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. Quantitative imaging of Yttrium-90 is complex, and prospective imaging with surrogate markers could deviate from actual biodistribution.
Activity: 1.85-3.7 GBq/m2 per cycle; four cycles at 6 to 8-week intervals
Administration: i.v.
[90Y]Y-DOTA-TOC was the first somatostatin analogue developed for treatment of 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 doses absorbed by both kidney and tumour showed extreme variability [158]. 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 PRRT next to or in combination with [177Lu]Lu-DOTA-TATE in clinical trial. Post-treatment scintigraphy after [90Y]Y-DOTA-TOC is hampered as only Bremsstrahlung can be detected. The direct gamma emission of Lutetium-177, however, provides information on the intensity of uptake and extent of the disease, and can therefore be used to assess the 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 [159]. Peri-therapeutic PET imaging can also be performed using the 0.003%/decay positron emission from Yttrium-90, and this has been shown to be feasible for quantifying the uptake in the renal cortex [160]. Theragnostic 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 [161,162]. When using a surrogate peptide, it is important to use the same amount and type of peptide as used in the therapeutic setting, otherwise corrections must be made for the differences in pharmacokinetics and binding affinity [163].
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 a phase I clinical trial using [86Y]Y-DOTA-TOC [164,165].
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 doses. Subsequent cycle dosages depend on response, and these are quite often adapted to (bone marrow) toxicity from previous treatment. This, consequently, leads to a wide range, from 1.1 to 26.5 GBq, in reported cumulative activities [166].
One study repeated administration according to a 1.85 GBq/m2 dosing scheme until a threshold dose of 37 Gy BED was reached, thereby, preventing renal toxicity [167]. 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 [168]. 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 [169].
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 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 [161].
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 [169]. In 21 patients, the bone marrow absorbed dose ranged between 0.3 and 1.7 Gy for the full therapy 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 [12].
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 [170,171]. These combination therapies were based on equal administered activity of both radionuclides, whereas over its cumulative decay, Yttrium-90 emits 2.5 times the energy emitted by Lutetium-177 [172].
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 [173].
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) [12,171]. 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).
Longer follow-up in a sub-group of patients treated in Belgium revealed a dose-response relation between renal toxicity and the Biologically Effective Dose (BED) when based on the actual kidney volume instead of the standard size [174]. It was observed that the activity, and hence absorbed dose per treatment cycle, significantly influenced the incidence of renal toxicity [168]. Late stage renal toxicity was shown to follow a classic sigmoidal shaped dose-effect curve with BED [31]. 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.