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`Evergreen Ex. 1010
`1 of 8
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`

`

`Original article
`
`[177Lu-DOTA0,Tyr3]octreotate:
`comparison with [111In-DTPA0]octreotide in patients
`Dik J. Kwekkeboom1, Willem H. Bakker1, Peter P. M. Kooij1, Mark W. Konijnenberg3, Ananth Srinivasan4,
`Jack L. Erion4, Michelle A. Schmidt4, Joe L. Bugaj4, Marion de Jong1, Eric P. Krenning1, 2
`1 Department of Nuclear Medicine, University Hospital Rotterdam, Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
`2 Department of Internal Medicine, University Hospital Rotterdam, the Netherlands
`3 Mallinckrodt Medical, Petten, the Netherlands
`4 Mallinckrodt Medical, St. Louis, Missouri, USA
`
`Received 26 February and in revised form 24 April 2001 / Published online: 4 July 2001
`© Springer-Verlag 2001
`
`Abstract. The somatostatin analogue [DOTA0,Tyr3]oct-
`reotate has a nine-fold higher affinity for the somatosta-
`tin receptor subtype 2 as compared with [DOTA0,
`Tyr3]octreotide. Also, labelled with the beta- and gam-
`ma-emitting radionuclide lutetium-177, this compound
`has been shown to have a very favourable impact on tu-
`mour regression and animal survival in a rat model. Be-
`cause of these reported advantages over the analogues
`currently used for somatostatin receptor-mediated radio-
`therapy, we decided to compare [177Lu-DOTA0,Tyr3]oct-
`reotate (177Lu-octreotate) with [111In-DTPA0]octreotide
`(111In-octreotide) in six patients with somatostatin recep-
`tor-positive tumours. Plasma radioactivity after 177Lu-
`octreotate expressed as a percentage of the injected dose
`was comparable with that after 111In-octreotide. Urinary
`excretion of radioactivity was significantly lower than
`after 111In-octreotide, averaging 64% after 24 h. The up-
`take after 24 h, expressed as a percentage of the injected
`dose of 177Lu-octreotate, was comparable to that after
`111In-octreotide for kidneys, spleen and liver, but was
`three- to fourfold higher for four of five tumours. The
`spleen and kidneys received the highest absorbed doses.
`The doses to the kidneys were reduced by a mean of
`47% after co-infusion of amino acids. It is concluded
`that in comparison with the radionuclide-coupled so-
`matostatin analogues that are currently available for so-
`matostatin receptor-mediated radiotherapy, 177Lu-octreo-
`tate potentially represents an important improvement.
`Higher absorbed doses can be achieved to most tumours,
`with about equal doses to potentially dose-limiting or-
`gans; furthermore, the lower tissue penetration range of
`177Lu as compared with 90Y may be especially important
`for small tumours.
`Dik J. Kwekkeboom (✉)
`Department of Nuclear Medicine, University Hospital Rotterdam,
`Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
`e-mail: djkwekkeboom@hotmail.com
`Tel.: +31-10-4635963, Fax: +31-10-4635997
`
`Keywords: Somatostatin – Somatostatin receptor imag-
`ing – Octreotate – Peptide receptor radiotherapy
`
`Eur J Nucl Med (2001) 28:1319–1325
`DOI 10.1007/s002590100574
`
`Introduction
`
`Somatostatin receptor imaging with [111In-DTPA0]oct-
`reotide (Octreoscan) is nowadays recognised to be an
`important, if not the primary imaging technique for the
`localisation and staging of neuroendocrine tumours.
`In patients with progressive, metastasised neuroendo-
`crine tumours, radionuclide therapy with high doses of
`[111In-DTPA0]octreotide is performed with encouraging
`results [1, 2, 3, 4]. However, 111In-coupled peptides are
`not ideal for peptide receptor radiotherapy (PRRT) be-
`cause of the small particle range and the resultant short
`tissue penetration. Therefore, another radiolabelled so-
`matostatin analogue, [90Y-DOTA0,Tyr3]octreotide, was
`developed. A preliminary study by Otte et al. [5] showed
`favourable results of [90Y-DOTA0,Tyr3]octreotide treat-
`ment in five patients with neuroendocrine tumours. Also,
`a recent analysis of the results of this treatment in a
`multicentre trial in 22 end-stage patients with progres-
`sive disease showed a partial tumour response in two, a
`minor response in three and stable disease in ten [6].
`Paganelli et al. [7] have also reported favourable prelimi-
`nary results regarding tumour growth with this 90Y-
`labelled compound.
`Recently, it was reported that compared with [DTPA0,
`Tyr3]octreotide, [DTPA0,Tyr3]octreotate (in which the C-
`terminal threoninol is replaced with threonine) showed
`improved binding to somatostatin receptor-positive tis-
`sues in animal experiments [8]. Also, its DOTA-coupled
`counterpart, [DOTA0,Tyr3]octreotate, labelled with the
`
`European Journal of Nuclear Medicine Vol. 28, No. 9, September 2001
`
`Evergreen Ex. 1010
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`

`

`1320
`beta- and gamma-emitting radionuclide lutetium-177,
`was reported to have a very successful impact on tumour
`regression and animal survival in a rat model [9]. Reubi
`et al. [10] reported a ninefold increase in affinity for the
`somatostatin receptor subtype 2 for [DOTA0,Tyr3]octreo-
`tate as compared with [DOTA0,Tyr3]octreotide, and a
`six- to sevenfold increase in affinity for their yttrium-
`loaded counterparts.
`Because of these reported advantages over both so-
`matostatin analogues currently used for PRRT, we decid-
`ed to study [DOTA0,Tyr3]octreotate in patients with so-
`matostatin receptor-positive tumours. It was complexed
`with 177Lu because this radionuclide, apart from interme-
`diate beta energy, also emits gammas suitable for scintig-
`raphy and subsequent dosimetry.
`
`Materials and methods
`
`Patients
`
`[177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) was administered
`in six patients (four women and two men, aged 15–76 years). In
`five of them, somatostatin receptor imaging with [111In-DTPA0]oct-
`reotide (111In-octreotide), performed during the 3 months preceding
`177Lu-octreotate scintigraphy, was available. None of the patients
`used somatostatin analogues.
`One patient had medullary thyroid carcinoma (MTC), one had
`non-Hodgkin lymphoma (NHL), one had a gastroenteropancreatic
`(GEP) tumour, one had aesthesioneuroblastoma, one had a rem-
`nant of a Hürthle cell carcinoma of the thyroid, and one had papil-
`lary thyroid carcinoma.
`All patients gave written informed consent to participation in
`the study, which was approved by the medical ethical committee
`of the hospital.
`
`Methods
`
`[DOTA0,Tyr3]Octreotate was obtained from Mallinckrodt (St
`Louis, Mo., USA). Kits were prepared consisting of 120 μg
`[DOTA0,Tyr3]octreotate, 37.8 mg sodium ascorbate and 7.5 mg
`gentisic acid in 300 μl 0.05 M HCl. Kits were stored at –20°C until
`use. 177LuCl3 was obtained from Missouri University Research
`Reactor (MURR; University of Missouri, Mo., USA). 177LuCl3
`was diluted in 0.05 M HCl to a concentration of 11.1 GBq/ml, and
`2,220 MBq 177LuCl3 was added to each kit. The mixture was heat-
`ed for 30 min at 80°C. The labeling yield was checked using in-
`stant thin-layer chromatography (ITLC-SG, Gelman, Ann Arbor,
`Mich., USA) with 0.1 M Na citrate, pH 5.0, as solvent. The la-
`belled peptide migrated from the origin till Rf=0.67, while the free
`radionuclide migrated with the solvent front (Rf=1).
`The radiochemical purity was determined by high-performance
`liquid chromatography (HPLC) according to the following proce-
`dure. Column: Symmetry C18 4.6×250 mm, 5 μm (Waters, Mil-
`ford, Mass., USA). Flow: 1 ml/min. Solvent A: methanol; solvent
`B: 0.06 M sodium acetate pH 5.5. From t=0 to 6.5 min 100% B;
`from t=6.5 to 7.0 min from 100% B to 50% B; from t=7.0 to
`27 min from 50% B to 40% B; from t=27 min to 27.2 min from
`40% B to 100% A; from t=27.2 min to 32 min: 100% A.
`The labeling yield always exceeded 98% and the radiochemi-
`cal purity was higher than 88%. The injected dose was 1,850 MBq
`
`(range 1,847–1,874 MBq); the injected mass of [DOTA0,Tyr3]oct-
`reotate was 90–100 μg.
`111In-octreotide was prepared using the Octreoscan kit from
`Mallinckrodt Medical (Petten, the Netherlands). The injected dose
`was about 220 MBq, coupled to 8–9 μg [DTPA0]octreotide.
`
`Imaging
`
`177Lu-octreotate. The infusion volume was 80 ml and the infusion
`speed was 10 min. The infusion line by which the radiopharma-
`ceutical was administered was thereafter rinsed with about 100 ml
`saline. Dynamic images of the upper abdomen were obtained from
`the time of injection up to 20 min p.i. Planar spot images of the
`upper abdomen and chest in five patients, and of the upper abdo-
`men and the head and neck in the sixth patient, were obtained
`with a dual-head camera (Picker Prism 2000) 4 h and 1, 3, 10 and
`17 days p.i. Counts from both gamma peaks (208 and 113 keV)
`were collected in separate windows (width 20%). The acquisition
`time was 15 min/view. For dosimetry, a standard with a known ali-
`quot of the injected dose was also counted.
`
`111In-octreotide. The windows were centered over both 111In
`photon peaks (245 and 172 keV) with a window width of 20%.
`Fifteen-minute spot images were obtained 24 h p.i.
`
`Co-infusion of amino acids
`
`In five patients the administration of the same amount and dose of
`177Lu-octreotate was repeated 6–9 weeks later. An infusion of ami-
`no acids (lysine 2.5%, arginine 2.5% in 1 l 0.9% NaCl; 250 ml/h)
`was started 30 min before the administration of the radiopharma-
`ceutical and lasted up to 3.5 h afterwards. Via a second pump
`system the radiopharmaceutical was co-administered.
`
`Measurement of radioactivity in blood and urine
`
`Blood samples were drawn 10, 20, 40, 60 and 90 min and 2, 5 and
`24 h after injection. Urine was collected at two 3-h intervals and
`thereafter up to 24 h after injection.
`Radioactivity in blood and urine was measured with a
`COBRA-Packard auto-gamma counting system (Packard, Meri-
`den, Conn., USA).
`The chemical status of the radionuclide in blood and urine was
`analysed as a function of time by HPLC techniques (see above).
`
`In vivo measurements
`
`The uptake in organs and tumours was calculated as described pre-
`viously [11]. Dosimetric calculations were performed using the
`MIRDOSE package, version 3.0.
`
`Statistics
`
`Analysis of variance (ANOVA) and paired t tests were used.
`P values <0.05 were considered significant.
`
`Results
`
`No side-effects or changes in ECG pattern or pulse rate
`were observed in any patient during the 10-min infusion
`
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`
`Fig. 1. Mean (±SEM) plasma radioactivity expressed as percent-
`age of the injected dose in six patients after 177Lu-octreotate
`(closed dots, stippled line), compared with that in four other pa-
`tients after 111In-octreotide from a previous study [12] (open dots,
`solid line). *P<0.05 vs other radiopharmaceutical at the same time
`point
`
`Fig. 2. Cumulative radioactivity excreted in the urine, expressed
`as mean (±SEM) percentage of the injected dose in four patients
`after 177Lu-octreotate (closed bars), compared with that in six other
`patients after 111In-octreotide from a previous study [12] (open
`bars). *P<0.05 and **P<0.01 vs other radiopharmaceutical during
`the same interval
`
`Fig. 3. Images comparing
`177Lu-octreotate and 111In-oct-
`reotide, 24 h p.i. Columns A
`and C: 177Lu-octreotate; col-
`umns B and D: 111In-octreotide.
`The first row shows corre-
`sponding images of tumour
`sites in a lymphoma patient
`(left two images) and a patient
`with an aesthesioneuroblastoma
`of the eye with a neck metasta-
`sis (right two images); second
`row: posterior (left two images)
`and anterior abdominal images
`in the same patients. The third
`row shows corresponding im-
`ages of tumours in a patient
`with residual Hürthle cell carci-
`noma (left two images) and a
`patient with papillary thyroid
`carcinoma (right two images);
`fourth row: anterior abdominal
`images in the same patients.
`Note the similar biodistribution
`and the clearer visualisation of
`the tumour sites, except in the
`patient with papillary thyroid
`carcinoma
`
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`
`Fig. 5. Ratios of 177Lu-octreotate to 111In-octreotide uptake in or-
`gans and tumour sites, with uptake expressed as a percentage of
`the administered dose. Means are indicated. There is comparable
`organ uptake and higher tumour uptake after 177Lu-octreotate in
`most tumours
`
`Table 1. Patient organ doses in cGy (rad)/3,700 MBq (100 mCi)
`
`Patient Kidneys
`
`Liver
`
`Spleen
`
`Without AA With AA
`
`Bone
`marrow
`
`1
`2
`3
`4
`5
`Mean
`
`825
`533
`692
`359
`648
`611
`
`403
`–
`282
`252
`366
`326
`
`90
`76
`112
`44
`75
`79
`
`803
`1,010
`770
`662
`740
`797
`
`26
`29
`27
`27
`20
`26
`
`With AA: Kidney dose after amino acid co-infusion
`
`Urinary excretion of radioactivity in the first 24 h af-
`ter the injection of 177Lu-octreotate is shown in Fig. 2. In
`comparison with 111In-octreotide, the urinary excretion
`was significantly lower after 177Lu-octreotate, averaging
`64% after 24 h. Peptide-bound radioactivity in urine col-
`lected after 1 h in one patient showed the same pattern as
`the original injection fluid (data not shown).
`The scans obtained 24 h p.i. showed the same biodis-
`tribution for 177Lu-octreotate and 111In-octreotide, with
`comparable uptake in the liver, spleen and kidneys
`(Fig. 3). Also, variable radioactivity was seen in the
`bowel and urinary bladder. The uptake in the tumours
`seemed higher after 177Lu-octreotate, except in the pa-
`tient who had papillary thyroid carcinoma (Fig. 3). At la-
`ter time points, there was retention of the radioactivity in
`the tumours, even 17 days p.i. (Fig. 4). The calculated,
`background-corrected, uptake 24 h after 177Lu-octreotate
`expressed as a percentage of the injected dose was com-
`parable to that after 111In-octreotide for kidneys, spleen
`and liver, but was three- to fourfold higher for four of the
`five tumours (Fig. 5). In the patient with papillary thy-
`roid carcinoma, this uptake was about the same after
`both radiopharmaceuticals.
`
`Fig. 4. Images after 4 h and 1, 3 and 17 days (top row to lower
`row) in patients with Hürthle cell carcinoma (left column) and aes-
`thesioneuroblastoma (right column). Note the retention of radioac-
`tivity in the tumour sites
`
`of 177Lu-octreotate or up to 20 min thereafter. The distri-
`bution pattern of 177Lu-octreotate was comparable to that
`of 111In-octreotide, with rapid visualisation of the kid-
`neys directly after injection, and with visualisation of the
`liver, spleen, kidneys and, in some patients, the pituitary,
`thyroid and tumours 4 h p.i.
`Plasma radioactivity after 177Lu-octreotate expressed
`as a percentage of the injected dose was slightly, but sig-
`nificantly lower compared with 111In-octreotide measure-
`ments from a previous study [12]. After 24 h, however,
`they were comparable (Fig. 1).
`HPLC analysis of plasma, taken at 1 h p.i. in two pa-
`tients, demonstrated the same pattern as the original in-
`jection fluid (data not shown).
`
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`
`Table 2. Dose estimates for 177Lu-octreotate, 111In-octreotide and 90Y-DOTA-octreotide
`
`Target organ
`
`Absorbed dose [cGy (rad)/3,700 MBq (100 mCi)]a
`
`177Lu-octreotate
`
`111In-octreotide
`
`90Y-DOTA-octreotide
`
`Kidneysb
`Liver
`Spleen
`Bone marrow
`Maximum cumulative dose (GBq)c
`Maximum cumulative dose (mCi)c
`
`610 (325)
`80
`800
`26
`26.4
`710
`
`(1)
`
`170
`30
`120
`7
`50.0
`1,350
`
`(2)
`
`190
`25
`130
`11
`44.8
`1,210
`
`(3)
`
`340
`90
`320
`23
`25.0
`680
`
`(4)
`
`2,240
`100
`1,980
`–
`
`(5)
`
`1,220
`260
`2,820
`11
`
`(6)
`
`1,040 (780)
`120
`–
`26
`10.9
`290
`
`(7)
`
`(788)
`–
`–
`–
`10.8
`290
`
`a Dosimetry data reported by: (1) Krenning et al. [13]; (2) Stabin
`et al. [14]; (3) McCarthy et al. [15]; (4) Kwekkeboom et al. [12]
`(dosimetry based on [111In-DOTA0,Tyr3]octreotide); (5) Crem-
`onesi et al. [16] (dosimetry based on [111In-DOTA0,Tyr3]octreo-
`tide); (6) Rosch et al. [17] (dosimetry based on [86Y-DOTA0,
`Tyr3]octreotide PET studies in primates); (7) Barone et al. [18]
`(dosimetry based on [86Y-DOTA0,Tyr3]octreotide PET studies in
`patients)
`
`b Kidney doses after amino acid co-infusion are shown within pa-
`rentheses
`c Mean maximum cumulative dose based on the maximum dose to
`the kidneys of 23 Gy. Values for 177Lu-octreotate and 90Y-DOTA-
`octreotide are with amino acid co-infusion
`
`Table 3. Theoretical maximum
`delivered tumour doses for
`three different radiolabelled so-
`matostatin analogues
`
`Absorbed dose (Gy)
`
`111In-octreotide
`
`90Y-DOTA-octreotide
`
`177Lu-octreotate
`
`Tumour 1 g
`Tumour 10 g
`Tumour uptake
`Maximum cumulative dose
`[mCi (GBq)]
`
`344
`36
`0.1%
`1,350 (50.0)
`
`563
`69
`0.2%
`290 (10.9)
`
`1,001
`102
`0.4%
`710 (26.4)
`
`Maximum cumulative doses are derived from Table 2. The calculations take into account the fact
`that the tumour uptake of [90Y-DOTA,Tyr3]octreotide is about two times higher [18], and that
`of 177Lu-octreotate about four times higher, (present study) than the tumour uptake of 111In-octreotide
`
`Dosimetry data are listed in Table 1. The highest ab-
`sorbed doses were to spleen and kidneys. In five pa-
`tients, scintigraphy was repeated several weeks later, af-
`ter co-infusion of amino acids (lysine 2.5%, arginine
`2.5%; 250 ml/h for 4 h, starting 30 min before the ad-
`ministration of 177Lu-octreotate). Calculated doses to the
`liver, spleen, bone marrow and tumours were about the
`same, whereas the doses to the kidneys were reduced by
`a mean of 47% (range 34%–59%) (Table 1).
`The dose estimates after 177Lu-octreotate are com-
`[90Y-
`those after 111In-octreotide and
`pared with
`DOTA,Tyr3]octreotide in Table 2. Compared with [90Y-
`DOTA,Tyr3]octreotide, the dose to the spleen and kid-
`neys was lower after 177Lu-octreotate, whereas the dose
`to the bone marrow was comparable or higher, depend-
`ing on the model that was used. Theoretical maximum
`tumour doses for 111In-octreotide, [90Y-DOTA,Tyr3]oct-
`reotide, and 177Lu-octreotate, based on a maximum kid-
`ney dose of 23 Gy, are listed in Table 3. The highest tu-
`mour doses in this model are achieved with 177Lu-octreo-
`tate, especially in smaller tumours.
`
`Discussion
`
`The somatostatin analogue Tyr3-octreotate, whether
`chelated with DTPA or DOTA, has been demonstrated to
`have a higher affinity than Tyr3-octreotide for the most
`frequently encountered somatostatin receptor, subtype 2,
`both in vitro and in vivo in animal experiments [8, 9,
`10]. Because the total administered therapeutic dose with
`radiolabelled somatostatin analogues is determined by
`organ dose limits, any newly developed analogues that
`show either a lower uptake in the dose-limiting organs
`(kidneys and/or bone marrow) or a higher uptake in the
`tumour targets, may improve such therapy. For this rea-
`son, we compared the distribution pattern and dosimetry
`of 177Lu-octreotate with those of 111In-octreotide in pa-
`tients. We found the same biodistribution for the ana-
`logues on scintigrams 24 h p.i., with comparable per-
`centage uptake in the liver, spleen and kidneys. The tu-
`mour uptake, however, was three- to fourfold higher in
`four of the five studied patients, implying that potentially
`higher doses to the tumour can be achieved with about
`
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`1324
`equal dose-limiting organ doses. The comparability of
`the percentage uptake in the liver and kidneys for the
`two analogues is most likely due to the fact that the up-
`take in these organs is for the most part not receptor me-
`diated and is accounted for by excretion of the radio-
`pharmaceutical. Our finding that the uptake in the spleen
`was comparable for the two analogues may indicate that
`a considerable part of this uptake is due to binding to a
`somatostatin receptor subtype other than subtype 2. So-
`matostatin receptor subtype 2 has been demonstrated in
`the red pulp of the spleen by autoradiography [19]; how-
`ever, with reverse transcriptase polymerase chain reac-
`tion (RT-PCR) techniques, mRNA for receptor subtype 3
`has also been demonstrated, located in the white pulp
`and with a much lower expression than for subtype 2
`[20]. It is therefore puzzling why the scintigraphic up-
`take in the spleen after 177Lu-octreotate is not much
`higher than after 111In-octreotide. The presence of other
`somatostatin receptor subtypes may explain why, in our
`patient with papillary thyroid carcinoma, uptake was not
`higher with 177Lu-octreotate than with 111In-octreotide.
`This is in agreement with an in vitro study using
`RT-PCR on human thyroid carcinoma cell lines, which
`demonstrated a predominance of mRNA for somatostatin
`receptor subtypes 3 and 5, but only very low amounts of
`mRNA for subtype 2 [21].
`We found a comparable, but slightly faster plasma
`disappearance for 177Lu-octreotate than for 111In-octreo-
`tide. More importantly, the cumulative urinary excretion
`after 24 h was significantly lower for 177Lu-octreotate
`than for 111In-octreotide. In another study [12], we found
`that the cumulative urinary excretion of [111In-DOTA0,
`Tyr3]octreotide was also significantly lower than that of
`[111In-DTPA0]octreotide. Because this analogue has the
`in common with [177Lu-DOTA0,
`tyrosine
`insertion
`Tyr3]octreotate, this may be the cause of the lower uri-
`nary excretion. This lower urinary excretion of 177Lu-
`octreotate results in a significantly higher absorbed bone
`marrow dose, because this dose is determined by the
`whole-body retention (i.e. injected minus excreted radio-
`activity minus activity in major target organs). Because
`of this, both the radiation dose to the kidneys and that to
`the bone marrow may be dose limiting in patient therapy
`with 177Lu-octreotate. It has previously been demonstrat-
`ed that the percentage uptake by and the radiation dose
`to the kidneys from 111In-octreotide can be lowered by
`the infusion of amino acids, both in animals and in pa-
`tients [22, 23]. In our group of patients, we found that
`this is also true for 177Lu-octreotate. This finding is im-
`portant because applying a dose limit to the kidneys of
`23 Gy, as is also applied for external beam radiation
`therapy, 14.0 GBq (380 mCi) would be the mean cumu-
`lative dose limit, whereas with the reduction due to ami-
`no acid
`infusion
`this
`limit would be 26.4 GBq
`(710 mCi). Barone et al. [18] compared the uptake after
`111In-octreotide and after [86Y-DOTA0,Tyr3]octreotide in
`the tumours and kidneys of five patients. They found
`
`that the percentage uptake in tumours was about two
`times higher after [86Y-DOTA0,Tyr3]octreotide, whereas
`it was about 1.4 times higher in the kidneys. Applying a
`dose limit of 23 Gy to the kidneys and accounting for
`amino acid co-infusion, the maximum cumulative dose
`of [90Y-DOTA0,Tyr3]octreotide would be 10.8 GBq
`(290 mCi) (Table 2). Using 177Lu-octreotate, the mean
`maximum cumulative dose that can be administered is
`26.4 GBq (710 mCi) (Table 2). Apart from the more than
`double mean maximum cumulative dose that can be ad-
`instead of [90Y-
`ministered using 177Lu-octreotate
`DOTA0,Tyr3]octreotide, it should be considered that in
`this study we found a three- to fourfold higher tumour
`uptake with 177Lu-octreotate than with 111In-octreotide,
`whereas with [86Y-DOTA0,Tyr3]octreotide the tumour
`uptake was reported to be about twofold that of 111In-oct-
`reotide [18]. In a model calculation, based on the maxi-
`mum cumulative dose that can be given, the tumour dos-
`es that can be achieved with 177Lu-octreotate were higher
`than those for 111In-octreotide or [90Y-DOTA0,Tyr3]oct-
`reotide.
`There are four reasons why we used 177Lu and not 90Y
`as the radionuclide to label [DOTA0,Tyr3]octreotate:
`1. 177Lu-octreotate has been reported to have a very fa-
`vourable impact on tumour regression in a rat model
`[9].
`2. Reubi et al. [10] reported comparable affinities in the
`low nanomolar range for non-radioactive In and Y
`complexed [DOTA0,Tyr3]octreotate, implying that the
`modification in the peptide, and not the change in the
`metal, is primarily responsible for the improved affin-
`ity.
`3. With the 177Lu-labelled analogue it is possible to per-
`form dosimetry and therapy with the same compound
`while no PET scans with short-lived radionuclides are
`needed.
`4. The tissue penetration range of 177Lu (maximum
`range ≈2 mm) is more favourable than that of 90Y
`(maximum range ≈12 mm), especially for smaller tu-
`mours from which much of the radiation dose of 90Y
`will be lost to the surrounding tissues.
`Because of the advantages that both the modified so-
`matostatin analogue and the different radionuclide offer,
`we think that 177Lu-octreotate represents an improve-
`ment in somatostatin receptor-mediated radiotherapy. In-
`deed, we have already observed improvements in com-
`plaints, decreases in serum tumour markers and CT-as-
`sessed tumour shrinkage in patients who are being treat-
`ed with this new compound, although none of these pa-
`tients has yet received the maximum cumulative dose.
`In conclusion: In comparison with the radionuclide-
`coupled somatostatin analogues that are currently avail-
`able for somatostatin receptor-mediated radiotherapy,
`177Lu-octreotate potentially represents an important im-
`provement because of the higher absorbed doses that can
`be achieved to most tumours and because of the more fa-
`
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`vourable tissue penetration range, which may be espe-
`cially important for small tumours.
`
`Acknowledgements. The authors want to thank all the co-workers
`of the technical staff of the Department of Nuclear Medicine for
`their expert coo