De Jong, M. et al. Somatostatin receptor-targeted radionuclide therapy of tumors: preclinical and clinical findings. Semin. Nucl. Med. 32, 133-140

Erasmus University Rotterdam, Rotterdam, South Holland, Netherlands
Seminars in Nuclear Medicine (Impact Factor: 3.34). 05/2002; 32(2):133-40. DOI: 10.1053/snuc.2002.31027
Source: PubMed


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.

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    • "Radiolabeled somatostatin analogues, such as [DOTA0,Tyr3]octreotate, further referred as DOTA-TATE have been subject of intensive research during the last 2 decades and play an important role in somatostatin receptor imaging and peptide receptor-targeted radionuclide therapy (PRRT) e.g. 177Lu-DOTA-TATE [1] [2] [3] [4] [5] [6] [7] . "
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    ABSTRACT: Purpose: Radiolabeled peptides like 177Lu-DOTA-TATE are vulnerable to radiolysis, which results in decreased radiochemical purity (RCP) of these radiopeptides. Gentisic acid (GA) and ascorbic acid (AA) are well known ingredients to reduce the effects of radiolysis. Currently, there is a trend to change the procedure from a manual to a cassette-based automated labeling and to introduce a C18 solid phase extraction (SPE) post-radiolabeling in order to remove non-incorporated 177Lu from the injection solution. However, with the introduction of SPE purification, GA and AA might effectively be removed from injection solution with a concordant dramatically drop of the RCP. Therefore we investigated the impact of tC18 SPE purification on the RCP of 177Lu-DOTA-TATE. Methods: We compared the manual radiolabeling procedure with the cassette-based automated radiolabeling procedure with/out tC18 SPE purification cartridge. The effect of tC18 purification on RCP of 177Lu-DOTA-TATE was investigated by HPLC as function of the post-radiolabeling time and the concentration of activity. Results: After tC18 SPE purification, GA and AA were effectively removed and resulted in volume-dependent decrease in RCP, e.g. <95% after 5h in 20 mL. Re-addition of AA directly after tC18 SPE purification resulted in a RCP ≥95% at 72h. In addition, with the cassette-based automated radiolabeling procedure we also found 28% of the original activity remaining in the activity-containing vial and tubing vs. < 1% with the manual procedure. Conclusion: Re-addition of AA post tC18 SPE purification is required to maintain RCP of 177Lu-DOTA-TATE.
    Full-text · Article · Feb 2014
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    • "From animal experiments it can be inferred that 90Y-labelled somatostatin analogues may be more effective in larger tumours, whereas 177Lu-labelled somatostatin analogues may be more effective in smaller tumours, but their combination may be even more effective [43]. Therefore, apart from comparisons between radiolabelled octreotate and octreotide, and between somatostatin analogues labelled with 90Y and those labelled with 177Lu, PRRT with combinations of 90Y- and 177Lu-labelled analogues should also be evaluated. "
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    ABSTRACT: Treatment with radiolabelled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumours. Symptomatic improvement may occur with (177)Lu-labelled somatostatin analogues that have been used for peptide receptor radionuclide therapy (PRRT). The results obtained with (177)Lu-[DOTA(0),Tyr(3)]octreotate (DOTATATE) are very encouraging in terms of tumour regression. Dosimetry studies with (177)Lu-DOTATATE as well as the limited side effects with additional cycles of (177)Lu-DOTATATE suggest that more cycles of (177)Lu-DOTATATE can be safely given. Also, if kidney-protective agents are used, the side effects of this therapy are few and mild and less than those from the use of (90)Y-[DOTA(0),Tyr(3)]octreotide (DOTATOC). Besides objective tumour responses, the median progression-free survival is more than 40 months. The patients' self-assessed quality of life increases significantly after treatment with (177)Lu-DOTATATE. Lastly, compared to historical controls, there is a benefit in overall survival of several years from the time of diagnosis in patients treated with (177)Lu-DOTATATE. These findings compare favourably with the limited number of alternative therapeutic approaches. If more widespread use of PRRT can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable neuroendocrine tumours.
    Full-text · Article · Mar 2012 · European Journal of Nuclear Medicine
    • "From the long-term follow-up of our patients, it can be inferred that both the tumor load, especially that of the liver, as well as the performance status influence the outcome of receptor radionuclide therapy. Although preclinical studies in rats have shown the dependence of treatment response on tumor size,[15] 90Y-DOTATOC seems to give a higher response rate of larger tumor lesions, while Auger-emitting analogs, such as 177Lu-Tyr3-octreotate, act on smaller lesions.[15] Earlier introduction of therapy and/or a “cocktail therapy” may thus potentially influence the outcome of PRRT. "
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    ABSTRACT: Peptide receptor radionuclide therapy (PRRT) has recently been established as an important treatment modality for somatostatin receptor (SSTR)-positive tumors. The purpose of this study was to evaluate the clinical response, side-effects as well as the quality of life following (90)Y-DOTA-lanreotide (DOTALAN) and/or (90)Y-DOTA-Tyr (3)-DPhe(1)-octreotide (DOTATOC) therapy in patients with progressive metastatic disease during a 6-year follow-up period. Following dosimetric evaluation with (111)In-DOTALAN and (111)In-DOTATOC, 13 patients with estimated absorbed tumor doses of >5 Gy/GBq (carcinoid, n = 5; radioiodine-negative thyroid cancer, n = 4; gastrinoma, n = 1; insulinoma, n = 1; glucagonoma, n = 1; glomus jugularis tumor, n = 1) were assigned for PRRT. A dose of 925 MBq of (90)Y-DOTALAN (four patients) or 1.85-3.7 GBq of (90)Y-DOTATOC (10 patients) was administered intravenously and repeated every 4-8 weeks. Tumor dosimetry was performed prior to and under therapy, re-staging every 2-3 months. Pain intensity, Karnofsky score and general symptoms were evaluated in order to determine quality of life. Patients were followed until death. Altogether, 53 infusions of PRRT (1.85-14.1 GBq) were administered. After the first follow-up of 3 months of (90)Y-DOTALAN therapy, stable disease (SD) was observed in one patient and progressive disease (PD) in three patients. With (90)Y-DOTATOC therapy, SD was found in all 10 patients. During the re-evaluation period (4-27 months), one patient had to be shifted from (90)Y-DOTALAN to (90)Y-DOTATOC therapy due to reduced (111)In-DOTALAN uptake after 5.5 GBq. In the first 6 months after PRRT with DOTATOC, SD was found in nine of 10 patients and PD in one patient. Thereafter, SD was observed in two patients and PD in eight patients. Nine of 13 patients after PRRT with either DOTALAN or DOTATOC died. None of the patients had experienced severe acute hematological side-effects. Transient thrombocytopenia or lymphocytopenia was seen in 10 patients after 3.7 GBq, and a skin reaction in one patient. Total accumulated kidney dose ranged between 4 and 64 Gy, with reduced creatinine clearance in two patients. Pain relief was achieved in three of three patients after ~3.7 GBq ERT within 4-6 months. Appetite, weight, Karnofsky score and general well-being had improved in patients with SD during and after therapy. Based on the results of this study conducted on a small group of patients, we conclude that PRRT may offer an alternative treatment option for SSTR-positive tumors, with only mild transient side-effects and a marked improvement in the quality of life.
    No preview · Article · Jul 2011
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