-
Flavio Forrer,
Eric P. Krenning,
Peter P. Kooij,
Bert F. Bernard,
Mark Konijnenberg, Willem H. Bakker,
Jaap J. M. Teunissen,
Marion de Jong,
Kirsten van Lom,
Wouter W. de Herder,
Dik J. Kwekkeboom
[show abstract]
[hide abstract]
ABSTRACT: PurposeAdequate dosimetry is mandatory for effective and safe peptide receptor radionuclide therapy (PRRT). Besides the kidneys,
the bone marrow is a potentially dose-limiting organ. The radiation dose to the bone marrow is usually calculated according
to the MIRD scheme, where the accumulated activity in the bone marrow is calculated from the accumulated radioactivity of
the radiopharmaceutical in the blood. This may underestimate the absorbed dose since stem cells express somatostatin receptors.
We verified the blood-based method by comparing the activity in the blood with the radioactivity in bone marrow aspirates.
Also, we evaluated the absorbed cross-dose from the source organs (liver, spleen, kidneys and blood), tumours and the so-called
“remainder of the body” to the bone marrow.
MethodsBone marrow aspirates were drawn in 15 patients after treatment with [177Lu-DOTA0,Tyr3]octreotate. Radioactivity in the bone marrow was compared with radioactivity in the blood drawn simultaneously. The nucleated
cell fraction was isolated from the bone marrow aspirate and radioactivity was measured. The absorbed dose to the bone marrow
was calculated. The results were correlated to the change in platelet counts 6weeks after treatment.
ResultsA strong linear correlation and high agreement between the measured radioactivities in the bone marrow aspirates and in the
blood was found (r=0.914, p<0.001). No correlation between the calculated absorbed dose in the bone marrow and the change in platelets was found. There
was a considerable contribution from other organs and the remainder of the body to the bone marrow absorbed dose.
Conclusion(1) After PRRT with [177Lu-DOTA0,Tyr3]octreotate, the radioactivity concentration in the bone marrow is identical to that in the blood; (2) There is no significant
binding of the radiopharmaceutical to bone marrow precursor stem cells; (3) The contribution of the cross dose from source
organs and tumours to the bone marrow dose is significant; and (4) There is considerable variation in bone marrow absorbed
dose between patients. These findings imply that for individual dose optimization, individual calculation of the bone marrow
absorbed dose is necessary.
European journal of nuclear medicine and molecular imaging 04/2012; 36(7):1138-1146. · 4.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Foregut carcinoid tumours have a different embryological origin than other gastroenteropancreatic neuroendocrine tumours (GEP NETs). In the total group of GEP NETs (n = 131), treatment with (177)Lu-octreotate resulted in tumour remission in 47% of patients, with a median time to progression (TTP) of >36 months. As patients with foregut carcinoids may respond differently, we here present the effects of this treatment in a subgroup of patients with foregut carcinoids of bronchial, gastric or thymic origin.
Nine patients with bronchial, five with gastric and two with thymic carcinoids were treated. All patients had metastasised disease. The intended cumulative dose of (177)Lu-octreotate was 22.2-29.6 GBq. Southwest Oncology Group criteria were used for response evaluation.
Bronchial carcinoids: Five patients had partial remission, one had minor response (MR, tumour size reduction: > or =25%, <50%), two had stable disease (SD) and one had progressive disease (PD). Median TTP was 31 months. Gastric carcinoids: One patient had complete remission, one had MR and two had SD, including one with PD at baseline. One patient developed PD. Thymic carcinoids: One patient had SD. In the other patient, disease remained progressive. All patients: Overall remission rate was 50%, including MR.
(177)Lu-octreotate treatment can be effective in patients with bronchial and gastric carcinoids. Its role in thymic carcinoids cannot be determined yet because of the limited number of patients. The overall remission rate of 50% in patients with the studied foregut carcinoids is comparable to that in the total group of GEP NETs.
European journal of nuclear medicine and molecular imaging 08/2007; 34(8):1219-27. · 4.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Therapy using the radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) has been used primarily in gastroenteropancreatic neuroendocrine tumors. Here we present the effects of this therapy in a small number of patients with metastasized or inoperable paragangliomas, meningiomas, small cell lung carcinomas (SCLCs), and melanomas.
Twelve patients with paraganglioma, 5 with meningioma, 3 with SCLC, and 2 with eye melanoma were treated. Three meningiomas were very large and exophytic and all standard treatments had failed. Patients with melanoma had rapidly progressive disease (PD). The intended cumulative dose of 177Lu-octreotate was 22.2-29.6 GBq. Effects of the treatment on tumor size were evaluated using the Southwest Oncology Group criteria.
Two of 4 patients with progressive paraganglioma had tumor regression and 1 had stable disease (SD). Of 5 patients with stable paraganglioma, 2 had SD, 2 had PD, and in 1 patient treatment outcome could not be determined. Paraganglioma was stable in 3 patients in whom the disease status at the beginning of therapy was unknown. One of 4 patients with progressive meningioma had SD and 3 patients had PD. One patient with stable meningioma at the beginning of therapy had SD. All patients with SCLC or melanoma died within 5 mo after starting therapy because of tumor progression. Although not statistically significant, a positive trend was found between high uptake on pretherapy somatostatin receptor scintigraphy and treatment outcome.
177Lu-octreotate can be effective in patients with paraganglioma and meningioma. Response rates are lower than those in patients with gastroenteropancreatic neuroendocrine tumors. Most meningiomas were very large. Further studies are needed to confirm the treatment outcome because of the limited number of patients. 177Lu-octreotate did not have antitumor effects in patients with small lung carcinoma and melanoma.
Journal of Nuclear Medicine 11/2006; 47(10):1599-606. · 6.38 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Because the role of chemotherapy, interferon, or somatostatin analogs as antiproliferative agents is uncertain, currently few treatment options exist for patients with metastatic or inoperable gastroenteropancreatic neuroendocrine tumors (GEP-NET). Fifty-eight patients with somatostatin receptor-positive GEP-NET were treated in a phase I dose-escalating study with cumulative doses of 47 mCi to 886 mCi of the radiolabeled somatostatin analog [(90)Y-DOTA(0),Tyr(3)]-octreotide. At baseline, 47 patients had progressive disease, and 36 were symptomatic. The extent of disease was: 4 patients without liver metastases and 52 patients with liver metastases, including 16 patients with very advanced disease, qualified as "end-stage," and 2 end-stage patients without liver metastases. The objective responses were 5 partial response (PR), 7 minor response (MR), 29 stable disease (SD), and 17 PD. Overall, 33 patients (57%) experienced some improvement in their disease status, including conversion from PD into SD and improvement from SD into MR. Accordingly, 21 of 36 patients (58%) had improvement in Karnofsky performance score or symptoms. The median overall survival (OS) was 36.7 months (95% confidence interval [CI] 19.4-54.1 months). The median progression-free survival in 41 patients who had at least stable disease at the end of the treatment period was 29.3 months (95% CI 19.3-39.3 months). Patients who had SD at baseline had a significantly better OS than patients who had PD at baseline. The extent of disease at baseline also was a significant predictive factor for OS. The OS after therapy with [(90)Y-DOTA(0),Tyr(3)]-octreotide was significantly better than in a historic control group of 32 comparable patients with GEP-NET who had been treated with another radiolabeled somatostatin analog, [(111)In-DTPA(0)]-octreotide (median OS 12.0 months, 95% CI 6.2-17.8 months). The difference in OS for both therapies remained highly significant in a multivariate Cox proportional hazard model including progression status and extent of disease at baseline as covariates. Although the objective response after therapy with [(90)Y-DOTA(0),Tyr(3)]-octreotide by standard criteria seems modest, the significantly longer OS compared with historic controls is most encouraging.
Seminars in Nuclear Medicine 05/2006; 36(2):147-56. · 4.31 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Most radiolabeled biological samples require extensive sample preparation to reduce quenching interference before quantification of radioactivity is possible. Clearly, a more rapid and simple method ensuring a constant count rate and optimal counting efficiency has important advantages. We report on the development and analytical method validation of a rapid and simple combustion method to quantify [3H]docetaxel excreted in human feces and urine. A 3-day validation procedure was performed; quality control (QC) samples, prepared in blank feces and urine, were combusted 5 times and aliquots of the produced tritiated combustion water were counted in a liquid scintillation counter. The validation runs demonstrated adequate precision (below 7.6%) across all QC levels. Sensitivity at the lowest QC level was excellent and recovery of radioactivity constant (ranging from 85 to 91.8%). Clinical applicability of the method was tested in a cancer patient receiving docetaxel and a tracer amount of [3H]docetaxel; during the first 72 h after [3H]docetaxel infusion, 60% of total radioactivity was excreted in the collected feces and urine, which is within the expected range. Combustion of tritiated feces and urine samples is a simple, rapid, sensitive, precise and reproducible method with high recovery. It can be applied to quantify [3H]docetaxel excretion after i.v. administration.
Anti-Cancer Drugs 02/2006; 17(1):63-7. · 2.41 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: There are few treatment options for patients with metastasized or inoperable endocrine gastroenteropancreatic (GEP) tumors. Chemotherapy can be effective, but the response is usually less than 1 year. Here, we present the results of treatment with a radiolabeled somatostatin analog, [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate).
One hundred thirty-one patients with somatostatin receptor-positive tumors were treated with up to a cumulative dose of 600 to 800 mCi (22.2 to 29.6 GBq) of 177Lu-octreotate.
One patient developed renal insufficiency, and another patient developed hepatorenal syndrome. Creatinine clearance did not change significantly in the other patients. WHO hematologic toxicity grade 3 or 4 occurred after less than 2% of the administrations. We observed complete remission in three patients (2%), partial remission in 32 patients (26%), minor response (tumor diameter decrease of 25% to 50%) in 24 patients (19%), stable disease (SD) in 44 patients (35%), and progressive disease (PD) in 22 patients (18%). Higher remission rates were positively correlated with high uptake on pretherapy somatostatin receptor imaging and a limited number of liver metastases, whereas PD was significantly more frequent in patients with a low performance score and extensive disease. Median time to progression in 103 patients who either had SD or tumor regression was more than 36 months.
Treatment with 177Lu-octreotate results in tumor remission in a high percentage of patients with GEP tumors. Serious side effects are rare. The median time to progression compares favorably with chemotherapy. Results are better in patients with a limited tumor load. Therefore, early treatment, even in patients who have no PD, may be better.
Journal of Clinical Oncology 05/2005; 23(12):2754-62. · 18.37 Impact Factor
-
Roelf Valkema,
Stanislas A Pauwels,
Larry K Kvols,
Dik J Kwekkeboom,
Francois Jamar,
Marion de Jong,
Raffaella Barone,
Stephan Walrand,
Peter P M Kooij, Willem H Bakker,
Janet Lasher,
Eric P Krenning
[show abstract]
[hide abstract]
ABSTRACT: The kidneys are critical organs in peptide receptor radiation therapy (PRRT). Renal function loss may become apparent many years after PRRT. We analyzed the time course of decline in creatinine clearance (CLR) in patients during a follow-up of at least 18 mo after the start of PRRT with (90)Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA),Tyr(3)-octreotide ((90)Y-DOTATOC) or (177)Lu-DOTA(0),Tyr(3)-octreotate ((177)Lu-DOTATATE).
Twenty-eight patients with metastasized neuroendocrine tumors received 1-5 cycles of (90)Y-DOTATOC, leading to renal radiation doses of 5.9-26.9 Gy per cycle and a total of 18.3-38.7 Gy. Median follow-up was 2.9 y (range, 1.5-5.4 y), with a median of 16 measurements (range, 5-53) per patient. Thirty-seven patients with metastasized neuroendocrine tumors received 3-7 cycles of (177)Lu-DOTATATE, leading to renal radiation doses of 1.8-7.8 Gy per cycle and a total of 7.3-26.7 Gy. Median follow-up was 2.4 y (range, 1.7-4.0 y), with a median of 10 (range, 6-27) measurements per patient. All renal dose estimates were calculated with the MIRDOSE3 model. All patients were infused with renoprotective amino acids during the administration of the radioactive peptides. The time trend of CLR was determined by fitting a monoexponential function through the data of individual patients, yielding the decline in CLR in terms of percentage change per year.
The median decline in CLR was 7.3% per y in patients treated with (90)Y-DOTATOC and 3.8% per y in patients treated with (177)Lu-DOTATATE (P = 0.06). The time trend of decline in CLR was sustained during the follow-up period. Eleven patients had a >15% per y decline in CLR. Cumulative renal radiation dose, per-cycle renal radiation dose, age, hypertension, and diabetes are probable contributing factors to the rate of decline in CLR after PRRT.
This study showed that the time course of CLR after PRRT was compatible with the pattern of sustained CLR loss in progressive chronic kidney disease.
Journal of Nuclear Medicine 02/2005; 46 Suppl 1:83S-91S. · 6.38 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In patients with progressive metastatic (or recurrent) differentiated thyroid carcinoma (DTC) who do not respond to radioiodine therapy or do not show uptake on radioiodine scintigraphy, treatment options are few. Because these tumors may express somatostatin receptors, peptide receptor radionuclide therapy might be effective. We evaluated the therapeutic efficacy of the radiolabeled somatostatin analog (177)Lu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid(0) (DOTA), Tyr(3)-octreotate ((177)Lu-DOTATATE) in patients with DTC. The uptake of radioactivity in tumors was also studied in relation to treatment outcome.
Five patients with DTC (3 with Hurthle cell thyroid carcinoma [HCTC], 1 with papillary thyroid carcinoma [PTC], and 1 with follicular thyroid carcinoma [FTC]) were treated with 22.4-30.1 GBq of (177)Lu-DOTATATE. Response to therapy was evaluated with CT. Uptake on (177)Lu-DOTATATE scintigraphy (24 h after treatment), expressed as percentage of injected dose, was compared with uptake on pretherapy (111)In-octreotide scintigraphy (24 h after injection).
After the last treatment with (177)Lu-DOTATATE, 1 patient with HCTC had stable disease as a maximum response, 1 patient with HCTC had minor remission (tumor shrinkage between 25% and 50%), and 1 patient with HCTC had partial remission (shrinkage > or =50%). The responses in PTC and FTC were stable disease and progressive disease, respectively. A decrease in serum thyroglobulin level was found in patients with HCTC. Patients with minor and partial remissions had the highest (177)Lu-DOTATATE-to-(111)In-diethylenetriamine pentaacetic acid(0)-octreotide ((111)In-octreotide) uptake ratios (3.2 and 2.4, respectively) whereas the other patients had uptake ratios smaller than 1.5.
(177)Lu-DOTATATE therapy can be effective in patients with progressive DTC who have no therapeutic options and sufficient uptake of (111)In-octreotide in tumor lesions as shown on (111)In-octreotide scintigraphy. This finding is especially important in patients with HCTC, because they cannot benefit from radioiodine therapy because of non-iodine-avid lesions at diagnosis.
Journal of Nuclear Medicine 02/2005; 46 Suppl 1:107S-14S. · 6.38 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Somatostatin analogues have been shown to inhibit smooth muscle cell proliferation after local administration in vivo in animal models and in vitro using human coronary smooth muscle cell cultures. However, the optimal dosage for attaining effective site-specific administration remains undefined. This study was performed to determine the required theoretical dose of the somatostatin analogue, octreotide, to be delivered site specifically, for prevention of restenosis after coronary angioplasty in humans using a previously described methodology to determine regional pharmacokinetics of site-specific intracoronary administrated compounds. In 7 patients, 111In-octreotide, a gamma-labeled somatostatin analogue, was infused post angioplasty at the site of dilatation via a coil-balloon and quantified using a radio-isotopic technique. Efficiency of delivery ranged from 0.1% to 2.7% of the total infused dose of 0.18 microg, corresponding to a mean peak delivered amount of 1.8 +/- 1.9 ng. Total locally bioavailable 111In-octreotide reached 2.28 +/- 2.15 ng h. Based on current in vitro bioavailability and peak concentration data to inhibit proliferation and thymidine incorporation in human coronary smooth muscle cells, a 4000x higher averaged dose (approximately 700 microg) should be infused site specifically to obtain a biologic efficacy in 50% of the treated patients (ED50). Quantification of regional pharmacokinetics enables the determination of a theoretical site-specific dose for achieving appropriate bioavailability above the therapeutic threshold concentration for smooth muscle cell inhibition. This approach is proposed for the determination of the appropriate site-specific coronary infusion dose for the inhibition of restenosis after balloon angioplasty.
Journal of Cardiovascular Pharmacology 02/2004; 43(1):133-9. · 2.29 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Percutaneous transendomyocardial injection with an injection catheter is a new drug delivery method for e.g. therapeutic angiogenesis. Little is known about the efficacy of this drug delivery technique. We studied efficiency and retention of transendomyocardial injections with a NOGA guided injection catheter system by using scintigraphy with radio-labeled model drugs.
Ten non-ischemic landrace pigs were used. In each animal 2-3 transendomyocardial injections were performed using a 3-D mapping based catheter system called NOGA. As a model for proteins like angiogenic growth factors we used (99m)Tc labeled albumin and as a model for small particles like microspheres or adenovirus we used (99m)Tc labeled colloid albumin. Efficiency of the injections and retention of the transendomyocardial deposited substance were evaluated by a gamma camera during and after injection of 0.1 or 0.2 ml.
All 29 injections showed scintigraphic proof of intramyocardial deposition. The average injection efficiency of all 29 injections was 26 +/- 23%. The average injection efficiency of 0.1 and 0.2 ml injections were 33 +/- 30% (n = 8) and 24 +/- 20% (n = 21), respectively (p = 0.33). Intramyocardial retention curves of albumin showed a rapid wash-out within the first 2 hours of the injection, whereas the retention of colloid albumin showed no decrease. In conclusion, transendomyocardial delivery of proteins or particles with an injection catheter show favorable efficiency rates, however the retention time of intramyocardial deposited small proteins like albumin is short. This may indicate the need for sustained release systems of angiogenic growth factors for intramyocardal injection in therapeutic angiogenesis.
Cardiovascular Drugs and Therapy 01/2003; 16(6):527-33. · 3.13 Impact Factor
-
Roelf Valkema,
Marion De Jong, Willem H Bakker,
Wout A p Breeman,
Peter P m Kooij,
Pieternella J Lugtenburg,
Frank H De Jong,
Arjan Christiansen,
Boen L r Kam,
Wouter W De Herder,
Mats Stridsberg,
Jan Lindemans,
Geert Ensing,
Eric P Krenning
[show abstract]
[hide abstract]
ABSTRACT: Fifty patients with somatostatin receptor-positive tumors were treated with multiple doses of [(111)In-diethylenetriamine pentaacetic acid(0)]octreotide. Forty patients were evaluable after cumulative doses of at least 20 GBq up to 160 GBq. Therapeutic effects were seen in 21 patients: partial remission in 1 patient, minor remissions in 6 patients, and stabilization of previously progressive tumors in 14 patients. Our results thus underscore the therapeutic potential of Auger-emitting radiolabelled peptides. The toxicity was generally mild bone marrow toxicity, but 3 of the 6 patients who received more than 100 GBq developed a myelodysplastic syndrome or leukemia. Therefore, we consider 100 GBq as the maximal tolerable dose. With a renal radiation dose of 0.45 mGy/MBq (based on previous studies) a cumulative dose of 100 GBq [(111)In-DTPA(0)]octreotide will lead to 45Gy on the kidneys, twice the accepted limit for external beam radiation. However, no development of hypertension, proteinuria, or significant changes in serum creatinine or creatinine clearance were observed in our patients including 2 patients who received 106 and 113 GBq [(111)In-DTPA(0)]octreotide without protection with amino acids, over a follow-up period of respectively 3 and 2 years. These findings show that the radiation of the short-range (maximal 10 microns) Auger electrons originating from the cells of the proximal tubules is not harmful for the renal function. The decrease in serum inhibin B and concomitant increase of serum FSH levels in men indicate that the spermatogenesis was impaired.
Seminars in Nuclear Medicine 05/2002; 32(2):110-22. · 4.31 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In preclinical studies in rats we evaluated biodistribution and therapeutic effects of different somatostatin analogs, [(111)In-DTPA]octreotide, [(90)Y-DOTA,Tyr(3)]octreotide and [(177)Lu-DOTA,Tyr(3)]octreotate, currently also being applied in clinical radionuclide therapy studies. [Tyr(3)]octreotide and [Tyr(3)]octreotate, chelated with DTPA or DOTA, both showed high affinity binding to somatostatin receptor subtype 2 (sst(2)) in vitro. The radiolabelled compounds all showed high tumor uptake in sst(2)-positive tumors in vivo in rats, the highest uptake being reached with [(177)Lu-DOTA,Tyr(3)]octreotate. In preclinical therapy studies in vivo in rats, excellent, dose dependent, tumor size responses were found, responses appeared to be dependent on tumor size at therapy start. These preclinical data showed the great promise of radionuclide therapy with radiolabelled somatostatin analogues. They emphasised the concept that especially the combination of somatostatin analogs radiolabeled with different radionuclides, like (90)Y and (177)Lu, is most promising to reach a wider tumor size region of high curability. Furthermore, different phase I clinical studies, using [(111)In-DTPA]octreotide, [(90)Y-DOTA,Tyr(3)]octreotide or [(177)Lu-DOTA, Tyr(3)]octreotate are described. Fifty patients with somatostatin receptor-positive tumors were treated with multiple doses of [(111)In-DTPA(0)]octreotide. Forty patients were evaluable after cumulative doses of at least 20 GBq up to 160 GBq. Therapeutic effects were seen in 21 patients: partial remission in 1 patient, minor remissions in 6 patients, and stabilization of previously progressive tumors in 14 patients. The toxicity was generally mild bone marrow toxicity, but 3 of the 6 patients who received more than 100 GBq developed a myelodysplastic syndrome or leukemia. Radionuclide therapy with [(90)Y-DOTA,Tyr(3)]octreotide started in 3 different phase I trials. Overall, antimitotic effects have been observed: about 20% partial response and 60% stable disease (N = 92) along with complete symptomatic cure of several malignant insulinoma and gastrinoma patients. Maximum cumulative [(90)Y-DOTA,Tyr(3)]octreotide dose was about 26 GBq, without reaching the maximum tolerable dose. New is the use of [(177)Lu-DOTA,Tyr(3)]octreotate, which shows the highest tumor uptake of all tested octreotide analogs so far, with excellent tumor-to-kidney ratios. Radionuclide therapy with this analog in a phase 1 trial started recently in our center in 63 patients (238 administrations), Interim analysis of 18 patients with neuroendocrine tumors was performed very recently. According to the WHO, toxicity criteria no dose limiting toxicity was observed. Minor CT-assessed tumor shrinkage (25% - 50% reduction) was noticed in 6% of 18 patients and partial remission (50% - 100% reduction, SWOG criteria) in 39%. Eleven percent of patients had tumor progression and in 44% no changes were seen. These data show that radionuclide therapy with radiolabelled somatostatin analogs, like [DOTA, Tyr(3)]octreotide and [DOTA, Tyr(3)octreotate is a most promising new treatment modality for patients who have sst(2)-positive tumors.
Seminars in Nuclear Medicine 05/2002; 32(2):133-40. · 4.31 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The somatostatin analogue [DOTA0,Tyr3]octreotate has a nine-fold higher affinity for the somatostatin receptor subtype 2 as compared with [DOTA0,Tyr3]octreotide. Also, labelled with the beta- and gamma-emitting radionuclide lutetium-177, this compound has been shown to have a very favourable impact on tumour regression and animal survival in a rat model. Because of these reported advantages over the analogues currently used for somatostatin receptor-mediated radiotherapy, we decided to compare [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) with [111In-DTPA0]octreotide (111In-octreotide) in six patients with somatostatin receptor-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 uptake 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 somatostatin analogues that are currently available for somatostatin receptor-mediated radiotherapy, 177Lu-octreotate potentially represents an important improvement. Higher absorbed doses can be achieved to most tumours, with about equal doses to potentially dose-limiting organs; furthermore, the lower tissue penetration range of 177Lu as compared with 90Y may be especially important for small tumours.
European journal of nuclear medicine and molecular imaging 08/2001; 28(9):1319-1325. · 4.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In vivo somatostatin receptor-mediated scintigraphy has proven to be a valuable method for the visualisation of neuroendocrine tumours and their metastases. A new application is the use of radiolabelled analogues for somatostatin receptor-mediated therapy. This paper presents a review on the basic science, historical background and current knowledge of somatostatin receptor subtypes and their expression in neuroendocrine tumours. New somatostatin analogues, new chelators, "new" radionuclides and combinations thereof are also discussed. Due attention is given to limitations and future perspectives of somatostatin receptor-mediated imaging and therapy.
European journal of nuclear medicine and molecular imaging 08/2001; 28(9):1421-1429. · 4.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cholecystokinin (CCK)-B receptors have been demonstrated on a high percentage of medullary thyroid carcinomas (MTC) in vitro. After encouraging results both in vitro and in animal studies, we studied the efficacy of an octapeptide [111In-DTPA]-CCK analogue in seven patients with MTC. In four of five patients in whom serum calcitonin levels were monitored, a significant rise was found following the injection, indicating retained biological activity of the radiopeptide. In all patients there was visualization of the CCK-B receptor-positive stomach. In one of two patients with known MTC lesions, some of the lesions were visualized; in addition some lesions were visualized in one of the five other patients who had elevated serum tumour markers but negative localizing studies. Radioactivity in the presumed tumour sites was still present at 48 h p.i. The uptake in the presumed tumour sites and stomach was low. Background radioactivity dropped rapidly owing to urinary excretion. After 1 h, breakdown products of the labelled analogue predominated both in urine and in serum, and virtually no intact peptide was present. In conclusion: (1) the CCK-B receptor-positive gastric mucosa and presumed MTC lesions could be visualized in patients using an octapeptide [111In-DTPA]-CCK analogue that is probably internalized, proving the feasibility of CCK-B receptor imaging in vivo; (2) there was a relatively low uptake of the CCK analogue in the strongly CCK receptor-positive stomach, and rapid degradation of the peptide in serum.
European journal of nuclear medicine and molecular imaging 07/2000; 27(9):1312-1317. · 4.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Radiolabelled tumour receptor-binding peptides can be used for in vivo scintigraphic imaging. Recently, the somatostatin
analogue [Tyr3]octreotide (d-Phe-c(Cys-Tyr-d-Trp-Lys-Thr-Cys)-Thr(ol)) was derivatized with the chelator DOTA (tetra-azacyclododecane-tetra-acetic acid), enabling stable
radiolabelling with both the high-energy beta particle-emitter yttrium-90 and the Auger electron-emitter indium-111. The thus
produced radiolabelled compounds are promising for peptide receptor radionuclide therapy. Our previous in vitro and in vivo
(rat) experiments with these radiolabelled compounds showed favourable binding and biodistribution characteristics with high
uptake and retention in the target organs. We also demonstrated receptor-specific, time- and temperature-dependent internalization
of radiolabelled [DOTA0,Tyr3]octreotide in somatostatin receptor subtype 2 (sst2)-positive rat pancreatic tumour cell lines. In this study we have investigated the effects of differences in the amount of
injected peptide on tissue distribution of 111In-labelled [DOTA0,Tyr3]octreotide in normal, i.e. non-tumour-bearing, and CA20948 tumour-bearing rats. This was done in order to find the amount
of peptide at which the highest uptake in target tissues is achieved, and thereby to increase the potential of radionuclide
therapy while simultaneously ensuring the lowest possible radiotoxicity in normal organs. Uptake of radiolabelled [DOTA0,Tyr3]octreotide in sst2-positive organs showed different bell-shaped functions of the amount of injected peptide, being highest at 0.05 (adrenals),
0.05–0.1 (pituitary and stomach) and 0.25 (pancreas)µg. Uptake in the tumour was highest at 0.5µg injected peptide. The
highest uptake was found at peptide amounts that were lower than those reported for [111In-DTPA0]octreotide ((d-Phe-c(Cys-Phe-d-Trp-Lys-Thr-Cys)-Thr(ol), DTPA = diethylene-triamine-penta-acetic acid), consistent with the higher receptor affinity of
the first compound. Our observations of mass-dependent differences in uptake of radiolabelled [DOTA0, Tyr3]octreotide, being the resultant of a positive effect of increasing amounts of peptide on, for example, receptor clustering
and a negative effect of receptor saturation, are of consequence for rat radionuclide therapy studies with radiolabelled peptides
and may also be of consequence for human radionuclide therapy studies with this compound.
European journal of nuclear medicine and molecular imaging 05/1999; 26(7):693-698. · 4.99 Impact Factor
-
Marion De Jong, Willem H. Bakker,
Wout A. P. Breeman,
Bert F. Bernard,
Leo J. Hofland,
Theo J. Visser,
Ananth Srinivasan,
Michelle Schmidt,
Martin Béhé,
Helmut R. Mäcke,
Eric P. Krenning
[show abstract]
[hide abstract]
ABSTRACT: We have evaluated the potential usefulness of radiolabelled [DTPA0,Tyr3]octreotide and [DOTA0,Tyr3]octreotide as radiopharmaceuticals for somatostatin receptor–targeted scintigraphy and radiotherapy. In vitro somatostatin receptor binding and in vivo metabolism in rats of the compounds were investigated in comparison with [111In-DTPA0] octreotide. Comparing different peptide–chelator constructs, [DTPA0,Tyr3]octreotide and [DOTA0, Tyr3]octreotide were found to have a higher affinity than [DTPA0]octreotide for subtype 2 somatostatin receptors (sst2) in mouse AtT20 pituitary tumour cell membranes (all IC50 values obtained were in the low nanomolar range). In vivo studies in CA20948 tumor-bearing Lewis rats revealed a significantly higher uptake of both 111In-labelled [DOTA0,Tyr3]octreotide and [DTPA0,Tyr3]octreotide in sst2-expressing tissues than after injection of [111In-DTPA0]octreotide, showing that substitution of Tyr for Phe at position 3 in octreotide results in an increased affinity for its receptor and in a higher target tissue uptake. Uptake of 111In-labelled [DTPA0]octreotide, [DTPA0,Tyr3]octreotide and [DOTA0,Tyr3]octreotide in pituitary, pancreas, adrenals and tumour was decreased to less than 7% of control by pre-treatment with 0.5 mg unlabelled octreotide/rat, indicating specific binding to sst2. Comparing different radionuclides, [90Y-DOTA0,Tyr3]octreotide had the highest uptake in sst2-positive organs, followed by the [111In-DOTA0,Tyr3]octreotide, whereas [DOTA0, 125I-Try3]octreotide uptake was low compared to that of the other radiopharmaceuticals, when measured 24 hr after injection. Renal uptake of 111In-labelled [DTPA0]octreotide, [DTPA0, Tyr3]octreotide and [DOTA0,Tyr3]octreotide was reduced over 50% by an i.v. injection of 400 mg/kg d-lysine, whereas radioactivity in blood, pancreas and adrenals was not affected. Int. J. Cancer 75:406–411, 1998. © 1998 Wiley-Liss, Inc.
International Journal of Cancer 01/1998; 75(3):406 - 411. · 5.44 Impact Factor
-
Marion de Jong, Willem H. Bakker,
Eric P. Krenning,
Wout A. P. Breeman,
Marcel E. van der Pluijm,
Bert F. Bernard,
Theo J. Visser,
Eduard Jermann,
Martin Béhé,
Pia Powell,
Helmut R. Mäcke
[show abstract]
[hide abstract]
ABSTRACT: In vitro octreotide receptor binding of [111In-DOTA0,d-Phe1,Tyr3]octreotide (111In-DOTATOC) and the in vivo metabolism of 90Y- or 111In-labelled DOTATOC were investigated in rats in comparison with [111In-DTPA0]octreotide [111In-DTPAOC). 111In-DOTATOC was found to have an affinity similar to octreotide itself for the octreotide receptor in rat cerebral cortex microsomes. Twenty-four hours after injection of 90Y- or 111In-labelled DOTATOC, uptake of radioactivity in the octreotide receptor-expressing tissues pancreas, pituitary, adrenals and tumour was a factor of 2-6 that after injection of 111In-DTPAOC. Uptake of labelled DOTATOC in pituitary, pancreas, adrenals and tumour was almost completely blocked by pretreatment with 0.5 mg unlabelled octreotide, indicating specific binding to the octreotide receptors. These findings strongly indicate that 90Y-DOTATOC is a promising radiopharmaceutical for radiotherapy and that 111In-DOTATOC is of potential value for diagnosis of patients with octreotide receptor-positive lesions, such as most neuroendocrine tumours.
European journal of nuclear medicine and molecular imaging 03/1997; 24(4):368-371. · 4.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Gamma-emitting radiopeptides are useful for scintigraphy of tumours on the basis of receptor binding. Likewise, -emitting radiopeptides may be used in radionuclide therapy of such tumours. As iodine-131 suggested to be suitable for this purpose, experiments were performed using three somatostatin analogues, in which the effects of coupling of a therapeutic dose of131I to such peptides were investigated. This study deals with the radioiodination of very small amounts of peptide on a therapeutic scale, the required purification procedures after radioiodination, and the influence of high beta fluxes from131I on a peptide during radioiodination and purification. Based on the regularly used therapeutic doses of131I in cancer treatment and our previous experience with [111In-DTPA-d-Phe1]-octreotide, it was assumed that a minimal effective therapeutic dose of 3.7 GBq131I has to be coupled to a maximum of 100 g peptide, representing only a slight excess of peptide over131I. This contrasts with non-peptide radiopharmaceuticals in which high compound to radionuclide ratios are usually used. Labelling at low peptide to radionuclide ratios (low labelling yields) results in the formation of di-iodinated compounds, whereas at high peptide to radionuclide ratios (high labelling yields) mono-iodinated products of low specific activity are formed. Thus, after radioiodination the desired mono-iodinated peptide has to be separated from unreacted iodide, and from di-iodinaled and unreacted peptide, as both compounds compete for the receptors. Possible radiolysis of the peptide during labelling and separation steps were investigated by irradiating 30 g unlabelled peptide with 370 MBq131I in a small volume. The peptide composition of the incubation mixtures was investigated by high-performance liquid chromatography after irradiation for 30 min to 24 h. The results showed that the peptide was degraded with a half-life of less than 1 h. During the preparation of a real therapeutic dose (at much higher -flux) the peptide will be degraded even faster during the various steps required. In conclusion, intact mono-iodinated131I-labelled somatostatin analogues for peptide receptor therapy will be difficult to obtain.
European journal of nuclear medicine and molecular imaging 06/1996; 23(7):775-781. · 4.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Technetium-99m hexakis-2-methoxyisobutylisonitrile (MIBI),99mTc-tetrofosmin and99mTc-Q12 were all introduced for myocardial imaging but found additional applications as they are taken up by different tumours, enabling imaging of these lesions in patients. The aim of this study was to compare the uptake characteristics of these compounds in vitro in the human adenocarcinoma breast cell lines MCF-7 and ZR-75. It was shown that99mTc-MIBI had the highest cellular uptake (15.9%0.5% dose/mg protein after 60 min in MCF-7, and 14.2%0.4% dose/mg protein in ZR-75), followed by99mTc-tetrofosmin (6.8%0.6% dose/mg protein in MCF-7, and 8.2%0.2% dose/mg protein in ZR-75) and99mTc-Q12 (3,2%0. I% dose/mg protein in MCF-7, and 3.5%0.3% dose/mg protein in ZR-75 cells). For all three compounds tenfold differences in specific activity did not influence total cell-associated radioactivity. Uptake of99mTc-MIBI and99mTc-tetrofosmin was obviously lower at 4 C than at 37 C, whereas99mTc-Q12 uptake showed only slight temperature dependence. When uptake was compared in cells grown to different cell densities (1 mg/ml cellular protein versus 0.3 mg/ml), no differences in uptake were detected when uptake was corrected for the amount of cellular protein present in the dishes. Furthermore, for all compounds it was shown that cellular radioactivity decreased rapidly after washing. Apart from the differences in cellular uptake of the three compounds after 60 min, no differences in residual cellular radioactivity after washing were found between the different compounds when expressed as a percentage of their 60-min uptake, suggesting that the efflux process of the radiolabelled compounds was similar. The differences in cell-associated activity after 60 min were thus presumably caused by differences in uptake. It was concluded that of the Tc-labelled compounds tested,99mTc-MIBI had the highest cellular retention in both human breast tumour cell lines. However, for imaging in vivo not only radioactivity in the target organ is important, but also the ratio of radioactivity in the target versus that in the background. Therefore, further studies in vivo need to be performed to investigate which compound is the optimal imaging agent
European journal of nuclear medicine and molecular imaging 01/1996; 23(10):1361-1366. · 4.99 Impact Factor
