTA, [DOTA⁰,Tyr³] octreotate	[11–26]
Bone pain palliation in skeletal metastases	EDTMP DOTMP	1.2 to 2.6 GBq	[27–33]
Radiation synovectomy	Hydroxyapatite (HA)	~400 ± 30 GBq (10.8 ± 0.8 mCi)	[38]
Radioimmonutherapy	Monoclonal antibodies (J591, cG250, J591)	Not established	[2]

Production of ¹⁷⁷Lu

The opportunity for production of ¹⁷⁷Lu in research reactors throughout the world indicates that all pertinent factors should be evaluated and assessed. Essentially every conceivable production and processing strategy has been exploited with a view to obtain ¹⁷⁷Lu in a chemical form having acceptable radionuclidic and radiochemical purity. Since the inherent success of any production strategy requires a thorough knowledge of all the pertinent key factors, the issues underlying the utility of ¹⁷⁷Lu in TRT are discussed below.

Specific Activity of ¹⁷⁷Lu

Before discussing production of ¹⁷⁷Lu in detail, it is relevant to discuss the importance of the specific activity (SA) of ¹⁷⁷Lu, since this key factor dictates its utility for TRT.

No-Carrier-Added ¹⁷⁷Lu

Radionuclides have maximum theoretical specific activity values referred to as “carrier-free” when all the atoms contain one isotope of the element. Carrier free (CF) thus denotes a radionuclide having 100 % isotopic abundance, i.e., free from any stable isotopes. A radionuclide is characterized as no carrier added (NCA or n.c.a.) to which no carrier atoms have been added and for which precautions have been taken to minimize contamination with stable isotopes of the element in question. It does not necessarily mean, however, 100 % isotopic abundance. ‘Carrier free’ is an idealistic situation and hence the current term used is ‘no carrier added (NCA)’ for a preparation having a specific activity value that approaches the calculated maximum theoretical specific activity.

The theoretical specific activity of ‘carrier-free (CF)’ ¹⁷⁷Lu is calculated from the following equation:

d N d T = λ N = 0.693 \times N T 1 2 / = 0.693 \times 6.023 \times 10 23 6.65 \times 24 \times 60 \times 60 \times 177 Bq / g = 0.693 \times 6.023 \times 10 20 6.65 \times 24 \times 60 \times 60 \times 177 Bq / mg = 4.10367 T B q / mg = 110.91 Ci / mg

Here,

N →, number of ¹⁷⁷Lu atoms.
λ →, decay constant of ¹⁷⁷Lu.
T_½ →, half life of ¹⁷⁷Lu.

Neutron-capture characteristics, target impurities, secondary nuclear reactions, target “burn-up” and post-irradiation processing/cooling periods are the main parameters affecting the SA of the ¹⁷⁷Lu product.

The Importance of ¹⁷⁷Lu-Specific Activity

Conscientious harnessing of the nuclear and chemical characteristics of ¹⁷⁷Lu in conjunction with the advancement in molecular and cellular biology has not only stimulated the progress of radionuclide therapy, but has also driven the field. As discussed earlier, the utility of ¹⁷⁷Lu in radionuclide therapy has undergone rapid and continual evolutionary cycles. Lutetium-177-labeled therapeutic radiopharmaceuticals comprising small molecules, large biomolecules and particles are currently being evaluated for myriad of clinical applications [11–46].

While targeted radionuclide therapy is primarily based on selecting appropriate radiopharmaceuticals and targeting mechanisms, the number of target sites (receptors, cells, etc.) available for radiopharmaceutical targeting dictates the SA of ¹⁷⁷Lu that is appropriate for a particular application. For instance, targeting to trabecular bone is considered a large-capacity site and does not require ¹⁷⁷Lu with highly specific activity. For this reason, the ¹⁷⁷Lu SA is basically of minimal consequence in applications involving preparation of ¹⁷⁷Lu-labeled radiopharmaceuticals used for treatment of bone pain palliation, hepatocellular carcinoma (HCC) and synovectomy, since high masses of the low SA agents are administered. Under this premise, medium-low SA ¹⁷⁷Lu produced by the “direct” route described below can generally be used. However, high SA ¹⁷⁷Lu is required for other applications involving low capacity sites, which are present in low numbers, such as receptor sites for peptide and antibody therapy. In the field of peptide receptor radionuclide therapy (PRRT) with radiolabeled peptide analogs, use of high SA ¹⁷⁷Lu constitutes a necessity owing to the limited concentrations of the different cellular cognate receptors expressed on the tumor cell surface. Similar is the case with radioimmunotherapy (RIT), where the use of radiolabeled monoclonal antibodies targets different tumor-associated antigens and exceeding the mass threshold for pharmacologic activity of the antibody could cause unwanted reactions. For this application, the tumor cell antigen concentrations are overexpressed compared to limited concentrations associated with normal cells. Unlike peptides, monoclonal antibodies are macromolecules with molecular weights of about 150,000 Da, so the specific activity values that can be achieved by adding one or two ¹⁷⁷Lu atoms to each molecule will also be low. Hence, RIT also requires high-specific-activity radionuclide preparations.

¹⁷⁷Lu Production Process

Both the “direct” and “indirect” reactor production routes can be followed to obtain ¹⁷⁷Lu for nuclear medicine applications: The direct production route is based on neutron irradiation of ¹⁷⁶Lu targets by the ¹⁷⁶Lu(n,γ)¹⁷⁷Lu reaction. The indirect ¹⁷⁶Yb(n,γ)¹⁷⁷Yb → ¹⁷⁷Lu production route necessitates a chemical separation of ¹⁷⁷Lu from the target ¹⁷⁶Yb target atoms.

The direct and indirect reactor routes for production of ¹⁷⁷Lu are shown in Fig. 2. Each route has specific advantages and disadvantages, which are elaborated in the following sections. The neutron activation products of natural lutetium and ytterbium targets along with the nuclear decay characteristics of the product radionuclides are given in Table 2.

Fig. 2

Two different routes for reactor production of ¹⁷⁷Lu

Table 2

Neutron activation products of natural lutetium and ytterbium targets along with the nuclear decay characteristics of the product radionuclides

Element	Target isotope	% Natural Abundance	Cross section σ (barn)	Activation product	Decay Mode	T_1/2	Decay product
Lu	¹⁷⁵Lu	97.41	16.7	^176mLu	β^-, γ	3.66 h	¹⁷⁶Hf
			6.6	¹⁷⁶Lu	β^-, γ	4 × 10¹⁰ y	¹⁷⁶Hf
	¹⁷⁶Lu	2.59	2.8	^177mLu	β^-, γ & IT	160.4 d	¹⁷⁷Hf (78.6 %) ¹⁷⁷Lu (21.4 %)
			2090	¹⁷⁷Lu	β^-, γ	6.65 d	¹⁷⁷Hf
Yb	¹⁶⁸Yb	0.13	2300	¹⁶⁹Yb	EC	32.02 d	¹⁶⁹Tm
	¹⁷⁰Yb	3.04	9.9	¹⁷¹Yb	Stable
	¹⁷¹Yb	14.28	58.3	¹⁷²Yb	Stable
	¹⁷²Yb	21.83	1.3	¹⁷³Yb	Stable
	¹⁷³Yb	16.13	15.5	¹⁷⁴Yb	Stable
	¹⁷⁴Yb	31.83	63	¹⁷⁵Yb	β^-, γ	4.18 d	¹⁷⁵Lu
	¹⁷⁶Yb	12.76	2.85	¹⁷⁷Yb	β^-, γ	1.9 h	¹⁷⁷Lu

Direct Production Route [¹⁷⁶Lu(n,γ)¹⁷⁷Lu]

The direct production route offers the following advantages.

The least intricate approach to target irradiation in a reactor and requires minor design changes in reactor irradiation and processing facilities.
Offers the potential to use the ¹⁷⁶Lu₂O₃ target, which remains stable under irradiation conditions and is compatible with reactor irradiation.
Irradiated target processing is easy, fast and technically less demanding as simple target dissolution in dilute mineral acid on gentle warming suffices. The facility required for target processing is straightforward to install and maintain.
Has the flexibility to scale the increase or decrease levels of production in response to requirements by adjusting the target size.
Processing generates negligible levels of radioactive waste.
This production method represents the most inexpensive option to obtain ¹⁷⁷Lu of requisite purity.
Unlike other medically useful radionuclides, the direct (n,γ) production route often offers the prospect of producing ¹⁷⁷Lu with SA adequate for preparing receptor-specific therapeutic radiopharmaceuticals. This is possible because ¹⁷⁶Lu has a very high thermal neutron capture cross section (σ = 2090 b, I₀ = 1087 b) for formation of ¹⁷⁷Lu. The neutron capture cross section of ¹⁷⁶Lu does not follow the 1/v law, and there is a strong resonance very close to the thermal region [50, 54].

In spite of the advantages of the direct production route, some concerns that have been raised on the use of this production route include:

With a view to augmenting the ¹⁷⁷Lu production yield as well as specific activity, the possibility of using enriched ¹⁷⁶Lu targets is necessary owing to the limited natural abundance (2.6 %) of ¹⁷⁶Lu in the unenriched target.
The specific activity of ¹⁷⁷Lu obtained by this method is generally 740–1,110 GBq (20–30 Ci)/mg versus the theoretical SA value of 4.07 TBq (110 Ci)/mg. This indicates that only 25 % of the atoms are ¹⁷⁷Lu, and 75 % consisting of the product mixture are nonradioactive contaminating ^175/176Lu atoms. Thus, the maximum obtainable SA that can be achieved only with high-flux reactors is about 70 % of the theoretical value.
These SA values are adequate for preparation of the ¹⁷⁷Lu-labled agents used for bone pain palliation, synovectomy, treatment of liver cancer and some other applications.
However, while the directly produced ¹⁷⁷Lu 740–1,110 GBq (20–30 Ci)/mg can be sufficient for PRRT, the SA of course decreases with time; therefore, the shelf life of ¹⁷⁷Lu obtained by this method is limited for PRRT and for use in other applications that may require higher SA.
A unique feature of this method is the co-production of ^177mLu, the presence of which can be associated with radiation protection and waste disposal challenges in some countries, which are discussed in more detail later in this section.

Target Selection

¹⁷⁵Lu (97.4 %) and ¹⁷⁶Lu (2.6 %) are the two naturally occurring isotopes of lutetium. While only ¹⁷⁵Lu is truly “stable,” ¹⁷⁶Lu decays by beta decay with a half-life of 4 × 10¹⁰ years. While undertaking the production of ¹⁷⁷Lu, the Lu₂O₃ is the preferred chemical form because of its chemical and thermal stability during irradiation and its solubility in dilute mineral acid. There appears to be great interest in the use of an enriched ¹⁷⁶Lu target in view of the explicit need to obtain high-specific-activity ¹⁷⁷Lu amenable for radionuclide therapy. Additionally, the targets used for production should be of exceptionally high purity as isotopic impurities are likely to decrease the specific radioactivity of the produced ¹⁷⁷Lu owing to high target nuclide burn-up during high neutron-flux irradiation.

Calculation of Irradiation Yield

The following traditional equation is used to project the irradiation yields:

d N L 177 u d t = (d N L 177 u d t) growth - (d N L 177 u d t) decay

d N L 177 u d t = N L 176 u σ L 176 u φ - N 177 L u λ L 177 u

NL176u → number of target atoms ¹⁷⁶Lu,
σL176u → neutron capture cross section of ¹⁷⁶Lu (cm²),
N_¹⁷⁷Lu → number of radioactive atoms ¹⁷⁷Lu formed
λL177u → decay constant of ¹⁷⁷Lu (s⁻¹),
φ → neutron flux (cm⁻² s⁻¹),

Integrating Eq. (2) leads to

N 177 L u = N L 176 u φ σ L 176 u λ L 177 u (1 - e - λ L 177 u t)

Owing to the abnormally high neutron absorption cross section (σ = 2065 barn), target burn-up and consumption of product atoms must be considered when undertaking long-term irradiations.

d N L 177 u d t = (d N L 177 u d t) growth - (d N L 177 u d t) decay - (d N L 177 u d t) product burn up

= N L 176 u σ L 176 u φ - N 177 L u λ L 177 u - N 177 L u φ σ L 177 u

Here

N 177 L u = N 0 L 176 u e - φ L 176 u t

N0L176u→ Initial number of target atoms ¹⁷⁶Lu

N 177 L u = N 0 L 176 u φ σ L 176 u λ L 177 u - φ σ L 176 u (e - φ L 176 u t - e - λ L 177 u t)

Equation (4) is generally used, provided the neutron capture cross section in the thermal neutron area is inversely proportional to the neutron velocity (the 1/_Vn law). However, owing to the resonance in the cross section of ¹⁷⁶Lu (Table 2) in the thermal neutron energy range [47], the neutron capture cross section of ¹⁷⁶Lu does not follow the 1/v law. Under this premise, using the simplified Westcott convention is an effective proposition for the calculation of the reaction rate of ¹⁷⁶Lu(n,γ)¹⁷⁷Lu in which an additional correction of the activation rate as a function of the thermal neutron flux temperature is necessary to account for the non-abeyance of the 1/_Vn law. This is expressed by the factor k [48–50]. Following the simplified Westcott convention and taking into the account the target burn-up of ¹⁷⁶Lu as well as ¹⁷⁷Lu atoms during irradiation, the accumulation of ¹⁷⁷Lu can therefore be expressed by a differential equation:

d N L 177 u d t = N 0 L 177 u e - (σ L 176 u k φ t) σ L 176 u k φ - (λ L 177 u + σ L 177 u φ) N L 177 u

The solution of Eq. (5) gives rise to

N L 177 u = N 0 L 176 u σ L 176 u φ k λ L 177 u + φ ( σ L 177 u - σ L 176 u k ) [e - σ L 176 u k φ t - e - (λ L 177 u + σ L 177 u φ t)]

Here,

k = G t h . g (T n) + G r . r (α) T n T 0 - - - \sqrt . S 0 (α)

G_th and G_r are, respectively, the thermal and epithermal neutron self-shielding factors (both can be set equal to 1 if diluted samples are irradiated), g(T_n) is the Westcott factor [51] , r(α)TnT0−−√ is the spectral index, S₀(α) = S_o(E_r)^− α, where S₀ = 1.67 and E_r =0.158 eV are constants of ¹⁷⁶Lu [52], and α is a measure of the epithermal flux deviation from the ideal 1/E distribution, where E is the neutron energy.

The activity produced ‘A’ (in Bq) at the end of irradiation can therefore be calculated using the formula:

A L 177 u = N 0 L 176 u σ L 176 u φ k λ L 177 u λ L 177 u + φ ( σ L 177 u - σ L 176 u k ) [e - σ L 176 u k φ t - e - (λ L 177 u + σ L 177 u φ t)]

The ‘k’ value is the so-called ‘k-factor,’ and the value of ‘k’ is reported to be between 1.5–2.5 [49]. The expression of the yield of ¹⁷⁷Lu (Eq. 7) is based on the assumption that the neutron flux is highly thermalized and there is practically no contribution of epithermal neutrons toward ¹⁷⁷Lu formation. Based on Eq. 7, the variation of yield of ¹⁷⁷Lu per mg of target irradiated with the duration of irradiation is shown in Fig. 3 when an enriched (82 % in ¹⁷⁶Lu) target is irradiated at a thermal neutron flux of 1.2 × 10¹⁴ n.cm^-2.s^-1. Figure 3 shows that the yield of ¹⁷⁷Lu passes through a maximum and then decreases as the time of irradiation increases. With increasing the ‘k’ value, the yield of ¹⁷⁷Lu during neutron irradiation increases.

Fig. 3

Variation of the specific activity of ¹⁷⁷Lu, theoretically calculated using k = 1.5, 2.0 and 2.5, with the duration of irradiation when the enriched (82 % in ¹⁷⁶Lu) target is irradiated at a thermal neutron flux of 1.2 × 10¹⁴ n.cm^-2.s^-1r

The time of irradiation at which the maximum activity of ¹⁷⁷Lu is achieved is expressed as [50]

t max = 1 λ L 177 u + φ ( σ L 177 u - σ L 176 u k ) ln λ L 177 u + σ L 177 u φ σ L 176 u k φ

It is evident from the equation [43] that by increasing the neutron flux and/or k-factor, a shorter period of irradiation is required to achieve the optimum yield of ¹⁷⁷Lu. It is worthwhile to point out that an irradiation period equal to t_max does not provide the maximum specific activity owing to the transformation of the target material in the nuclear reaction. As reported by Zhernosekov et al. [50] , the actual specific activity of ¹⁷⁷Lu is different from the value obtained by dividing the production of the yield of ¹⁷⁷Lu by the mass of the target irradiated, since the actual mass of lutetium present in the system post irradiation is different from the initial mass of the target irradiated owing to target burn-up. During irradiation, ¹⁷⁷Lu absorbs neutron and leads to the formation of ^177/178Hf, which results in the accumulation of the ¹⁷⁷/¹⁷⁸Hf carrier in the target system. While the presence of ^177/178Hf(IV) has no consequences in the efficiency of ¹⁷⁷Lu(III)-labeling reactions [53], accumulation of hafnium atoms decreases the specific activity.

Using the burn-up correction, the actual specific activity S (Bq/mol) of ¹⁷⁷Lu can be expressed as:

S = A N l 177 u + N 0 L 176 u ( e - σ L 176 u k φ t + σ L 176 u φ k ( λ L 177 u + φ ( σ L 177 u - σ L 176 u k ) ) [ e - σ L 176 u k φ t - e - ( λ L 177 u + σ L 177 u φ ) t ]

Figure 4 compares the variation of the burn-up corrected specific activity of ¹⁷⁷Lu calculated using Eq. 9 with these calculated values without taking target burn-up into consideration. It is evident from the estimates that the period of irradiation at which the maximum yield of ¹⁷⁷Lu is achieved does not provide the highest available specific activity. Theoretical calculation shows that the available specific activity (burn-up corrected) of ¹⁷⁷Lu passes through a maxima at ~21 days of irradiation when the enriched Lu target (82 % ¹⁷⁶Lu) is irradiated at a thermal neutron flux of 1.2 × 10¹⁴ n.cm^-2.s^-1. This duration is significantly higher than the theoretically calculated ‘t_max’ of ¹⁷⁷Lu yield, which is ~14 days at the same irradiation condition. Irradiation longer than the ‘t_max’ leads to some loss of activity, but also to an increased ¹⁷⁷Lu/¹⁷⁶Lu ratio and hence increased specific activity due to burn-up of ¹⁷⁶Lu. This theoretical analysis justifies the 21-day irradiation cycle used for ¹⁷⁷Lu production in the Dhruva reactor in India [54, 55]. The Indian experience has demonstrated that the theoretically calculated value of the actual or available specific activity of ¹⁷⁷Lu after 21 days of continuous irradiation of an enriched Lu target (82 % ¹⁷⁶Lu) at a thermal neutron flux of 1.2 × 10¹⁴ n.cm^-2.s^-1 (1,142 GBq/mg, using k = 2.5) is close to the practically obtained value (1,108 ± 24 GBq/mg) [54, 55] .

Fig. 4

Comparison of variation of calculated ¹⁷⁷Lu specific activity taking into account the burn-up correction with that calculated without burn-up correction (both considering k =2)

While the calculation of ¹⁷⁷Lu yield based on the simplified Westcott convention is precise enough, the utility of this computation requires accurate knowledge of the neutron flux parameters of the reactor. The accuracy of the ¹⁷⁷Lu irradiation yield calculation strongly depends on the stability of the neutron flux parameters during the target irradiation period. The relatively small variations in the calculated and actual ¹⁷⁷Lu-specific activities are mostly due to the variation of the neutron flux levels due to the power level of the reactor operation. It is not practicable to normalize the neutron flux level in the multipurpose research reactor.

Therefore, the maximum obtainable specific activity that could be achieved through the direct production route is about 70 % of the theoretical value; this is only possible for irradiations conducted in high neutron-flux nuclear reactors, which are available in a limited number of countries. It has been reported that it is possible to achieve specific activities of 1,850−2,405 GBq/mg (50−65 Ci/mg) by irradiation in higher flux reactors such as the HIFR reactor at Oak Ridge National Laboratory [56, 57]. Lutetium-177 with specific activity values of >740−1,110 GBq (20–30 Ci)/mg could be produced using an enriched ¹⁷⁶Lu target up to approximately 60–80 % in medium flux reactors [54, 55] . The SA values are adequate for all established applications of ¹⁷⁷Lu for radionuclide therapy.

While using lutetium oxide enriched in ¹⁷⁶Lu up to approximately 60–80 % constitutes a successful paradigm for producing ¹⁷⁷Lu of specific activities >740 GBq (20 Ci)/mg amenable to radionuclide therapy, the coproduction of ^177mLu with a half-life of 160.1 days owing to the ¹⁷⁶Lu(n,γ)^177mLu (σ = 2 barn) nuclear reaction has emerged as one factor that may be an impediment restricting its utility in some countries. The ^177mLu content in the final product depends not only on the irradiation time, but also on the time elapsed after the end of the irradiation (EOI). Under this premise, it is pertinent to note that owing to the long half-life and low neutron absorption cross section, the activity levels of ^177mLu formed will be low but still be of possible concern. Whereas the ^177mLu waste issue must be locally resolved, estimates have clearly shown that the resulting radiation dose increase from the presence of ^177mLu is insignificant at clinically significant dose levels, at least for PRRT [53]. Under the optimized production conditions, the reported values for the ^177mLu/¹⁷⁷Lu ratio vary between 0.01 %–0.02 % at EOB [57].

The presence of ^177mLu may raise the following concerns:

Radiation dose: As hospitals are using their ¹⁷⁷Lu for the preparation of radiopharmaceuticals up to 1 week after EOB, the ^177mLu/¹⁷⁷Lu ratio would likely be doubled. A usual therapeutic dose of ¹⁷⁷Lu ranges between 7 and 9 GBq. When the ^177mLu/¹⁷⁷Lu ratio is 0.02 %, this means that a dose includes approximately 1.4–1.8 MBq ^177mLu.
Laboratory waste: During the radiolabeling process and treatment, the loss of radioactivity is typically 2 to 5 % of ¹⁷⁷Lu activity, which corresponds to levels of 28–90 kBq ^177mLu. In view of the permissible release limit for ^177mLu waste (10 Bq/g), all laboratory radioactive waste is required to be collected separately and shipped to a radioactive waste management facility where it is allowed to decay. With a half life of 160.1 days, a considerable amount of time is required to decay ^177mLu.
Waste water: A patient excretes approximately 80 % of the administered dose (1.45 MBq ^177mLu) after administration of ¹⁷⁷Lu-labeled octreotide through the urine. The patient-excreted activity in urine and feces must be stored in waste water where there is a considerable chance of accumulation of ^177mLu in the radioactive waste water holding tanks. According to the European radiation safety regulation, the maximum permissible radioactive concentration of ^177mLu in the municipal sewage is 50 kBq/m³ [58]. This means that radioactive waste water from the holding tanks needs to be diluted significantly before discharging into the municipal sewage line. The presence of ^177mLu might exceed the activity limits alone or with other nuclides (sum activity) in the radioactive waste water holding tanks and must be evaluated in each case.

While the radiation dose to patients from ^177mLu (0.01 %–0.02 %) is of little consequence [53], the problem of safe handling and disposal of the residual quantities of ^177mLu by the hospital user may emerge as a major roadblock, which can hardly be circumvented, in principal, through the storage of the radioactive wastes that is customary in hospitals. Despite the above-mentioned drawbacks, however, ¹⁷⁷Lu obtained from the (n,γ) route is preferred by many hospitals owing to the cost-effective availability of acceptable quality and quantities on demand. This can be seen as the window of opportunity to lay the basis for realizing the widespread radiopharmeutical use of ¹⁷⁷Lu.

Indirect Production Route [¹⁷⁶Yb(n,γ)¹⁷⁷Yb β−−→¹⁷⁷Lu]

The indirect production route offers the following advantages:

The highest >2.96 TBq (80 Ci)/mg vs. theoretical 4.07 TBq(110 Ci)/mg specific activity of ¹⁷⁷Lu is attainable by this production route.
Offers the potential to provide ¹⁷⁷Lu of the highest possible radionuclide purity.
The presence of long-lived radioactive impurities (e.g., ^177mLu, <10^–5 %) is precluded (below the detection limit) and therefore associated with minimum radiation protection and waste disposal issues.
Specific activity is independent of neutron flux.
Offers satisfactory radiolabeling performance.
The ¹⁷⁷Lu obtained by this method has a longer shelf-life (up to 2 weeks) owing to no appreciable decrease in specific activity.

However, this production route also has the following shortcomings, which may be expected to obstruct the path toward widescale utility.

Low production yields due to the poor ¹⁷⁶Yb thermal neutron reaction cross section (2.5 barn) as compared to the 2090 barn for the “direct” production from ¹⁷⁶Lu.
The effective separation of micro amounts of ¹⁷⁷Lu from macro amounts of the irradiated Yb target is not only challenging, but also requires an elaborate radiochemical separation as well as purification procedure.
Generates significant amounts of radioactive waste.
By far, this method of production emerges as the most expensive option to obtain ¹⁷⁷Lu of requisite purity.
Not only requires an enriched ¹⁷⁶Yb target but also its recovery and recycling.

Despite the above-mentioned drawbacks, there are tremendous prospects associated with the use of NCA ¹⁷⁷Lu in TRT; hence, this production route is being aggressively pursued by several institutions. The inherent success of this production route resides in the development of an effective strategy for the efficient separation of pure ¹⁷⁷Lu from bulky masses of the neutron irradiated Yb target since Yb follows an identical coordination chemistry with the chelating agents used for the preparation of Lu-based radiopharmaceuticals as well as successful recovery of the Yb target for recycling.

Selection of the Target

As described in Table 2, natural ytterbium consists of a mixture of seven stable isotopes, including ¹⁶⁸Yb, ¹⁷⁰Yb, ¹⁷¹Yb, ¹⁷²Yb, ¹⁷³Yb, ¹⁷⁴Yb and ¹⁷⁶Yb, among which ¹⁷⁴Yb is the most abundant.

Using natural Yb is a major deterrent because of the following:

Neutron irradiation of natural Yb will lead to the co-production of ¹⁶⁹Yb (T_½ = 32.026 d) and ¹⁷⁵Yb (T_½ =4.185 d). The presence of these contaminants will not only complicate the irradiated target handling owing to augmentation of the radiation dose, but also involves higher shielding requirements. The radiation dose to the chemical reagents used for sequestering ¹⁷⁷Lu will be significantly higher and may lead to radiation degradation.
Generates significant amounts of radioactive waste.
While the cooling of the irradiated target is an effective measure to reduce the contribution of ¹⁶⁹Yb and ¹⁷⁵Yb, this will reduce the yield of ¹⁷⁷Lu owing to radioactive decay.
Decay of ¹⁷⁵Yb via β^- emission to ¹⁷⁵Lu leads to the accumulation of stable lutetium, which will decrease the specific activity of the separated ¹⁷⁷Lu.

In view of these considerations, assessing the potential of enriched ¹⁷⁶Yb (up to ~97 %) is not only an interesting prospect, but may also be viewed as a necessary one. Owing to the low target burn-up of enriched ¹⁷⁶Yb during production, development of a process for the recovery of the unused enriched target is one of the key factors that would be expected to ultimately contribute to the economic success of ¹⁷⁷Lu production by this indirect route.

Chemical Form of the Target

While the use of a metallic target is successful for neutron irradiation, using ytterbium metal as a target is precluded as it readily oxidizes in air and under oxygen. Furthermore, the implicit need to use concentrated acid to dissolve irradiated Yb metal continues to thwart efforts toward its utilization as a target for neutron irradiation. In this context, the use of Yb₂O₃ is the only practical choice since it not only possesses sufficient chemical and thermal stability under reactor irradiation, but also allows easy post-irradiation processing by simple target dissolution in dilute acid.

Irradiation Yields

176 Y b (n, γ) 177 Y b β \to 177 L u

In this case, the net production rate of nuclide ¹⁷⁷Lu is given by

d N L u d t = N Y b (1 ‐ e ‐ λ Y b t) ϕ σ Y b

Assuming that the number of target atoms, N_Yb, remains constant (no considerable

target burn-up) and N_Yb = N_Lu = 0 at t = 0 (start of irradiation), integration of Eq. (1) gives rise to

N L u = N Y b ϕ σ Y b ⎡ ⎣ ⎢ (1 ‐ e ‐ λ L u t λ L u + e ‐ λ Y b t ‐ e ‐ λ L u t λ Y b ‐ λ L u) e ‐ λ L u t d + ( 1 ‐ e ‐ λ Y b t ) ( e ‐ λ Y b t ‐ e ‐ λ L u t d ) λ L u ‐ λ Y b ⎤ ⎦ ⎥

Here N_Yb is the initial number of ¹⁷⁶Yb atoms, σ_Yb is the cross section of the ¹⁷⁶Yb(n,γ)¹⁷⁷Yb reaction, ϕ is the neutron flux of the irradiation source, t is the irradiation time, t_d is the decay time after irradiation, and λ_Yb and λ_Lu are the decay constants of ¹⁷⁷Yb and ¹⁷⁷Lu, respectively. Figure 5 compares the calculated yields of production of ¹⁷⁷Lu by the indirect route at different neutron flux values and different irradiation times.

Fig. 5

Calculated yields of ¹⁷⁷Lu activity produced via the indirect route at different neutron fluxes and different irradiation times

Chemical Separation of ¹⁷⁷Lu from Neutron-Irradiated ¹⁷⁶Yb

While the indirect ¹⁷⁷Lu production method resides at the interface between many disciplines, the inherent determinant for the success of this production route lies in the selection of an appropriate Yb/Lu radiochemical separation. The isolation and purification of ¹⁷⁷Lu from the neutron-irradiated target have been subjects of considerable interest. The technical issues associated with the separation of microscopic levels of ¹⁷⁷Lu from the macroscopic levels of the ¹⁷⁶Yb target represent a challenging task. With a view to realizing the objective, it is imperative to evaluate the differences in chemical and physical characteristics of the Yb and Lu elements that could be used to obtain ¹⁷⁷Lu of the requisite purity and yield.

As shown in Table 3, the chemical properties of Yb and Lu are very similar. As a result of the similar characteristics of the group elements, the stability constants of metal ions with a particular ligand show only slight differences. However, such ligands could provide the potential for the separation of these two ions using either ion-exchange chromatography or a solvent extraction technique. Careful scrutiny of Table 3 reveals that the differences are only observed with the existence of a relatively stable oxidation state +2 for Yb and the high solubility of metallic Yb in mercury.

Table 3

Chemical and physical characteristics of Lu and Yb

Properties	Yb	Lu
Electronic configuration	[Xe]4f ¹⁴6s ²	[Xe]4f ¹⁴5d ¹6s ²
Ionic radius of Ln³⁺ [pm]	86.8	86.1
Ionic radius of Ln²⁺ [pm]	114	-
E_{0(Ln³⁺/Ln)}	-2.267	-2.255
E_{0(Ln³⁺/Ln²⁺)}	1.05	-
Solubility in Hg	High	Low

Due to the fully filled 4f subshell, unlike lutetium, the oxidation state Yb⁺² is relatively stable. The properties of Yb²⁺ are very similar to group 2 metal cations such as Ca²⁺ and Sr²⁺. Therefore, Yb²⁺ forms an insoluble sulfate, whereas Lu³⁺ does not. This property has been exploited for separation of the Yb⁺³ and Lu⁺³ ions. The principal shortcoming of this method is that the separation is not clean and requires multiple steps in order to achieve satisfactory decontamination.

Ion exchange separation is of course also possible using cation exchangers and elution by complexing agents. In this case the difference in the stability constant of Yb and Lu with the complexing agents is exploited to realize separation. The order of elution of Yb and Lu depends on the values of stability constants of the formed complexes, and the one that forms a strong complex is initially eluted.

In addition, the selective reduction of Yb can be judiciously exploited to achieve separation from Lu. Alkali metal amalgam, which is one of the strongest reducing agents, can be used for the reduction of Yb³⁺ to Yb²⁺ as well as Yb²⁺ to the free element, which can then enter the mercury phase owing to its ability to form amalgam with Hg.

Technological realization of Yb/Lu separation strategies poses several challenges and requires a thorough assessment to evaluate their prospects. The following are some key features that must be taken in to consideration when selecting a separation process.

The chemical separation process chosen must be effective for the separation of micro amounts of ¹⁷⁷Lu from macro amounts of Yb.
Separation must be performed rapidly not only to minimize decay losses of ¹⁷⁷Lu, but also to reduce the radiation dose to reagents to circumvent radiation degradation.
The separation method selected should be proficient to provide ¹⁷⁷Lu with the highest possible decontamination factor from ytterbium.
The process must ensure consistency, reproducibility and high product yield (ideally > 85 %) on a continual basis.
The separation process should be capable of providing ¹⁷⁷Lu in a suitable chemical form (ionic form) amenable to radiolabeling with a broad class of carrier molecules.
To undertake production of ¹⁷⁷Lu on a weekly basis annually makes it essential to have a very high degree of robustness of the separation process. Nevertheless, the process should be simple, safe and insensitive to subtle variation in operating parameters.
Amenability to safe operation in a remotely operated shielded facility with negligible operational constraints.
Flexibility to scale up or down to its level of operation in response to requirements.
Generates a minimum quantity of radioactive waste.
Offers the possibility of recovering the ytterbium for target recycling.

Taking into consideration the above-mentioned criteria, a great deal of effort has been expended upon the development of a number of Yb/Lu separation strategies. Essentially every conceivable separation approach has been profusely exploited. Methods ranging from ion exchange chromatography to electrochemical separation strategies have been employed. Brief overviews of these approaches are elaborated in the following sections.

Ion-Exchange Chromatography

Among the techniques used in radiochemical separation, ion-exchange chromatography has been generally proved to be a widely utilized, reliable, and straightforward way to separate radionuclides of interest for myriad applications. While the ion-exchange chromatography technique is appealing in terms of operation simplicity and amenability to a remotely operated facility, a straightforword separation of Yb and Lu is a difficult task owing to their striking similarities in chemical properties. Following a somewhat different path is required in which both Yb and Lu can be adsorbed on a cation exchanger and elution by an appropriated complexing agent. In this premise, two equilibria are required to be considered, i.e., the equilibrium between the complexing agent and the ion exchanger and the equilibrium between the Yb and Lu and the complexing agent. The difference in stability constants for the Yb and Lu with complexing agents forms the genesis of separation. The order of elution of Yb and Lu as well the resolution of the elution band depends on the stability constant values of the formed complexes. Since the smaller ions show a greater preference for complexation, Lu_aq³⁺ is the first to emerge from the column, followed by Yb. While the well-characterized α-hydroxyisobutyrate (α-HIBA) complexant as an eluting agent is useful for the separation of Lu from Yb, a Lu/Yb separation factor (α) of only 1.55 [59, 60] has been a major limitation. Owing to the low separation factor, the lutetium fraction contains significant levels of ytterbium because of the “peak tailing.” Moreover, the α-HIBA complex of ¹⁷⁷Lu is not optimally suited for the routine synthesis of ¹⁷⁷Lu-labeled radiopharmaceuticals. In light of the explicit need to use ¹⁷⁷Lu for the preparation of radiopharmaceuticals, α-HIBA must be decomposed and removed prior to labeling because of its high stability constant. The transfer of ¹⁷⁷Lu out of the thermodynamically very stable ¹⁷⁷Lu-α-HIBA species prior to labeling constitutes a necessity as its presence not only leads to poor labeling yield, but also requires post-labeling purification. In an attempt to circumvent this drawback, one of the methods used for the removal of α-HIBA is the adsorption on a cation exchanger followed by elution with ~9 M HCl [61]. Use of ethylene-diamine-tetra-acetate or 1,2-diamino-cyclohexanetetraacetate (α = 1.7) in lieu of α-HIBA met with limited success because of solubility problems and the requirement of additional steps to obtain ¹⁷⁷Lu of desired purity amenable for the preparation of radiopharmaceuticals [62]. Despite these inherent shortcomings, interestingly and surprisingly enough, the enthusiasm for using the ion-exchange chromatography technique has resulted in some investigators evaluating this pathway.

Balasubramanian reported [63] the separation of ¹⁷⁷Lu from 10.35 mg of neutron-irradiated ytterbium using Dowex 50 W × 8 (200–400 mesh), a cation exchanger in Zn²⁺ form. ¹⁷⁷Lu was eluted using 0.04 M α-hydroxyisobutyric acid at pH 4.6 ± 2 at 26 ± 1 °C in about 4 h. Lutetium-177 was separated in 70 % yield and with a radionuclidic purity greater than 99 %. While the reported method was successful in isolating ¹⁷⁷Lu, more than 30 % of ¹⁷⁷Lu contaminated with ytterbium was sacrificed. Lutetium-177 obtained from this method has low specific volume and contains the barrier-ion Zn²⁺. The presence of Zn²⁺ in the eluate is a major obstacle in the complexation chemistry of ¹⁷⁷Lu and therefore necessitates purification as well as concentration prior to labeling.

On a similar theme, Hashimoto et al. reported the utility of reversed-phase ion-pair chromatography using a Resolve C18 column in which ¹⁷⁷Lu was eluted with a mixture of 0.25 M α-HIBA as a complexing agent and 0.1 M 1-octanesulfonate as an ion-pairing agent [64]. In this procedure, 5 mg of the neutron-irradiated Yb₂O₃ target was used, and the process was effective to provide radiochemically pure ¹⁷⁷Lu with 84 % yield. Although this method was productive with small amounts of Yb₂O₃ target (0.01-1 mg), the separation efficiency deteriorated when higher amounts of the Yb₂O₃ target were used, resulting contamination from distortion of the ytterbium peak tailing into the lutetium peak.

Solvent Extraction

Liquid-liquid extraction is one of the most promising techniques often used for radiochemical separation. Significant practical experience has accumulated over the years in using this technique in a highly radioactive environment and on an industrial scale. Although use of the liquid-liquid extraction method based on the different extractability of Lu and Yb acidic organ phosphorus extractants holds promise, the requirement of a multistage process, which is essential to achieve the necessary decontamination of Yb from Lu owing to the low Lu/Yb separation factor (α), constitutes the major impediment that probably limits its wide-scale utility. The liquid cation exchanger, di-(2-ethylhexyl)phosphoric acid (HDEHP), has effectively been utilized as an extractant for the isolation of ¹⁷⁷Lu in proton-activated ytterbium [65]. In this method, 0.2 g of proton-irradiated nat Yb₂O₃ target was dissolved in 1 M HCl, and the ¹⁷⁷Lu formed was extracted in the organic phase containing 1 % HDEHP in cyclohexane. It is apparent that liquid-liquid extraction for ¹⁷⁷Lu separation is still in its infancy and presently represents a potential separation technique, but much additional effort is required in order to realize its potential.

Supported Liquid Membrane Extraction

The supported liquid membrane (SLM) method for Lu/Yb separation has its roots in the liquid-liquid extraction method in which a Lu-selective organic extractant is impregnated on an inert semipermeable membrane, and separation of Lu is achieved by its selective transport through the pores of the impregnated membrane. In order to tap the potential of SLM for the radiochemical separation of ¹⁷⁷Lu from Yb, HDEHP in hexane was impregnated on a membrane consisting of two blocks (one made of PVDF and the other of PTFE) with identical channels of dimensions. The membrane thickness was 200 μm, and its nominal pore size was 0.2 μm. The donor side of the membrane contained 0.2 mol dm⁻³ of ammonium acetate buffer at pH 5–5.5 in which the neutron-irradiated Yb target solution was added and the acceptor side contained 2 mol dm⁻³ HCl in which ¹⁷⁷Lu was collected [66]. Despite promising results, this separation procedure has never been extended for the separation of ¹⁷⁷Lu from neutron-irradiated Yb. The scale of ¹⁷⁷Lu separation possible by this route will be limited but could still be of interest and utility in meeting local needs. Continuing research in this separation methodology can be expected in the near future.

Extraction Chromatography

An alternative to liquid-liquid extraction is the possibility to incorporate an extractant or a solution of an extractant into an inert substrate that can be used as a support in a column chromatographic technique. The most striking feature of the extraction chromatography (EXC) technique is that it combines the selectivity of liquid-liquid extraction with the ease of operation and rapidity of a column-based separation system. It is critical, however, that an appropriate extractant needs to be chosen that offers a satisfactory Lu/Yb separation factor (α).

The EXC technique has been explored by Knapp et al., leading to the development of a one-step extraction chromatography separation process [56, 57, 67] and making use of the commercially available LN Resin, which comprises di(2-ethyl-hexyl) ortho-phosphoric acid (HDEHP), commercially available from Eichrom Technologies, Inc. The reported method was found to be effective for the quantitative separation of ¹⁷⁷Lu from 10 mg of nonradioactive Yb carrier using HCl of different concentrations for sequential elution of ¹⁷⁰Tm ¹⁷⁶Yb and ¹⁷⁷Lu. The elution sequence consisted of an initial elution with 2 M HCl (fraction 1) followed by increasing the acid concentration to 3 M HCl (fraction 2) and then 6 M HCl (fraction 2). The first peak (fraction 1) in the chromatogram contained ¹⁷⁰Tm formed by neutron activation of a stable ¹⁶⁹Tm impurity in the enriched ¹⁷⁶Yb target material. The ytterbium peak (fraction 2) then appeared and finally the ¹⁷⁷Lu was eluted with 6 M HCl. The specific activity of ¹⁷⁷Lu obtained by this method was estimated to be 3.7 TBq (100 Ci)/mg (i.e., 91 % of the 110 Ci/mg theoretical value).

The aforementioned EXC technique was further exploited by Horwitz et al. and culminated in a conceptual flow sheet that was found to be successful for the separation of NCA ¹⁷⁷Lu from a 300-mg irradiated ytterbium target [68]. The process is essentially based on the use of two different EXC resins, namely a resin containing HEH[EHP] (LN2) and a resin containing tetraoctyl diglycolamide (DGA) sorbed onto Amberchrom® CG-71. The whole separation process can be broadly divided into three steps: (1) the front-end target removal step, (2) primary separation step and (3) secondary separation step. While the goals of each separation step differ, it basically consists of separation of Yb and Lu using the LN2 resin followed by the concentration and acid adjustment of the Lu-rich eluate using Amberchrom® CG-71 resin. The use of the diglycolamide EXC material to purify the Lu-rich eluate is the novelty of this technique. Using Amberchrom® CG-71 resin seemed attractive as it precludes lengthy evaporations and acidity adjustments between successive LN2 resin column runs and at the same time is effective in removing adventitious metal ion impurities from the ¹⁷⁷Lu fraction. It is worth mentioning that during the purification of the ¹⁷⁷Lu fraction by LN2 resin, metal ions such as Zr^4+, and Hf³⁺ (¹⁷⁷Hf is the daughter of ¹⁷⁷Lu) are strongly retained and therefore free ¹⁷⁷Lu from metallic impurities. With a view to eliminating all traces of nitrate ions, a small anion-exchange column in the final step of the secondary separation step has been added. All the ¹⁷⁶Yb fractions of the target removal step, primary separation step and secondary separation step were pooled together and could be used for recycling in successive neutron irradiations.

A notable feature of this method is thus the recovery of the isotopically enriched ¹⁷⁶Yb target material. The individual decontamination factors for the front-end target removal system, primary separation system and secondary separation system are 10¹, 10² and 10³, respectively. The overall recovery of ¹⁷⁷Lu was reported to be 73 %. The total processing time employing the three steps was reported to be 4 h. The simplified flow sheet of the front-end target removal step, primary separation step and secondary separation step are depicted in Figs. 6, ,77 and and8,8, respectively. This method is attractive owing to the commercial availability of LN2 and Amberchrom® CG-71 resin, adaptation of the user-friendly EXC process, shorter processing time, satisfactory ¹⁷⁷Lu yield and amenability to routine remote operation as well as automation, and it offers the potential to recover the enriched ¹⁷⁶Yb target for recycling. The prospects of adopting such a scheme appear promising for the routine production of NCA ¹⁷⁷Lu .

Fig. 6

Front-end enriched ¹⁷⁶Yb target removal step [68]. The first step involves the separation of the enriched Yb target from ¹⁷⁷Lu using LN2 resin, and the second step constitutes the concentration and acid adjustment of the Lu-rich eluate using a chromatography column containing DGA resin

Fig. 7

Primary NCA ¹⁷⁷Lu separation step [68]. The first step involves the purification of ¹⁷⁷Lu from micro amounts of Yb using LN2 resin, and the second step using DGA resin is for the concentration and acid adjustment of the ¹⁷⁷Lu eluate

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Fig. 8

Secondary NCA ¹⁷⁷Lu separation step [68]. This process is essential for removing adventitious impurities from the ¹⁷⁷Lu

In another independent study, a multicolumn solid-phase extraction (SPE) chromatography technique using di-(2-ethylhexyl)orthophosphoric acid (HDEHP)-impregnated, OASIS-HLB sorbent-based SPE resins (OASIS-HDEHP) was used [69, 70] for the separation of ¹⁷⁷Lu from a 50-mg Yb target irradiated in a nuclear reactor with medium neutron flux (ϕ = 5 · 10¹³ n · cm⁻² · s⁻¹). The reported technique exploited the selectivity of OASIS-HDEHP resin for Lu in different concentrations of HCl solution for the consecutive loading-eluting cycles performed on different columns. The method was successful for the isolation of several hundred mCi of NCA ¹⁷⁷Lu using a 50-mg Yb target irradiated in a medium neutron flux nuclear reactor (ϕ = 5.10¹³ n/cm²/sec). The overall separation could be carried out in 5-6 h.

Electrochemical Method

As the name suggests, the electrochemical separation strategy exploits the difference between the standard reduction potentials of two radionuclides in an electrolytic medium to selectively deposit the radionuclide of interest under the influence of the controlled applied potential. The inherent advantages of electrochemical separation processes have been elaborately discussed in recent reviews [71, 72].

While the selective deposition of the radionuclide of interest from ionic state to metallic state under the influence of the controlled applied potential is a successful paradigm, applicability of this strategy for Lu/Yb separation is precluded owing to the deeply negative reduction potentials of lanthanides (more negative than hydrogen discharge) and difficulty in controlling their electrolytic deposition onto the solid cathode. In light of the perceived need to realize the potential for Lu/Yb separation following an electrochemical strategy, a somewhat different path is required. This alternate electrochemical path basically consists of selective reduction of Yb³⁺ to Yb²⁺ and its preferential transfer onto a mercury cathode exploiting the ability of Yb²⁺ to form amalgams with Hg.

This strategy seems attractive for the following reasons:

An examination of the redox potentials of the Yb and Lu indicates the possibility of Yb forming the bivalent state, whereas in the case of Lu, a stable bivalent state is unknown.
While Yb²⁺ is known to form an amalgam, Lu³⁺ cannot [73–76]. Therefore, Lu is difficult to deposit on the Hg cathode from aqueous electrolytes.
Offers the possibility of electrolytic reduction of Yb³⁺ to Yb²⁺ in a mildly acidic solution owing to its high hydrogen over-voltage. Such an attribute ensures no reoxidation of Yb²⁺ and offers easy handling and deposition of Yb onto Hg.

The electrochemical separation method is essentially based on the formation of the Yb amalgam by electrolysis into a mercury cathode or extraction into an amalgam aimed at its removal from the Yb-Lu mixtures. With a view to removing Yb, the potential of using Hg is enticing because of its high density, the insolubility of mercury in aqueous medium and the absence of adsorptive effects. In the quest for innovative approaches to separate Yb from other lanthanides, Marsh successfully exploited the electrochemical pathway using a mercury cathode [73–76], which represents one of the very early electrochemical separation strategies at a time when the utility of the electrochemical technique in separation science had not yet been established. This elegant separation technique was later effectively harnessed by McCoy, which paved the way for the first laboratory-scale separation of Lu from Yb [77] and showed the extraction was quite specific for Yb. Extending this theme, Onstott [78, 79] reexamined Yb reduction using a series of alkali metal salts and employed lithium citrate in place of potassium citrate.

These three successful preparative-scale separations of Lu from Yb using mercury cathodes have been reported in the literature and are discussed below.

Cementation Process

In order to tap the potential of the electrochemical method, Lebedev et al. reported a method [80] that essentially consists of dissolution of irradiated Yb₂O₃ in hydrochloric acid, addition of sodium acetate to form sodium amalgam and extraction of Yb by sodium amalgam from Cl^–/CH₃COO^– electrolytes into mercury. A series of four successive cementation steps each was performed in order to achieve a satisfactory decontamination factor. With a view to achieving the desired purity, the ¹⁷⁷Lu precipitate containing trace amounts of ytterbium was dissolved in acid and adsorbed on a cation-exchange column from which ¹⁷⁷Lu was selectively eluted using α-HIBA. In light of the explicit need to remove α-HIBA, the eluted ¹⁷⁷Lu solution was then adsorbed on a cation-exchange column wherein both Lu and Yb were adsorbed and ¹⁷⁷Lu was eluted with 9 M HCl. The recovery yield of ¹⁷⁷Lu in this process was 75 %, and decontamination factor from ytterbium was found to be >10⁶. While the reported method is appealing in terms of recovery yield of ¹⁷⁷Lu and product quality, the requirement of a time-consuming, complicated process involving multiple cementation cycles together with the elaborate purification steps emerged as the major impediment that would be expected to restrict its wide-scale applicability. The logistics are expected to be unfavorable to carry out such a complicated process on a very regular basis.

In order to mitigate the limitation of this method, Bilewicz et al. [81] developed a method based on the reduction of Yb(III) to Yb(II) with sodium amalgam followed by removal of Yb by selective precipitation as the sulfate. The principal shortcoming of this precipitation method is that the separation is not clean and requires an additional ion exchange purification step to achieve the desired purity amenable for clinical use. While the reported method obviously holds promise, the processing is quite complex because of several factors influencing its performance and requires a purification step to achieve satisfactory purity. This separation strategy is not only user-unfriendly, but also could lead to varying consistencies of the purity as well as yield.

Electro-Amalgamation Process

The electro-amalgamation approach developed by Chakravarty et al. [82] is based on the electrolytic reduction of Yb³⁺ to Yb²⁺ in lithium citrate medium followed by formation of Yb amalgam by electrolysis and extraction of Yb from the mercury cathode. A schematic diagram of the electrochemical setup used in this procedure is depicted in Fig. 9. In the two-cycle electrolysis, the first step is is the pre-elimination of the bulk of the Yb target mass, and the second step is the further purification of ¹⁷⁷Lu. This process provides NCA ¹⁷⁷Lu with acceptable purity and satisfactory separation yield (>90 %) within 3-4 h. The flow chart of this electro-amalgamation process is shown in Fig. 10. This strategy thus far has been confined to laboratory-scale investigations but could still be of interest and utility if adequate technological attention is imparted. The prospects for adopting such a scheme appear promising in the foreseeable future.

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Fig. 9

Schematic diagram of the electrochemical setup used for the production of ¹⁷⁷Lu [82]

Fig. 10

Production flow chart used for the isolation of NCA ¹⁷⁷Lu following electrochemical separation technique [82]

Accelerator-Based Production of ¹⁷⁷Lu

Accelerator technologies could be used to produce small quantities of ¹⁷⁷Lu, and although a number of routes can be explored that would be useful in basic research, these are not expected to really serve as the basis to undertake large-scale cost-effective production because of the extremely low cross sections of the reaction routes envisaged.

With a view to realizing the accelerator production of ¹⁷⁷Lu, a number of studies concerning activation cross sections of the deuteron-induced nuclear reactions as well as excitation functions of the ^natYb(d,xn)^{177,173,172mg,171mg,170,169}Lu reactions have been reported, and the following are of interest. Hermanne et al. studied the cross sections of deuteron-induced reactions on Yb targets and measured the cross sections between 3 and 20 MeV for Yb(d,xn)¹⁷⁰Lu/¹⁷¹Lu/¹⁷²Lu/¹⁷³Lu/¹⁷⁴Lu/¹⁷⁷Lu, and Yb(d,xnp)¹⁶⁹Yb/¹⁷⁵Yb [83]. Manenti et al. measured the activation cross sections of Yb(d,xn)¹⁶⁹Lu/¹⁷⁰Lu/¹⁷¹Lu/¹⁷²Lu/¹⁷³Lu/¹⁷⁴Lu/¹⁷⁶Lu/¹⁷⁷Lu,Yb(d,xnp)¹⁶⁹Yb/¹⁷⁵Yb/¹⁷⁷Yb reactions up to 18.18 MeV [84].

Tárkányi et al. performed a systematic study of the activation cross sections of deuteron-induced nuclear reactions and excitation functions of the ^natYb(d,xn) ^{177,173,172mg,171mg,170,169}Lu,^natYb(d,x)^175,169Yb and ^natYb(d,x)^{173,172,168,167,165}Tm reactions up to 40 MeV. Some of these reactions were evaluated for the first time [85]. Although promising, substantial R&D and large resources are required for the technological development and assessment owing to the challenges associated with target preparation as well as the sustained operation of accelerators on a reliable and continuous basis.

Quality Control of ¹⁷⁷Lu

Having reviewed in detail the direct and indirect strategies for reactor production and the various processing technologies used to obtain ¹⁷⁷Lu, the quality evaluation of ¹⁷⁷Lu is the next important issue with regard to providing this radioisotope for clinical use. Because of the requirements imposed by pharmaceutical legislation to ensure safety and efficacy, despite these encouraging prospects and the favorable results of the various production and processing methodologies, quality evaluation of ¹⁷⁷Lu is, of course, a prerequisite before preparation of radiopharmaceuticals in the daily nuclear medicine routine.

Radionuclidic Purity

Radionuclidic purity is defined as the ratio, expressed as a percentage, of the radioactivity of ¹⁷⁷Lu to the total radioactivity content of the sample. Gamma spectroscopy using a high-purity germanium (HPGe) detector in conjunction with a multichannel analyzer (MCA) is used for routine determination of the radionuclidic purity of ¹⁷⁷Lu. To be able to quantify the ¹⁷⁷Lu and the possible impurities, the detector system must be properly calibrated for both energy and efficiency using either a series of standardized sources, each containing a single radionuclide, or a single calibrated source containing a radionuclide having several gamma photon of different energies (e.g., ¹⁵²Eu) obtained from a National Metrology Institute (NMI) or commercial laboratories that can demonstrate measurement traceability to an NMI. Because of the requirement to maintain dead time and pile-up at acceptable levels (dead time <10 %) during measurement, it is mandatory to dilute the ¹⁷⁷Lu sample appropriately. While gamma spectrometry constitutes a successful example of the determination of the radionuclidic purity of ¹⁷⁷Lu, direct spectral analysis of ^177mLu co-produced with ¹⁷⁷Lu and other longer lived contaminants is not possible because of the overwhelming contribution of ¹⁷⁷Lu. This difficulty is mitigated by keeping an aliquot of a ¹⁷⁷Lu sample, which is allowed to decay for an appropriate time (i.e., ~60 days), and then analyzing it using the gamma spectrometric technique. Gamma photon peaks pertaining to ^177mLu and other long-lived radionuclides can then be easily identified based on their characteristic gamma rays. A typical gamma spectrum of ¹⁷⁷Lu obtained from the (n,γ) ¹⁷⁷Lu production route immediately after radiochemical processing and after 70-day decay is shown in Fig. 11.

Fig. 11

A typical gamma spectrum of a ¹⁷⁷Lu sample aliquot obtained from the (n,γ) ¹⁷⁷Lu production route recorded immediately (a) after radiochemical processing and (b) after 70-day decay

Radiochemical Purity

Radiochemical purity is defined as the ratio, expressed as a percentage, of the radioactivity of ¹⁷⁷Lu present as ¹⁷⁷LuCl₃ to the total radioactivity of ¹⁷⁷Lu present in the sample. With a view to determining the radiochemical purity of ¹⁷⁷Lu after chemical separation, both paper chromatographies (PC) as well as high-performance liquid chromatography (HPLC) techniques are used. Paper chromatography using Whatman 3MM strips is the method most commonly used to test ¹⁷⁷Lu for radiochemical purity. The PC method is simple, fast and inexpensive. A small aliquot (~5 μL) of the test solution can be spotted at 1.5 cm from the bottom of a paper chromatography strip. The strip needs to be eluted using 0.9 % NaCl (w/v) in 0.02 M HCl as the eluting solvent. After elution, the strip can be dried and cut into segments (i.e., typically 1 cm). The radioactivity associated with each segment can be determined by using a well-type NaI(Tl) scintillation counter by keeping the base line at 150 keV and with a window of 100 keV, thereby utilizing the 208-keV gamma photon of ¹⁷⁷Lu. A typical paper chromatography pattern of ¹⁷⁷Lu³⁺ is shown in Fig. 12. For HPLC analysis, a typical system utilizing water (A) and acetonitrile (B) mixtures with 0.1 % trifluoroacetic acid is used as the mobile phase. A typical HPLC pattern of ¹⁷⁷Lu³⁺ is illustrated in Fig. 13.

Fig. 12

Paper chromatography pattern of ¹⁷⁷Lu³⁺

Fig. 13

HPLC pattern of ¹⁷⁷Lu³⁺

Chemical Purity

In light of the explicit need to perform radiolabeling with ¹⁷⁷Lu, the chemical purity is also of paramount importance, especially for receptor-targeted agents. In view of the extremely low concentration of ¹⁷⁷Lu, the metal ion impurities even at ppb levels act as pseudocarriers, requiring higher concentrations of the targeting vectors to achieve high radiolabeling yields. Recognizing the ability of competing metal ion impurities, such as Al, Ca, Cu, Fe, Pb and Zn, likely to be present in the ¹⁷⁷LuCl₃ solution, to form thermodynamically and kinetically stable coordination complexes with the targeting vectors, it is of utmost importance to determine their concentration, which could be effectively achieved by the inductively coupled plasma atomic emission spectrometry (ICP-AES) technique.

Another noteworthy chemical impurity is the hafnium isotope, which is produced through the decay of ¹⁷⁷Lu, ¹⁷⁷Hf (¹⁷⁷Lu β−−→¹⁷⁷Hf ). Fortunately, its presence is not of much concern owing to the negligible ingrowth and due to the fact that Hf does not interfere with the labeling [53].

Specific Activity

With a view to using ¹⁷⁷Lu for targeted radionuclide therapy, the goal of attaining the highest possible specific activity is crucial. With a view to realizing this objective, the presence of cold Lu should be minimized to the extent possible as it acts as a competitor for labeling positions on targeting vehicles. On this premise, determination of the specific activity of ¹⁷⁷Lu prior to radiolabeling was deemed worthy of consideration.

The specific activity of ¹⁷⁷Lu can be expressed as:

S = A L 177 u m L 177 u + m L 175 u + m L u

Here A_177Lu is the measured activity of ¹⁷⁷Lu at any particular point in time, and m_177Lu, m_175Lu, m_Lu are the mass of ¹⁷⁷Lu, ¹⁷⁵Lu and cold Lu present in the sample.

The activity of ¹⁷⁷Lu in a given aliquot is generally measured following gamma spectroscopy using an HPGe detector. The sample can be placed for the appropriate time at a suitable geometry, and the counts acquired under 208 keV after chemical processing can be used for assay of ¹⁷⁷Lu. The total concentration of ¹⁷⁷Lu, ¹⁷⁵Lu and cold Lu in the sample can be determined by the ICP-AES technique. From the determination of the activity and total Lu concentration, the specific activity of ¹⁷⁷Lu is computed.

The current worldwide suppliers of good manufacturing practices (GMP) producing ¹⁷⁷Lu as a radiochemical are provided in Table 4. In addition to the major producers and suppliers, some countries also produce small quantities of ¹⁷⁷Lu for domestic use.

Table 4

Current suppliers of GMP-produced ¹⁷⁷Lu as a radiochemical

Suppliers	Specific activity	Chemical form	Category	Radiochemical concentration
Perkin Elmer,USA	~20 Ci(740 GBq) /mg at production	¹⁷⁷Lu as LuCl₃ in ~0.05 M HCl.	CA	~3 Ci(111GBq)/ml on the day of production
ORNL, USA	50–80 Ci(1.85 - 2.96 TBq)/mg	¹⁷⁷Lu as LuCl₃ in 0.1 M HCl	CA	8 Ci(296 GBq)/ml
MURR, USA	25 Ci(925 GBq)/mg	¹⁷⁷Lu as LuCl₃ in 0.05 M HCl	CA	3 Ci(111 GBq)/ml
MDS Nordion, Canada	45 Ci(1.665 TBq)/mg	¹⁷⁷Lu as LuCl₃ in 0.05 M HCl	NCA	≥200 mCi( 7.4 GBq)/ml
ITG, Garching, Germany	80 Ci(2.96 TBq)/mg	¹⁷⁷Lu as LuCl₃ in 0.04 M HCI	NCA	8 Ci(296 GBq)/ml
IDB Holland BV	~20 Ci(740 GBq)/mg	¹⁷⁷Lu as LuCl₃ in 0.05 M HCI	CA	3 Ci(111 GBq)/ml

Regulatory Requirements and Automation

Lutetium-177 produced from any of these production routes is considered as an active pharmaceutical ingredient (API) since it is used as a starting material for the preparation of radiopharmaceuticals for human use and production must be regulated. The emphasis on quality is most prominently manifested by the fact that all equipment, instruments and technologies in ¹⁷⁷Lu production facility and the associated accessories must meet the preset criteria and the product obtained has to meet strict specifications. Written and approved protocols specifying the critical steps and acceptance criteria must be in place. Confirmation of appropriate regulatory conditions for aseptic processing and its supportive activities is mandatory. Production of ¹⁷⁷Lu should be carried out according to GMP, which is becoming mandatory in most countries.

In order to achieve GMP compliance, it is essential to have a full documentation system providing traceability that includes:

A Site Master File
Drug Master Files for the individual batch
Validation Master File
Specifications for materials
Operating procedures
Batch processing records
Training of staff

The US Food and Drug Administration (FDA) approved a set of regulations describing production of radionuclides used as APIs according to cGMP, outlined in the Code of Federal Regulations. In order to address these regulatory demands, radionuclide production is migrating toward the use of automated modules. The advantages of using automated production strategies include:

Assuring reproducibility in production yield as well as consistency in product quality.
Improving the robustness of the production as well as providing on-line documentation of the process, thus improving GMP compliance.
Providing a log of the steps performed during the processing of ¹⁷⁷Lu. Electronic record keeping is not only accurate and complete, but also helps in accomplishing regulatory compliance.
Precluding the possibility of cross-contamination.
Ability to handle multiple GBq levels of radioactivity safely, enabling the manufacturer to produce and distribute the required quantities of ¹⁷⁷Lu for therapy.
Facilitating regulatory compliance through manufacturer installation qualification/operational, qualification/performance, qualification and scheduled maintenance protocols performed for ¹⁷⁷Lu production by trained personnel.
Improving radiation safety through the reduction (or elimination) of manual operations.

Use of automated production strategies represents an appealing vision where significant resources and effort have been expended. While automation holds promise and offers numerous advantages, it presents radiochemists with the challenge of re-configuring the chemical processing steps that require integration of several steps while maintaining full automation. Nonetheless, to be effective in addressing the particular regulatory barriers, automated processing modules must be customized to local legislative, regulatory and institutional conditions for which a comprehensively designed and correctly implemented quality assurance system is of utmost importance.

In addition to meeting pharmaceutical GMP and gross domestic product (GDP) regulations, manufacturers undertaking regular production of ¹⁷⁷Lu must be licensed by a Nuclear Regulatory Authority (NRA). In this context, it is mandatory for the manufacturer to demonstrate that its facility used for ¹⁷⁷Lu production is adequate to protect health and minimize danger to life and property. Additionally, the manufacturer must be qualified to use radioactive material, establish a radiation protection program as well as the controls and procedures for the management, record keeping, accounting and use of radioactive materials.

Summary

This overview of the existing ¹⁷⁷Lu reactor production and processing technologies along with the recent developments reveals two competitive options, each having relative advantages and disadvantages. Production of ¹⁷⁷Lu is inextricably linked to the advancements in TRT. A wide range of innovative new targets, lead compounds and new radiolabeled ligands as vectors are emerging far more rapidly than over the past decade. As radionuclide therapy is moving to the forefront of molecular-targeted radionuclide therapy of cancer and other diseases, the demand for ¹⁷⁷Lu is evolving.

Although the accelerator-based ¹⁷⁷Lu production option holds promise as an innovative approach, current global trends in this production route are demonstrably unsustainable both technically and economically. Completing the technological development as well as establishing the economics of this approach is expected to be years away, and its success will depend on how these challenges are tackled in the years to come. Of the two reactor production options discussed, the prospect of using CA ¹⁷⁷Lu produced by the “direct” route is appealing as it is the least intricate way to obtain ¹⁷⁷Lu of reasonable specific activity and will suffice for most applications. While the “direct” production route is attractive in terms of simplicity in target processing and cost effectiveness, the burden of ^177mLu in the final product is the key factor in determining its usefulness. Owing to the inherent requirement of an elaborate intricate radiochemical processing technology for the isolation of NCA ¹⁷⁷Lu, significant expertise, skilled technicians and adequate resources for undertaking regular production, the number of commercial radioisotope suppliers of NCA ¹⁷⁷Lu remains finite, and its current production capabilities are still limited.

In recent years, targeted radionuclide therapy has been moving from an exotic treatment modality for a very few patients to a mainstream modality. The future of targeted radionuclide therapy is, of course, difficult to predict, and there will be surprising inventions that, as in the past, may have an unexpected application that will continue to fuel the field. These represent the niche areas where NCA ¹⁷⁷Lu will have an advantage over CA ¹⁷⁷Lu. While undertaking large-scale ¹⁷⁷Lu production, it is essential to assess both options, weigh pros and cons, and select the one based on the technical and economic resources. It is important to note that these two reactor production routes should not be approached as competitive, but instead provide ¹⁷⁷Lu for a variety of clinical applications to benefit needy patients.

Lutetium-177 seems destined to find important applications in the personalized therapy of patients using low-abundance gamma photons for diagnosis. This paradigm, when properly enforced, would not only provide a clear understanding of the disease following its detection and progression, but also provide vital clues for making decisions about individualized treatments. Administering suitable ¹⁷⁷Lu-labeled radiopharmaceuticals in their required doses and providing personalized treatment planning constitute a major step forward to meet the challenges of personalized medicine. Implementation of this regimen is likely to trigger profound structural changes in the treatment strategy and potentially to create a situation where treatments can be tailored to individual patient-specific diseases. Effective harnessing of such a treatment regimen requires a constant and reliable supply of ¹⁷⁷Lu of the required quality in the desired quantities at a reasonable cost. Because of the pace at which the personalized therapy scene is evolving, ¹⁷⁷Lu production strategies need a vision for today and tomorrow.

The advances made in large-scale ¹⁷⁷Lu production so far are exciting, and there are no apparent barriers to its adoption for large-scale production. With the appropriate selection of a production route, it would be possible to envision a future where the scale and potential of ¹⁷⁷Lu production technology can be tailored to institutional needs. The progressive fusion of existing ¹⁷⁷Lu production technologies with automation can be consciously nurtured in effective ways to respond to GMP compliance and to surmount regulatory barriers. Potentially the infusion of automation into ¹⁷⁷Lu production technology may be hastened by the creation of a positive platform for future growth. Interest in and expansion of ¹⁷⁷Lu production and processing technologies as well as the development and clinical introduction of ¹⁷⁷Lu-based therapeutic radiopharmaceuticals have passed many milestones, and it is expected that broader use and regulatory approval of ¹⁷⁷Lu-agents will move forward rapidly.

Conflict of Interest

Ashutosh Dash, Maroor Raghavan Ambikalmajan Pillai and Furn F. (Russ) Knapp, Jr., declare that they have no conflict of interest.

Informed Consent

The manuscript does not contain clinical studies. There is no identifiable patient information in this manuscript.

The information comes from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463871/

Educational

Theranostics in nuclear medicine practice

Abstract: The importance of personalized medicine has been growing, mainly due to a more urgent need to avoid unnecessary and expensive treatments. In nuclear medicine, the theranostic approach is an established tool for specific molecular targeting, both for diagnostics and therapy. The visualization of potential targets can help predict if a patient will benefit from a particular treatment. Thanks to the quick development of radiopharmaceuticals and diagnostic techniques, the use of theranostic agents has been continually increasing. In this article, important milestones of nuclear therapies and diagnostics in the context of theranostics are highlighted. It begins with a well-known radioiodine therapy in patients with thyroid cancer and then progresses through various approaches for the treatment of advanced cancer with targeted therapies. The aim of this review was to provide a summary of background knowledge and current applications, and to identify the advantages of targeted therapies and imaging in nuclear medicine practices.

Keywords: theranostics, nuclear medicine, personalized medicine, PET/CT, therapy, diagnostics

Introduction: goals of theranostics in nuclear medicine

Challenges in modern oncology include the fact that patients are getting older and are typically unfit for conventional chemotherapy regimens because of comorbidities or poor performance status.¹ Furthermore, the occurrence of side effects may aggravate treatment compliance in both young and elderly patients.² To manage these problems, it is important to improve patient selection, reduce side effects, and enhance therapeutic efficacy. Taking these factors into consideration, the combination of targeted cancer imaging and therapy is a considerable achievement for personalized medicine.

The theranostic approach in nuclear medicine couples diagnostic imaging and therapy using the same molecule or at least very similar molecules (Figure 1), which are either radiolabeled differently or given in different dosages. For example, iodine-131 and lutetium-177 are gamma and beta emitters; thus, these agents can be used for both imaging and therapy. Furthermore, different isotopes of the same element, for example, iodine-123 (gamma emitter) and iodine-131 (gamma and beta emitters), can also be used for theranostic purposes.^3,4 Newer examples are yttrium-86/yttrium-90 or terbium isotopes (Tb): ¹⁵²Tb (beta plus emitter), ¹⁵⁵Tb (gamma emitter), ¹⁴⁹Tb (alpha emitter), and ¹⁶¹Tb (beta minus particle).^5,6

Figure 1 The theranostic principle in nuclear medicine involves combining diagnostic imaging and therapy with the same molecule, which is radiolabeled differently, or administered in other dosages. In case of radioiodine therapy (RAI), the radioisotope (¹³¹I or ¹²³I) can be directly mediated by the sodium-iodide symporter in the thyroid cells. In other cases, it can be more complex. The image shows a simplified model of a radiopharmaceutical, which consists of a binding molecule that binds the target, and a linking molecule, which binds the radioisotope. Examples of such theranostic molecules are DOTA-TOC, DOTA-TATE, and PSMA-617.

The detection of potential targets can help predict whether a patient will benefit from a particular treatment. Theranostics can be useful for estimating the potential response and eventual toxicity. During the treatment, theranostics can be applied in monitoring the therapy course. However, one cause of concern is the safety of high cumulative doses of radioactive agents after multiple repeated cycles. For instance, reports concerning irreversible high-grade toxicity followed soon after the first treatments with radioiodine (iodine-131).⁷ However, there have been remarkable advances in nuclear medicine, especially in the field of targeted therapies. After a proper preselection of candidates, targeted nuclear therapies have proven to be effective in the majority of cases with a favorable safety profile.^8–11 Recent studies have shown no evidence of grade 3/4 toxicity in patients with neuroendocrine tumors after repeated (≥8 cycles) radiopeptide therapy with a cumulative dose of up to 97 GBq.¹² Good tolerability has also been observed in patients with prostate cancer (PC) after a cumulative dose of 36 GBq and up to six cycles of radioligand therapy.^13,14

Nuclear imaging utilizes gamma and positron emitters (β⁺). Gamma emitters, such as technetium-99m (^99mTc) or iodine-123 (¹²³I), can be located using gamma cameras (planar imaging) or SPECT (single photon emission computed tomography).¹⁵ However, better resolution can be achieved via PET (positron emission tomography) using positron emitters, such as gallium-68 (⁶⁸Ga) and fluor-18 (¹⁸F).¹⁶

Most therapeutic radiopharmaceuticals are labeled with beta-emitting isotopes (β⁻). The tissue penetration of these particles is proportional to the energy of the radioisotopes.¹⁷ Beta particles have a potential cytocidal effect, but they also spare the surrounding healthy tissue due to having a tissue penetration of only a few millimeters.⁸ Commonly used beta emitters in routine nuclear oncology practices include lutetium-177 (¹⁷⁷Lu, tissue penetration: 0.5–0.6 mm, maximum: 2 mm, 497 keV, half-life: 6.7 days) and yttrium-90 (⁹⁰Y, tissue penetration: mean 2.5 mm, maximum: 11 mm, 935 keV, half-life: 64 hours).^{8,10,13,18–20}

The first theranostic radiopharmaceutical in nuclear medicine history was radioiodine, which was used for therapy and imaging in thyroid diseases.²¹ Since then, the use of theranostic agents has been consistently increasing. Nuclear targeted therapies play an essential role, especially in patients with advanced neuroendocrine tumors, such as gastroenteropancreatic (GEP) tumors, bronchopulmonary neuroendocrine tumors, pheochromocytoma, and neuroblastoma.^{10,11,20,22–27} Furthermore, there are positive results with radioligand therapies in metastatic PC and metastatic melanoma.^{8,13,19,28,29}

The aim of this review was to discuss the most important milestones of nuclear theranostics in current practice (Table 1), and to provide a summarized background and overview of current applications and advantages of targeted therapies and imaging.

Table 1 Overview of theranostic agents
Abbreviations: mIBG, metaiodobenzylguanidine; SSA, somatostatin analogs; SSTR, somatostatin receptors; NEN, neuroendocrine neoplasia; GEP, gastroenteropancreatic system; SPECT, single photon emission computed tomography; PET, positron emission tomography.

Radioiodine therapy: “the gold standard” in thyroid diseases

Iodine (stable isotope: iodine-127) is taken up by the thyroid gland for the production of thyroid hormones, namely, thyroxine (T4) and triiodothyronine (T3).³⁰ Thyroid hormones are vital for the embryonic and neonatal development of the brain, normal growth, and metabolic balance.^9,31–33 In 1936, Dr Saul Hertz, director of the Thyroid Clinic in Massachusetts (1931–1943), developed the idea of administering radioactive iodine in patients with thyroid diseases. Iodine and external beam radiation were well-known tools in thyroid disease therapy, but the combination of these was a considerably innovative approach. This idea followed a few years of preclinical studies in collaboration with the Massachusetts Institute of Technology (MIT), where the first cyclotron for medical use had been built. The MIT Cyclotron produced 90% iodine-130 (¹³⁰I, half-life: 12 hours) and 10% iodine-131 (¹³¹I, half time: 8 days). Subsequently, on March 31, 1941, Dr Hertz treated the first patient with radioiodine (¹³⁰I).^21,34,35

The first radioiodine therapy (RAI) with ¹³¹I in patients with thyroid cancer (TC) was undertaken by Seidlin et al in 1946.³⁶ This group studied the use of RAI in patients with metastatic thyroid carcinomas.^36,37 Seidlin et al also reported one of the first cases of acute myeloid leukemia after repeated RAI treatments.⁷

To date, ¹³¹I is still the gold standard for the therapy and diagnosis of differentiated TC.³⁸ It is a low-cost nuclear reactor product from the neutron bombardment of tellurium-131. ¹³¹I combines the characteristics of a beta (β⁻, approximately 90% of the radiation, mean: 192 keV, mean tissue penetration: 0.4 mm) and gamma (approximately 10% of the radiation, mean: 383 keV) emitter. In this way, it irradiates the TC and the thyroid remnant from the inside and, at the same time, targeted lesions can be visualized using a gamma camera or SPECT.^9,32,33 Another radioisotope is ¹²³I, which is a pure gamma emitter and is used for pre- and post-therapeutic diagnostics. The advantages of imaging with ¹²³I include a higher quality of whole-body scans, which improves the sensitivity in detecting thyroid remnants.^3,4

Figure 2A shows the initial ¹³¹I-planar images of a 74-year-old female with metastatic TC (lung, bone, and intracranial soft-tissue metastases). The level of tumor marker thyroglobulin (Tg) before RAI was 572 ng/mL. After two administrations of RAI (cumulative activity: 14.3 GBq), the patient was in complete remission with a Tg level of 0.2 ng/mL (Figure 2B).

Figure 2 (A) Initial ¹³¹I-planar images of a 74-year-old female with metastatic thyroid cancer (lung, bone, and intracranial soft-tissue metastases, marked with arrows). The tumor marker thyroglobulin (Tg) before radioiodine therapy (RAI) was 572 ng/mL. (B) After two administrations of RAI (cumulative activity: 14.3 GBq), the patient was in complete remission with the Tg at 0.2 ng/mL. The planar images show only a physiological uptake of the radiotracer in the gastrointestinal tract and pharyngeal mucosa (marked with an asterisk).

Diagnostics and therapy with metaiodobenzylguanidine

Metaiodobenzylguanidine (mIBG), or iobenguane, is a molecule similar to noradrenaline and enters neuroendocrine cells from the sympathetic nervous system, either by endocytosis or passive diffusion before being stored in neurosecretory granules.³⁹ Among the used radiolabeled molecules, [¹²³I]I-mIBG has a lower gamma energy than [¹³¹I]I-mIBG (159 keV vs 360 keV), which makes it more suitable for planar imaging/SPECT. Furthermore, the pure gamma emitter [¹²³I]I-mIBG consists of a shorter half-time of 13 hours compared to 8 days for the combined beta and gamma emitter [¹³¹I]I-mIBG, leading to a smaller radiation burden. Thus, higher quantities of [¹²³I]I-mIBG can be injected.⁴⁰ Both [¹³¹I]I-mIBG and [¹²³I]I-mIBG are used in mIBG scintigraphy for the detection of neuroendocrine tumors, such as neuroblastomas, pheochromocytomas, paragangliomas, medullary thyroid carcinomas, and other neuroendocrine neoplasias.⁴¹ In patients with inoperable or advanced tumors with distant metastases, mIBG imaging plays an essential role in response assessment after therapy and in the evaluation of potential [¹³¹I]I-mIBG therapy.^42,43 In patients with neuroblastoma and pheochromocytoma, [¹²³I]I-mIBG has high sensitivity (97% and 94%) and specificity (up to 96% and 92%), respectively.^44–46 If available, [¹²⁴I]I-mIBG-PET can be equally used for the planning of mIBG targeted therapy.^47,48

Targeted therapy with [¹³¹I]I-mIBG presents an encouraging efficacy with tolerable toxicity in relapsed or refractory neuroblastomas with response rates between 20% and 40% being used alone or in combination with high-dose chemotherapy followed by autologous stem cell transplantation.^23–25,49 Recently, the NB2004 Trial for Risk Adapted Treatment of Children with Neuroblastoma closed, and further analysis of the usage of mIBG therapy as a first-line therapy is outstanding.^23,25

Palliation of bone metastases

Radiolabeled phosphonates have a high bone affinity and can be used for imaging and palliation of painful bone metastases. Depending on the degree of osseous metabolism, the tracer accumulates via adhesion to bones and, preferably, to osteoblastic bone metastases.⁸

Therapy planning requires a bone scintigraphy with technetium-99m-hydroxyethylidene diphosphonate (HEDP) to estimate the metabolism and the extent of the metastases involvement. Bisphosphonate HEDP can be labeled for therapy either with rhenium-186 (beta-emitter, half-life: 89 hours, 1.1 MeV maximal energy, maximal range: 4.6 mm) or rhenium-188 (beta-emitter [to 85%, 2.1 MeV] and gamma-emitter [to 15%,155 keV], half-life: 16.8 hours, maximal range in soft tissue: 10 mm).⁵⁰

Both agents induce pain relief in ≥90% of patients.⁵¹ However, rhenium-188 is of particular interest because it can be cost-effectively produced using a tungsten-188/rhenium-188 generator. The gamma component of the agent allows post-therapeutic imaging of good quality.⁸ Furthermore, patients with prostatic cancer have shown, after two [¹⁸⁸Re]Re-HEDP injections, a significantly higher response rate (92%), a prostate-specific antigen (PSA) decline >50% (38%), and a longer PFS (7 months) compared to patients who have had a single injection.^52,53 Biersack et al showed an improved OS of 15.7 months in patients after repeated injections (≥3 injections) compared to patients with a single therapy.⁵⁴ Besides transient bone marrow toxicity (thrombocytopenia grade III), the reported toxicity is low to moderate.⁵¹

New promising radiopharmaceuticals for bone palliation therapy include radiolabeled complexes of zoledronic acid. Zoledronic acid belongs to a new, most potent generation of bisphosphonates with cyclic side chains. The bone affinity of zoledronic acid labeled with scandium-46 or lutetium-177 has shown excellent absorption (98% for [¹⁷⁷Lu]Lu-zoledronate and 82% for [⁴⁶Sc]Sc-zoledronate), which is much higher than of bisphosphonates labeled with samarium-153 (maximum: 67%).⁵⁵

Radiolabeled somatostatin analogs

Neuroendocrine neoplasia (NEN) of the GEP system originates most frequently from the pancreas, jejunum, ileum, cecum, rectum, appendix, and colon. The common characteristic of all GEP-NEN is the compound features of endocrine and nerve cells.^56–58 Well-differentiated NEN overexpresses somatostatin receptors (SSTRs), especially the SSTR-2 subtype. Thus, SSTRs are theranostic targets in NEN that have been known for almost three decades and have become well established.^59–61

SSTR imaging is necessary for staging, therapy planning, and follow-up. In the PET diagnostics, there are three routine somatostatin analog (SSA) tracers labelled with gallium-68: DOTA-TATE, DOTA-TOC, and DOTA-NOC. All three tracers bind specifically with SSTRs.^62,63 Gallium-68-labeled SSTRs have high sensitivity (82%–97%) and specificity (80%–92%) in the detection of small primary tumors or metastases of GEP-NEN.^64–66 Alternatively, a conventional whole-body scintigraphy (planat plus SPECT) or SPECT alone can be performed using indium-111-labeled SSTR, which is available at many institutions. Even if the ¹¹¹In imaging does not have as good a quality as PET, this method has been shown to be superior to chromogranin A measurements alone for the management of GEP-NET patients and is better than computed tomography or ultrasound.^67,68

Peptide receptor radionuclide therapy (PRRT) is a systemic therapy in patients with advanced metastatic NEN. PRRT requires a good tumor uptake in the SSTR imaging. For therapeutic purposes, the peptides DOTA-TATE and DOTA-TOC can be labeled with either ⁹⁰Y or ¹⁷⁷Lu. Because of the renal excretion and the proximal tubular reabsorption of these tracers, the kidneys are one of the primary limiting organs for this therapy.⁶⁹ Due to the smaller range (2 mm) and lower energy, ¹⁷⁷Lu is less nephrotoxic than ⁹⁰Y (range maximum: 11 mm, pure beta emitter, higher energy). ¹⁷⁷Lu is also less hematotoxic.⁷⁰ This allows for the performance of several PRRT cycles without any relevant toxicity. Furthermore, the overall survival is not significantly different between the therapies. For that reason, [¹⁷⁷Lu]Lu-DOTA-TATE and DOTA-TOC are, in many centers, the preferred agents for NEN therapy.^10,11,71,72

PRRT has been increasingly gaining attention. The first randomized controlled phase III study, NETTER-1 (started 2012), compared the standard therapy of Sandostatin^® LAR (somatostatin analog) with PRRT in patients with midgut NEN. The study showed a significant clinical benefit from the therapy, achieving a prolonged progression-free survival (median not reached, approximately 40 months, p<0.001), an overall response of 18%, and a presumably longer overall survival (median not reached, p=0.004).¹¹

Figure 3 represents the image of a male patient with a neuroendocrine tumor (unknown origin), with a recurrence of the disease nearly 2 years after the baseline PRRT. After a salvage therapy of PRRT, the patient had a partial response.

Figure 3 (A) [⁶⁸Ga]Ga-DOTA-TOC-image* of a male patient with a neuroendocrine tumor (unknown origin) 23 months after the baseline PRRT (three cycles, cumulative activity: 19.6 GBq). The patient had a recurrence of the disease with multiple metastases in the bone, lung, liver, and lymph nodes (marked with arrows). (B) After another course of PRRT (three cycles, cumulative: 43.4 GBq), the PET images showed a partial response.
Note: *Maximum-intensity projection (MIP) PET image is a visualization technique that provides an initial overview of the case.
Abbreviations: PET, positron emission tomography; PRRT, peptide receptor radionuclide therapy.

Radiolabeled PSMA-ligands

PC is the most common cancer in men in Western countries.⁷³ Hormone- and chemotherapy-refractory patients with metastatic PC have a poor prognosis.^8,74,75 The main cause of death in these patients is progression to the androgen-independent stage.⁸

PC cells overexpress prostate-specific membrane antigen (PSMA) on the cell surface.^76–79 There are several available radiopharmaceuticals that target PSMA including [⁶⁸Ga]Ga-PSMA-HBED-CC (also known as [⁶⁸Ga]Ga-PSMA-11 [PET]), a monoclonal antibody (mAb) [¹⁷⁷Lu]Lu/[⁹⁰Y]Y-J591 (therapy), [¹²³I]I-MIP-1072 (planar/SPECT), [¹³¹I]I-MIP-1095 (therapy), and the theranostic agents PSMA-I&T and DKFZ-PSMA-617 (PSMA-617), which are labeled with ⁶⁸Ga for PET or with ¹⁷⁷Lu for therapy.

The specificity of the two commercially available PET-tracers, [⁶⁸Ga]Ga-PSMA-617 and [⁶⁸Ga]Ga-PSMA-11, is similar – 99% and 100%, respectively.^80–82 However, due to slower kinetics, PSMA-617 was suggested for labeling with the long-half-life Lutetium-177 for therapy and, therefore, there is sparse systematic evaluation of [⁶⁸Ga]Ga-PSMA-617 for diagnostics.⁸³ The high kidney uptake of PSMA-11 in the kidneys makes it unsuitable for therapy and does not fit the definition “theranostics.”⁸⁴ Still, it is at issue if molecules with affinity to identical target structures might already present a “theranostic surrogate” even if more than the isotope differs between the diagnostics and the therapeutics.

The latest studies have shown that treatment with [¹⁷⁷Lu]Lu-PSMA-617 is effective and well tolerated. In fact, nearly 70% of patients have benefited from this therapy.^{13,28,85–90} Dosimetry studies have shown that the most critical organs are the kidneys, with a maximum kidney radiation dose of 0.88 Gy/GBq for [¹⁷⁷Lu]Lu-PSMA-617 and 0.93 Gy/GBq for [¹⁷⁷Lu]Lu-PSMA-I&T.^91,92 Okamoto et al stated that a cumulative activity of 40 GBq [¹⁷⁷Lu]Lu-PSMA-I&T could be safely applied in patients.⁹¹ Furthermore, [¹⁷⁷Lu]Lu-PSMA-617 has been shown to produce no relevant increase in renal toxicity in the salvage setting or in patients with kidney radiation doses >19 Gy.¹⁴

Figure 4A shows the pre-therapeutic [⁶⁸Ga]Ga-PSMA-11 images of a patient with multiple lymph node, peritoneal, and bone metastases (arrows), and a history of chemotherapy (first and second line), enzalutamide, and abiraterone. After three cycles of [¹⁷⁷Lu]Lu-PSMA-617, the follow-up images show a very good response with a substantial PSA decline (Figure 4B).

Figure 4 (A) Pre-therapeutic [⁶⁸Ga]Ga-PSMA-11 images* of a patient with multiple lymph node, peritoneal, and bone metastases (arrows), and history of chemotherapy (first and second line) with enzalutamide and abiraterone. (B) After three cycles of [¹⁷⁷Lu]Lu-PSMA-617, the follow-up images showed a very good response with a substantial PSA decline.
Note: *Maximum-intensity projection (MIP) PET image is a visualization technique that provides an initial overview of the case.
Abbreviations: PET, positron emission tomography; PSA, prostate-specific antigen.

Melanin targeting in patients with metastatic melanoma

A promising approach in patients with metastatic melanoma is the specific targeting of melanin. The newly developed theranostic agents include [¹²³I]I-/[¹³¹I]I-BA52 and [¹⁸F]F-/[¹³¹I]F-ICF15002, which may play a considerable role in the future.

BA52 is a melanin-binding benzamide. Labeled with ¹²³I, it shows a specific binding of the pigmented metastases in planar imaging/SPECT and can help select patients who would probably benefit from the therapy. In a pilot study, [¹³¹I]I-BA52 was effective in three of five patients who were treated with more than 4.3 GBq.²⁹

ICF15002 is an arylcarboxamide derivative and, as a small molecule, can passively enter the cell and bind to melanin. The PET tracer is radiolabeled with ¹⁸F and [¹³¹I]I-ICF15002 is designed for the therapy. However, both tracers are still in the preclinical phase of their studies. One major problem may be the absorbed dose in melanin-rich tissues, such as skin, dark eyes, and the brain. For instance, in a murine model, there was a 30% decrease of the retinal thickness after two cycles of [¹³¹I]I-ICF15002.⁹³

Conclusion

In nuclear medicine, theranostics combine diagnostic imaging and therapy with the same, but differently radiolabeled, molecule, or the same agent in different dosages. The visualization of potential targets can help predict if a patient would benefit from a particular treatment. In properly preselected patients, targeted nuclear therapies have proven to be effective with a favorable safety profile. To conclude, the combination of targeted cancer imaging and therapy is a considerable contribution to personalized medicine and may play an increasingly important role in the future.

The information comes from:
https://www.dovepress.com/theranostics-in-nuclear-medicine-practice-peer-reviewed-fulltext-article-OTT

Educational

Technical and dosimetric aspects of iodine-125 seed reimplantation in suboptimal prostate implants

Abstract

Objective:

Brachytherapy employing iodine-125 seeds is an established treatment for low-risk prostate cancers. Post-implant dosimetry (PID) is an important tool for identifying suboptimal implants. The aim of this work was to improve suboptimal implants by a subsequent iodine-125 seed top-up (reimplantation), based on the PID results.

Methods:

Of 255 patients treated between 2009 and 2012, 6 were identified as having received suboptimal implants and were scheduled for seed top-up. Needle configurations and the number of top-up seeds were determined based on post-implant CT images as well as a reimplantation treatment plan. An average of 14 seeds per patient were implanted during each top-up. Dosimetric outcome was assessed via target parameters and doses received by organs at risk.

Results:

All six patients had a successful top-up, with a 67% increase in the mean dose delivered to 90% of the prostate volume and a 40% increase in the volume that receives 100% of the prescribed dose. However, the final dosimetric assessment was based on the same seed activity, as the planning system does not account for the decay of the initially implanted seeds. Although physical dosimetry is not influenced by different seed activities (doses are calculated to infinity), the radiobiological implications might be slightly different from the situation when optimal implantation is achieved with one treatment only.

Conclusion:

Seed reimplantation in suboptimal prostate implants is feasible and leads to successful clinical outcomes.

Advances in knowledge:

Suboptimal prostate implants can occur for various reasons. This work shows that seed reimplantation as salvage therapy can lead to an optimal dosimetric outcome with manageable normal tissue effects.

Low dose rate (LDR) brachytherapy employing radioactive seeds is a well-established treatment for low-risk prostate cancers. In our centre, implants are conducted with iodine-125 seeds (Oncura RAPID Strand, model 6711; Oncura Inc., Arlington Heights, IL) with an average seed activity of 0.395 mCi to deliver a prescribed dose of 145 Gy (to >98% of the prostate). Treatment planning and post-implant dosimetry (PID) are completed using SPOT-PRO™ v. 3.1 (Nucletron, Utrecht, Netherlands) software based on transrectal ultrasound images (for treatment planning) and CT images (for PID).

The most commonly reported parameters that are indicative of the dosimetric quality of the implant are D₉₀ (the dose delivered to 90% of the prostate volume) and V₁₀₀ (the volume that receives 100% of the prescribed dose). Several studies showed a link between the quality of implants and the biochemical outcome [1–3]. Therefore, to minimise the risk of recurrence, it is recommended to achieve a post-implant D₉₀>140 Gy and V₁₀₀>90% [1].

PID is an important quantitative tool for the assessment of LDR implants; therefore, it is recommended as a routine procedure by several professional organisations [2–5]. Besides evaluating the overall quality of the implant, PID can assist in the dosimetric assessment of the organs at risk (OARs). Although the dosimetry of OARs cannot be adjusted if overdosed, the radiation oncologist can have a closer follow-up of those patients at risk of developing normal tissue sequelae.

Another role of PID is to identify suboptimal implants that can arise owing to organ movement during the procedure, geographical misses of seeds or technical equipment errors. Despite all the efforts and experience of the brachytherapy team, suboptimal implants do occur and they have to be dealt with. Although several centres encounter such events, there is a lack of guidelines or even indications as to how to proceed to improve the final outcome. The major challenge is perhaps the planning, which cannot be done in a conventional way, i.e. based on the ultrasound study of the transrectal volume, owing to lack of previously implanted seed visibility [6]. Therefore, post-implant CT images are the most convenient to use for this task, as the original seeds can be seen and extra seeds can be added to cover the underdosed areas of the prostate.

The aim of this work was to present our experience with iodine-125 seed reimplantation (top-up) in a cohort of six patients whose initial implant was suboptimal as identified by PID. The technical and dosimetric challenges of seed top-up implants are investigated.

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MATERIALS AND METHODS

Of 255 patients treated with iodine-125 permanent seed brachytherapy between January 2009 and July 2012 at the Royal Adelaide Hospital, SA, 6 were identified as having received suboptimal implants and were scheduled for seed top-up. The suboptimal implants were attributed to equipment/technical problems (two cases), patient movement during implantation (one case) and uncommonly large oedema (one case); however, for two patients, the causes of underdosage were unidentified. Therefore, the cold spots were random from patient to patient, although underdosage of the base was more common than the involvement of other prostate regions.

The decision to undergo reimplantation was based on the PID results using ultrasound–CT image coregistration, which our centre’s standard technique (the methods are described in detail in a previous report [7]). However, in all situations, the main dosimetric parameters were independently confirmed by a second medical physicist, and in some cases, when the result was uncertain, an alternative PID technique was also used, such as CT-delineation-based PID or MR–CT image coregistration-based PID. As with all our PID data, the results were reviewed by the patient’s radiation oncologist, who, after following the PID prostate D₉₀ criteria given below, decided whether the patient should be scheduled for a seed top-up or not.

At our centre, we categorise the quality of the implants according to the following PID D₉₀ values:

D₉₀>145 Gy—good implant [as recommended by Groupe Européen de Curiethérapie–European Society for Radiotherapy & Oncology (GEC-ESTRO) guidelines] [5]
130 Gy<D₉₀<145 Gy—adequate by local definition (within 10% of the prescribed dose).
110 Gy<D₉₀<130 Gy—potentially acceptable, subject to re-assessment of PID with another PID technique and evaluation of cold spots. If cold spots are identified in areas that were not positive on transrectal ultrasound biopsy, we consider the implant acceptable. If the implant is subsequently deemed inadequate, the patient is scheduled for a seed top-up procedure.
D₉₀<110 Gy—the implant is inadequate [1,5]. The patient is scheduled for a seed top-up procedure.

For those patients identified as having an inadequate implant, a top-up treatment plan is generated. This is designed using the initial PID ultrasound–CT images as the reference to determine the location and the number of seeds required to improve the dosimetry.

The prostate target (hereafter referred to as the target) is defined as the clinical target volume, and acceptable target volumes for initial implants are between 15 and 55 cm³. A planning target volume (PTV) is also defined during preplanning but is not considered in this report, as its dosimetry trends reflect those of the target values.

Method of setting up the seed top-up plan

This is perhaps the most demanding step in the reimplantation process owing to the limitations of the treatment planning system (as will be discussed later). Some explanations of our PID technique are first required to help understand the seed top-up planning method.

The PID CT images are scanned at 2-mm slice thickness and 2-mm spacing. As described in the study by Marcu et al [7], the PID CT images are coregistered (matched) to the pre-implant ultrasound images, with the image fusion module of the SPOT-PRO treatment planning system, by manually shifting and rotating the overlaid image sets until anatomical references are aligned. Once image sets are matched, the target and PTV from the ultrasound images are copied onto the CT images; the rectum and urethra are drawn directly onto the CT images. Subsequent analysis of the PID is performed on the CT images with the copied and drawn contours. Following computerised seed identification, the PID is assessed.

Analysis of the PID dose–volume histogram (DVH) data and visual dose coverage identifies the “cold spots” (areas of target receiving less than the prescription dose) and potential areas that require a top-up of seeds. The two main problems that arise with relating the planned positioning of the top-up seeds to the actual desired positions for implant are: (1) the orientation of the CT images and (2) the implant template grid pattern.

(1) Orientation of the CT images: as the CT is performed with the patient supine and the ultrasound is performed with the patient in the lithotomy position, the orientation of the prostate and local anatomy is different in each setting. Although this can be overcome for the purposes of matching two data sets together for copying contours, it presents a problem for determining the seed/needle locations when viewing the CT data set in the planning module. If we assume that the ultrasound data set is the normal orientation, then the CT data set is rotated (approximately 20–40°) about the patient's left/right axis during the matching process; however, when subsequently viewing the CT images in the post-implant planning module, the CT images are in their normal scanned orientation. This means that the needle tracks are not in the horizontal plane, when viewed laterally, but angled anteriorly in the inferior to superior direction (Figure 1). This therefore causes problems with relating possible top-up seed locations (as determined from the CT images) to their equivalent positions when viewed on the ultrasound.

Figure 1.
Right lateral views of post-implant CT images at various positions through the prostate. The superimposed manually added lines indicate the needle tracks for the visible seeds. Also visible are the target and planning target volume contours. The central image shows the catheter balloon with contrast and a part of the urethra contour.
The following paragraph describes the method implemented in our department using the SPOT-PRO software. Nevertheless, the essentials of the process could be easily adapted for use with other brachytherapy treatment planning systems. Firstly, we scroll through the lateral CT images and determine the angle of the implanted needles by visualising the seed positions. As the seeds are implanted in the Rapid Strand form, we have confidence in identifying their corresponding needle tracks. Figure 1 shows some superimposed lines that help to illustrate this. Once the angle is determined, we then adjust the CT data set such that we can visualise the transverse CT images that are perpendicular to the angle of the needle tracks.
To achieve this, we use the three-dimensional cube facility within the SPOT-PRO software. Figure 2 demonstrates the steps involved in changing the transverse views from the original to those that are perpendicular to the angle of the needle tracks. The CT needle tracks would now be horizontal if viewed laterally. When we now scroll through the angle-corrected transverse views, they are in the same orientation as the transverse views in the original treatment plan of the ultrasound images. Therefore, determining grid positions for the top-up seeds/needles is achievable.

Figure 2.
Demonstration of the steps involved in changing transverse CT images from the normal axial orientation to that which is perpendicular to the needle tracks. Starting from top left in clockwise rotation: a transverse image through the prostate is established within the three-dimensional (3D) cube image set, next a cut plane is created through the image set at an angle perpendicular to the angle of the needle tracks (as shown in Figure 1 and indicated by the protruding line), then the 3D cube is rotated so that the angle-corrected transverse slice is vertical; this is followed by a further rotation to visualise the angle-corrected transverse slice in the conventional way.
(2) Implant template grid pattern: unfortunately, the treatment planning system does not show the implant template grid pattern on the CT images, so mapping out the needle locations according to this grid can be difficult. However, after following the steps above to orientate the post-implant CT images, the grid positions can be determined by simultaneously viewing the CT images and the ultrasound images by using the target contour and seeds as the common reference guide. In the case of the SPOT-PRO planning system, this cannot be done on screen, so we print out a selection of transverse ultrasound images with the template visible and scroll through the CT images on screen. In addition, the base and apex of the target can be identified and compared, so that the depth of needle insertion (for seed deployment) can be determined.

The top-up seeds are then added to the plan (with known potential grid positions) until the cold spots are sufficiently covered with target and satisfactory OAR DVH values. The patients are notified of the treatment outcome and advised that they should undergo a reimplantation procedure. The procedure is guided by transrectal ultrasound and seed deployment is checked on fluoroscopic images, where the previously implanted seeds are also visible. Fluoroscopic guidance is particularly useful in those situations where the underdosage occurs in the base of the prostate, and the new baseline enables a good dosimetric coverage of that area. Dosimetric outcome of the top-up implant is assessed, the following day, via a second post-implant CT scan, coregistered to the original pre-implant ultrasound images as done previously with the initial PID CT. Target parameters (D₉₀ and V₁₀₀) and doses received by OAR, i.e. urethra [the dose delivered to 10% of the prostatic urethra (D₁₀) and the dose delivered to 30% of the prostatic urethra (D₃₀)] and rectum [the dose to 0.1 cm³ of the rectum (D_0.1 cm³) and the dose to 2 cm³ of the rectum (D_2 cm³)], are assessed and are reported later.

RESULTS

Number of seeds implanted and the time interval between implants

The number of seeds needed for the initial implant as well as the extra number of seeds used for top-up for all six patients is listed in Table 1. An average of 14 seeds per patient was implanted during each top-up. Table 1 also lists the time interval between the implant and the top-up day. Depending on the waiting list and also the patient’s availability, the top-up was scheduled, on average, within 3 months after the implant.

Table 1.

Seed top-up data

Patient number	Target volume (cm³)	Number of seeds originally implanted	Number of seeds implanted during top-up	Time interval between the implants (days)
1	28	67	8	21
2	26	73	12	49
3	37	85	18	141
4	33	76	11	85
5	42	61	18	91
6	30	59	18	63
Average	32	70	14	75

Target dosimetry before and after the top-up

Individual charts showing the target implant dosimetry and the dosimetry after the top-up are represented in Figures 3 and and4.4. The improvement in dosimetry is clearly observed.

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Figure 3.

Dose delivered to 90% of the prostate volume (D₉₀) target values before and after the top-up individually shown for the six treated patients.

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Figure 4.

Volume receiving 100% of the prescribed dose (V₁₀₀) target values before and after the top-up individually shown for the six treated patients.

Figures 3 and and44 illustrate that, if the cold spots had been covered from the initial implant, the main dosimetric parameters D₉₀ and V₁₀₀ would have significantly increased. Therefore, although the dose to target after the top-up leads to an average D₉₀ of 150 Gy (which represents a 67% increase when compared with the implant dosimetry), the volume to be covered by 100% of the prescribed dose (V₁₀₀) increased by 40%, reaching an average of 92% for the six studied patients.

All patients but one had D₉₀>140 Gy and V₁₀₀>90%. Patient 3 had an initial D₉₀=43.5 Gy, increasing to D₉₀=124 Gy after reimplantation. Although the dosimetry is still below the recommended limit, the diseased areas, as proven by biopsies, were all well implanted and the corresponding cold spots were adequately covered. Since the urethral dose was already high before the reimplantation (D₁₀=203 Gy and D₃₀=185 Gy), after the addition of top-up seeds the urethral dose exceeded the recommended safety limits (D₁₀=243 Gy and D₃₀=221 Gy). Thus, to avoid increasing the risk for toxicities, the plan had to be compromised.

Organs-at-risk dosimetry before and after the top-up

The dosimetric evaluation of the OARs was undertaken using the GEC-ESTRO recommendations whereby the urethral primary dosimetric parameter, D₁₀, should be <150% of the prescribed dose and the secondary parameter, D₃₀, should be <130% of the prescribed dose [5].

Urethra

The urethral dose related to D₁₀ reached values above the recommended limit for two patients, while according to the secondary dosimetric parameter, D₃₀, three patients received higher doses than recommended limits, as a compromise for a better tumour dosimetry (Table 2).

Table 2.

Post-top-up dosimetry for target and organs at risk

Patient number	Target (prostate)		Prostatic urethra		Rectum
Patient number	D₉₀ (Gy)	V₁₀₀ (%)	D₁₀ (Gy)	D₃₀ (Gy)	D_0.1 cm³ (Gy)	D_2 cm³ (Gy)
1	156.7	93.3	176.4	164.6	232.8	124.3
2	142.4	89.4	204.5	183.6	189.2	112.9
3	124.0	85.5	243.0	221.0	236.0	94.0
4	168.3	95.6	274.2	228.6	205.0	120.0
5	148.5	91.6	219.4	202.1	296.0	169.0
6	159.0	94.0	199.0	187.0	155.0	68.0
Mean value (standard deviation)	150 (±15)	92 (±4)	219 (±35)	198 (±24)	219 (±48)	115 (±34)
Recommended limits	>145	>90%	<218	<189	<200	<145

D₁₀, dose delivered to 10% of the prostatic urethra; D₃₀, dose delivered to 30% of the prostatic urethra; D₉₀, dose delivered to 90% of the prostatic urethra; D_0.1 cm³, dose to 0.1 cm³ of the rectum; D_2 cm³, dose delivered to 2 cm³ of the rectum; V₁₀₀, volume receiving 100% of the prescribed dose.

Rectum

Similarly to the prostatic urethra, the dosimetric requirements for the rectum were established based on the GEC-ESTRO recommendations [5]. Therefore, D_2 cm³<145 Gy was used as a primary parameter and D_0.1 cm³<200 Gy was used as a secondary parameter. One patient had D_2 cm³=169 Gy after top-up, whereas, for all the others, the primary dosimetric parameter for the rectum was kept below the 145-Gy limit (Table 2). When assessing the secondary dosimetric indicator, it was noticed that four out of six patients received D_0.1 cm³ above the recommended 200 Gy (Table 2). However, two of these patients already had elevated levels before the top-up owing to geographic misplacements of seeds during the original implantation. These patients underwent a closer follow-up to ensure minimum discomfort owing to possible treatment-related side effects. However, no rectal morbidities have been reported so far.

Summary of dosimetry data before and after the top-up

All six patients had a successful top-up, with a 67% increase in the mean D₉₀ value and a 40% increase in V₁₀₀. Unavoidably, doses to OARs have increased as well, in some cases exceeding the recommended limits. It should be noted that the final dosimetric assessment (implant+top-up) was based on the same seed activity (0.395 mCi), as the planning system does not account for the decay of the initially implanted seeds. The DVH values obtained post top-up are presented in Table 2 both for the target and for the OARs. Table 2 also shows the recommended limits for these structures. It should be noted that, through the top-up procedure, the dose to the target was increased to enable good tumour control, while as a compromise, for the OARs, some values were marginally higher than the recommended limits.

DISCUSSION

There are two main challenges involving the top-up procedure and its outcome: one covers the physical aspect of seed dosimetry and the other relates to the radiobiological implications of the top-up.

(1)
Some planning systems, such as the one used in the current study, do not allow treatment plans with different seed activities related to different implant dates. This means that although on the implant day the average seed activity was 0.395 mCi, by the time of the top-up implant these seeds have decayed by an amount which depends on the time gap between the implant and the top-up day. However, the top-up was conducted using 0.395 mCi seeds, as for the implant; thus, for dose calculation SPOT-PRO assumes that all seeds were implanted on the same date and with the same activity. Despite this discrepancy between the two implanted seed batches used in the dose calculation, any potential differences in physical effect owing to the dose delivered is probably not important for iodine-125 seeds of the same strength but implanted at different times (provided that top-up is given within a couple of isotope half-lives), as they would yield the same cumulative (physical) dose after 2 years (knowing that 80% of the total dose is delivered in about 140 days), to within <0.1%. In our case, the SPOT-PRO dose calculation algorithm uses 10 half-lives to determine the cumulative dose, so any discrepancy in the dose displayed on the plan relating to the different seed activities or dates is insignificant (again provided the top-up is given within 2 isotope half-lives).
(2)
Radiobiological effects could be influenced by the time difference between the two implant dates as the 145-Gy prescribed dose is delivered in two separate sessions, thus over a longer time period than initially planned (Figure 5, in which the dose rate over time is calculated considering that the initial dose rate for iodine-125 is about 7 cGy h^–1 [8]). Although patient 1 had his top-up 21 days after implant, thus well within the half-life of iodine-125, and when the dose rate was 5.5 cGy h^–1, patient 3 underwent the seed boost 141 days after the implant (owing to logistics problems), at a time when the initially implanted seeds decayed with a dose rate of 1.35 cGy h^–1, delivering the remaining 20% of the prescribed dose.

Figure 5.
Variation of the initial dose rate of a typical iodine-125 implant with time between implant and top-up.

Nevertheless, considering that permanent seed implants are conducted on patients with low-risk and low-grade prostate cancer, the time gap between the implant and the top-up might not induce any radiobiological events that differ from a single procedure.

Our study was based on the dosimetric evaluation of post-implant CT images registered to ultrasound images. Although this image coregistration was the most convenient in our situation, we acknowledge the fact that fused post-implant CT/MR images registered to ultrasound images are most likely to be the optimum [8,9].

There are limited studies in the literature recommending an external beam radiotherapy (EBRT) boost for suboptimal implants. One such study suggests salvage EBRT using a multimodality dose summation between intensity-modulated radiotherapy and brachytherapy dose matrices by overcoming the challenges imposed by planning systems [10]. For this task, Bice et al [11] have used image coregistration employing a post-implant CT and ultrasound volume study. In their study, the dosimetric results of the original implant were overlaid on the salvage plan and the total doses to the target and the OARs were evaluated. The main dosimetric parameter reported was V₈₀, which improved from an average of 56% to 93%.

We suggest that LDR seed reimplantation for suboptimal implants presents certain advantages over an EBRT boost. Therefore, when compared with an EBRT boost, LDR top-up offers a better dosimetric outcome owing to more accurate targeting of the cold spots. In addition, the dosimetry and radiobiology of a composite LDR brachytherapy/EBRT plan still remains a challenge for many treatment planning systems. Regarding the dose to OARs, with LDR top-up, the added urethral dose can be kept to a minimum with careful placement of seeds, as compared with EBRT when the urethra would almost certainly be included in the radiation field. Also, an advantage from the patient’s perspective is that only one visit is required for treatment, instead of several visits, which a fractionated EBRT would require.

A salvage reimplantation technique for suboptimal implants was reported by Hughes et al [6] using fluoroscopic guidance, whereby an underdosed base owing to systematic seed misplacement led to a V₁₀₀=46%. For better localisation of the seeds to be implanted, a grid was superimposed on the original post-implant CT images and digitised into the planning system to facilitate dosimetric evaluation (similar to planning on transrectal ultrasound images). The reimplantation results showed V₁₀₀=98%, although with increased urinary morbidity.

Keyes et al [12] have described the salvage implants undertaken on seven patients with poor initial dosimetry. Their planning simulation principle was similar to the one reported in the current work, whereby extra seeds were simulated on the underdosed areas of prostate on post-implant CT images, maintaining the original 5-mm distance between seeds. A composite dose was determined by adding the doses for the two implants together, without taking into account the radioactive decay of the initially implanted seeds.

A recent case report has described the salvage reimplantation of a suboptimally implanted prostate cancer patient by employing post-implant CT guidance and real-time intra-operative planning using loose seeds [13]. PID revealed an underdosed base, leading to D₉₀=92.9 Gy and V₁₀₀=71%, which after the addition of 20 seeds increased to D₉₀=173.24 Gy and V₁₀₀=96.88%. The flexibility of intra-operative planning has allowed continuous adjustments of seed positioning, thus making this technique suitable for salvage implants.

As a drawback, LDR top-up is labour intensive and involves a large team of professionals to actively participate in treatment preparation and delivery. Furthermore, the patient requires a second general anaesthetic, which might be a problem for those patients with an underlying condition. Also, since patients might live in other cities, thus a long distance from the hospital, top-up sessions would have to accommodate their travel arrangements, which might sometimes delay the boost implant. Nevertheless, the same problem might be encountered if EBRT is chosen as boost treatment.

CONCLUSION

PID is a valuable tool in assessing the quality of an implant. Despite all team efforts taken to achieve high-quality implants, every so often implants can be suboptimal owing to technical-, staff experience- or patient-related matters.

To correct the dosimetry of an unsatisfactory implant, a top-up procedure was implemented in our centre, involving the implantation of extra seeds to account for the cold spots and other geographical misses. A description of the methods used to overcome the technical difficulties in planning top-up implants has been presented.

Although the final target dosimetry achieved was satisfactory, the procedure was compromised by higher doses being delivered to the OARs than the recommended limits. The affected patients are kept under close observation to identify and treat any normal tissue toxicities.

In conclusion, we found that iodine-125 seed top-up is a feasible method for improving the quality of a previous suboptimal implant.

ACKNOWLEDGMENTS

The authors would like to acknowledge the radiation oncologists, urologists, radiation therapists, medical physicists, nursing staff and all other members of the prostate brachytherapy team at the Royal Adelaide Hospital for their dedication to the prostate brachytherapy service over the years.

The information comes from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664978/

Educational

Educational

Production of 177Lu for Targeted Radionuclide Therapy: Available Options

Abstract

Introduction

Why is 177Lu Expected to Be So Important in Targeted Radionuclide Therapy?

Table 1

Production of 177Lu

Specific Activity of 177Lu

No-Carrier-Added 177Lu

The Importance of 177Lu-Specific Activity

177Lu Production Process

Table 2

Direct Production Route [176Lu(n,γ)177Lu]

Target Selection

Calculation of Irradiation Yield

Indirect Production Route [176Yb(n,γ)177Yb β−−→177Lu]

Selection of the Target

Chemical Form of the Target

Irradiation Yields

Chemical Separation of 177Lu from Neutron-Irradiated 176Yb

Table 3

Ion-Exchange Chromatography

Solvent Extraction

Supported Liquid Membrane Extraction

Extraction Chromatography

Electrochemical Method

Cementation Process

Electro-Amalgamation Process

Accelerator-Based Production of 177Lu

Quality Control of 177Lu

Radionuclidic Purity

Radiochemical Purity

Chemical Purity

Specific Activity

Table 4

Regulatory Requirements and Automation

Summary

Conflict of Interest

Informed Consent

Theranostics in nuclear medicine practice

Technical and dosimetric aspects of iodine-125 seed reimplantation in suboptimal prostate implants

Abstract

Objective:

Methods:

Results:

Conclusion:

Advances in knowledge:

MATERIALS AND METHODS

Method of setting up the seed top-up plan

RESULTS

Number of seeds implanted and the time interval between implants

Table 1.

Target dosimetry before and after the top-up

Organs-at-risk dosimetry before and after the top-up

Urethra

Table 2.

Rectum

Summary of dosimetry data before and after the top-up

DISCUSSION

CONCLUSION

ACKNOWLEDGMENTS

Recent Posts / Educational

Why is ¹⁷⁷Lu Expected to Be So Important in Targeted Radionuclide Therapy?

Production of ¹⁷⁷Lu

Specific Activity of ¹⁷⁷Lu

No-Carrier-Added ¹⁷⁷Lu

The Importance of ¹⁷⁷Lu-Specific Activity

¹⁷⁷Lu Production Process

Direct Production Route [¹⁷⁶Lu(n,γ)¹⁷⁷Lu]

Indirect Production Route [¹⁷⁶Yb(n,γ)¹⁷⁷Yb β−−→¹⁷⁷Lu]

Chemical Separation of ¹⁷⁷Lu from Neutron-Irradiated ¹⁷⁶Yb

Accelerator-Based Production of ¹⁷⁷Lu

Quality Control of ¹⁷⁷Lu