European Nuclear Medicine Guide
Radiopharmaceutical: [90Y]Yttrium ([90Y]Y-DOTA0,Tyr3) octreotide or [90Y]Y-DOTA-TOC)
Nuclide: Yttrium-90 is a pure high-energy beta emitter (mean energy 0.93 MeV), while a minute fraction (0.0032%) leads to internal pair production photons at 511 keV and Bremsstrahlung emission at higher energies [49]. 90Y has a maximal tissue penetration of 11 mm (mean 2.5 mm), and a half-life of 2.7 days. Due to such characteristics, 90Y has in general higher efficacy in bulky disease than small lesions, with also higher toxicity than 177Lu. Being affected by the low branching ratio, quantitative imaging of Yttrium-90 is complex; however, Yttrium-90 bremsstrahlung imaging is feasible with both SPECT/CT and PET/CT.
[90Y]Y-DOTA-TOC is one of the first somatostatin analogue ue developed to treat patients with SSTR-positive NETs. A phase I clinical trial prospectively evaluated the pharmacokinetics and dosimetry of [86Y]Y-DOTA-TOC using quantitative PET imaging and showed that individual patient dosimetry was needed because absorbed doses by both kidney and tumour showed extreme variability [21]. No dosimetry was performed during the phase II trial for this compound, and patients were administered either a single or several administrations of 3.7 GBq/m2 [12].
Currently, [90Y]Y-DOTA-TOC is used for SSTR therapy in clinical trials. Post-treatment scintigraphy after [90Y]Y-DOTA-TOC is hampered as only Bremsstrahlung can be detected. In case of combination treatment with Yttrium-90 and Lutetium-177 labelled SSTRpeptides, the direct gamma emission of Lutetium-177 may, however, provide information on the intensity of uptake and extent of the disease, and can therefore be used to assess the post-PRRT biodistribution and response to the prior therapy cycles.
Since Yttrium-90 is a pure beta-emitter, direct imaging of the therapeutic compound is possible using its induced bremsstrahlung spectrum in planar whole body or SPECT [23]. Post-therapeutic PET imaging can also be performed using the 0.003% per decay positron emission from Yttrium-90, and this is feasible for quantifying the uptake in the renal cortex [24]. Theranostic companion compounds have been used to prospectively quantify biodistribution of [90Y]Y-DOTA-TOC using either the gamma-emitter [111In]In-DOTA-TATE or the PET emitter [86Y]Y-DOTA-TATE [25,26]. When using a surrogate peptide, it is important to use the same amount and type of peptide used in the therapeutic setting, otherwise, corrections must be made for the differences in pharmacokinetics and binding affinity [27].
Pre-treatment planning and tumour dosimetry is seldom performed for [90Y]Y-DOTA-TOC, most probably due to the highly metastasized nature of the tumours. Nevertheless, it has been performed using [111In]In-DOTA-TOC as a companion diagnostic and in phase I clinical trial using [86Y]Y-DOTA-TOC [28,29].
Treatment protocols are mostly based on administration schemes using a fixed activity or activity per body surface area (typically at 1.85-3.7 GBq/m2) with a 6 to 8-week interval between administrations. Subsequent cycle dosages depend on response, which often adapted to (red bone marrow) toxicity from previous treatment. This, consequently, leads to a wide range, from 1.1 to 26.5 GBq, in reported cumulative activities [30].
One study repeated administration according to a 1.85 GBq/m2 dosing scheme until a threshold renal AD of 37 Gy biological effective dose (BED) was reached, thereby, preventing renal toxicity [31]. The BED has been semi-empirically defined in MIRD (Medical Internal Radiation Dose) pamphlet 20 by using a sub-lethal damage repair half-life of 2.8 h and a radiobiology parameter a/ß = 2.5 Gy for late renal toxicity [32]. A multi-factorial dose-effect model for blood platelet response was defined using prior platelet counts as an additional weighting factor. This led to a correlation between the weighted bone marrow dose and platelet count nadir after therapy [33].
A dosimetry study performed in 18 patients using [86Y]Y-DOTA-TOC PET quantification showed an interpatient variability of a factor of 4, and the renal absorbed dose per activity ranged between 1.2 and 5.1 Gy/GBq (72). A comparable variability of 1.3-4.9 Gy/GBq was observed for [111In]In-DOTA-TOC-based dosimetry [25].
Bone marrow dosimetry is performed less often, but image-based methods have been used with [86Y]Y-DOTA-TOC, and a correlation was observed with [111In]In-DTPA-Octreotide thoracic spine uptake [33]. In 21 patients, the bone marrow cumulative absorbed dose ranged between 0.3 and 1.7 Gy of 370 MBq.
In a phase II, single-centre, open-label clinical trial, 60% of the patients showed clinical response, biochemical response, and/or morphologic disease control after a single administration of 3.7 GBq/m2 [90Y]Y-DOTA-TOC with amino-acid infusion [22].
Several studies have been performed to compare Yttrium-90 labelled SSTR peptides alone with a combination of Yttrium-90 and Lutetium-177 labelled SSTR peptides [34,35]. These combination therapies were based on the equal administered activity of both radionuclides, whereas over its cumulative decay, Yttrium-90 emits 2.5 times the energy emitted by Lutetium-177 [36].
No randomized comparative studies have been performed using [90Y]Y-DOTA-TOC. Reduction in tumour volume was shown to be significant above tumour absorbed doses of 200 Gy [37].
Both single [90Y]Y-DOTA-TOC therapy and combination treatment with Yttrium-90 and Lutetium-177 labelled SSTR peptides have led to permanent and sometimes even fatal renal toxicity (grade 4 and 5) [22,35]. Kidneys are considered to be the critical organ after therapy. When the peptide is cleared by the primary renal filter elements (the glomeruli), radiolabelled peptides are reabsorbed and remain in the secondary filter elements (proximal tubules). Therefore, also with 90Yttrium PRRT it is advisable to use adequate nephroprotective aminoacidic premedications.
Longer follow-up in a sub-group of patients treated in Belgium revealed a dose-response relation between renal toxicity and the (BED) when based on the actual kidney volume instead of the standard size [38]. It was observed that the activity, and hence absorbed dose per treatment cycle, significantly influenced the incidence of renal toxicity [32]. Late-stage renal toxicity was shown to follow a classic sigmoidal-shaped dose-effect curve with BED [39]. The threshold for late renal toxicity was found around a BED of 40 Gy for patients without additional risk factors for renal disease, including high blood pressure, diabetes, or prior chemotherapy.
[90Y]Y-DOTA-TOC is an investigational compound.