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![Fig. 2 Serum creatinine values at the times of [ 111 In-DTPA 0 ]...](profile/Eric-Krenning/publication/6290995/figure/fig1/AS:601642311376915@1520454113677/Serum-creatinine-values-at-the-times-of-111-In-DTPA-0-octreotide-scintigrams-before_Q320.jpg)
![Table 2 Left kidney uptake of [ 111 In-DTPA 0 ]octreotide during...](profile/Eric-Krenning/publication/6290995/figure/tbl2/AS:601642311356444@1520454113732/Left-kidney-uptake-of-111-In-DTPA-0-octreotide-during-octreotide-treatment-expressed_Q320.jpg)
![Table 3 Spleen, liver and tumour uptake of [ 111 In-DTPA 0 ]octreotide...](profile/Eric-Krenning/publication/6290995/figure/tbl3/AS:601642311360523@1520454113751/Spleen-liver-and-tumour-uptake-of-111-In-DTPA-0-octreotide-during-treatment-with_Q320.jpg)
![Table 4 Tumour uptake of [ 111 In-DTPA 0 ]octreotide during treatment...](profile/Eric-Krenning/publication/6290995/figure/tbl4/AS:601642311356445@1520454113767/Tumour-uptake-of-111-In-DTPA-0-octreotide-during-treatment-with-unlabelled-octreotide_Q320.jpg)
Renal irradiation is a dose-limiting factor in peptide receptor radionuclide therapy using radiolabelled somatostatin analogues. This irradiation is mainly caused by reabsorption of radiolabelled peptides in the proximal tubule. In the human kidney, somatostatin receptors are expressed in the vasa recta, tubuli and glomeruli. It is not clear to wha...
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Patients with somatostatin receptor subtype 2-positive metastasised neuroendocrine tumours can be treated with [(177)Lu-DOTA(0),Tyr(3)]octreotate. Some use octreotide as the peptide for peptide receptor radionuclide therapy (PRRT). We compared in seven patients [(177)Lu-DOTA(0),Tyr(3)]octreotide ((177)Lu-DOTATOC) and [(177)Lu-DOTA(0),Tyr(3)]octreot...
Citations
... Uptake via these receptors also contributes to the uptake of radiolabeled somatostatin analogues, such as radiolabeled octreotide derivatives. About 20% of the kidney uptake with OctreoScan is related to the somatostatin receptor expression in the kidney [15]. This is also the case for ligands binding PSMA (prostate-specific membrane antigen), which is overexpressed in prostate cancers. ...
Targeted radionuclide therapy (TRT) is an emerging field and has the potential to become a major pillar in effective cancer treatment. Several pharmaceuticals are already in routine use for treating cancer, and there is still a high potential for new compounds for this application. But, a major issue for many radiolabeled low-to-moderate-molecular-weight molecules is their clearance via the kidneys and their subsequent reuptake. High renal accumulation of radioactive compounds may lead to nephrotoxicity, and therefore, the kidneys are often the dose-limiting organs in TRT with these radioligands. Over the years, different strategies have been developed aiming for reduced kidney retention and enhanced therapeutic efficacy of radioligands. In this review, we will give an overview of the efforts and achievements of the used strategies, with focus on the therapeutic potential of low-to-moderate-molecular-weight molecules. Among the strategies discussed here is coadministration of compounds that compete for binding to the endocytic receptors in the proximal tubuli. In addition, the influence of altering the molecular design of radiolabeled ligands on pharmacokinetics is discussed, which includes changes in their physicochemical properties and implementation of cleavable linkers or albumin-binding moieties. Furthermore, we discuss the influence of chelator and radionuclide choice on reabsorption of radioligands by the kidneys.
... Renal irradiation primarily occurs because radiolabeled peptides are filtered through the glomerular capillaries in the kidneys and efficiently reabsorbed by cells in the proximal tubule of the nephron, where a significant amount of radioactivity is retained [5,6]. Additionally, somatostatin receptor subtype-2 (SSTR2) expression in human kidneys, including vasa recta, tubular cells of the cortex, and distal tubule cells, also contributes to the total renal uptake of radiolabeled somatostatin analogs [7]. ...
Rationale: The kidneys are commonly considered as the potential dose-limiting organ for peptide receptor radionuclide therapy (PRRT), making the risk of nephrotoxicity a primary concern. This retrospective analysis with prospective documentation and long-term follow-up aims to assess the risk of nephrotoxicity after PRRT in a large cohort of patients with neuroendocrine neoplasms (NENs) treated at our institution over the past 18 years.
Methods: A total of 1361 NEN patients treated with 1-10 cycles of ¹⁷⁷Lu-DOTA-TOC/-NOC/-TATE, ⁹⁰Y-DOTA-TOC/-NOC/-TATE, DUO-PRRT (sequential administration of ⁹⁰Y- and ¹⁷⁷Lu-), or TANDEM-PRRT (combination of ⁹⁰Y- and ¹⁷⁷Lu- on the same day concomitantly) were included in this analysis. All parameters were prospectively documented in a structured database comprising over 250 items per patient and retrospectively analyzed. Kidney function, including serum creatinine, blood urea nitrogen, cGFR, and electrolytes, was evaluated before each PRRT cycle and during follow-up. Restaging was regularly performed at 6-month intervals until death. Treatment-related adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE v.5.0).
Results: Between 2000 and 2018, a total of 5409 cycles of PRRT were administered to 1361 NEN patients. Follow-up after complete treatment was available for 1281 patients receiving 4709 cycles of PRRT, with a median follow-up time of 69.2 months (interquartile range, 32.8-110.5 months) and a maximum follow-up time of 175 months. Baseline creatinine levels were normal in 1039/1281 (81.1%) subjects, while grade 1 (G1) renal insufficiency was present in 221/1281 (17.3%) prior to PRRT. G2 was present in 19/1281 (1.5%), and G3 in 2/1281 (0.2%). After treatment, the proportion of G3/G4 grade patients only increased from 0.2% to 0.7%. Mean creatinine levels increased from a baseline of 0.90 ± 0.30 to 1.01 ± 0.57 mg/L (80.0 ± 26.7 to 89.4 ± 50.8 μmol/L) after treatment. In our main analysis cohort of 1244 patients (4576 cycles), 200 patients experienced an increase in CTCAE creatinine grade. Age, number of treatment cycles, type of radionuclides, and length of follow-up time were the main factors affecting CTCAE creatinine grading after treatment. When comparing the subgroups treated with different radionuclides, the risk of nephrotoxicity after ⁹⁰Y treatment alone and the ⁹⁰Y/¹⁷⁷Lu combination group was higher than after ¹⁷⁷Lu treatment alone. In the ⁹⁰Y treatment subgroup, the two significant risk factors for an increased CTCAE creatinine grade were identified to be age (≥60) and a long follow-up time.
Conclusions: This retrospective analysis with prospective documentation in a large cohort of 1281 NEN patients receiving 4709 cycles of PRRT co-administered with renal protection, treated through the individualized approach at a single institution over 18 years, did not reveal any evidence of long-term PRRT-related renal toxicity. The results of our study suggest that with the use of proper renal protection, nephrotoxicity due to PRRT is more likely a myth than a reality.
... This hypothesis seems to be confirmed by considering the 7 other studies, for which the delay between the 2 images was greater. Five of the 7 studies measured tumor uptake, without any ratio, and found no change 8,10,11,13 or a moderate decrease 15 under cSAs. The remaining 2 studies, using ratios, confirm an increased uptake. ...
Purpose:
The interactions between the administration of cold somatostatin analogs (cSAs) and their radiolabeled counterpart remain unclear, and discontinuation before imaging is still advised as a precaution. The aim of this systematic review is to evaluate the consequences of cSA administration on tumoral and surrounding healthy organs' uptake at somatostatin receptor (SSTR) imaging with SPECT or PET.
Methods:
After registration of the study on Prospero (CRD42022360260), an electronic search of PubMed and Scopus databases was performed. Inclusion criteria were as follows: human patients referred for SSTR imaging for oncological purposes; at least 1 examination performed either before cSA administration or after a long-enough withdrawal of cSA treatment; at least 1 examination was performed under cSA treatment. Included articles were independently appraised by 2 authors using the standardized protocol provided by the Quality Assessment of Diagnostic Accuracy Studies. Discrepancies were solved by consensus.
Results:
A total of 12 articles were included, 4 using 111In-pentetreotide and 8 using 68Ga-DOTA peptides. Administration of cSAs consistently resulted in decreased spleen and liver uptake (from 6.9% to 80% for spleen, 10% to 60% for liver) and increased tumor-to-background or tumor-to-healthy organ ratios. After cSA treatment, tumor uptake alone was unchanged or moderately decreased. Similar results were noted whether patient was octreotide-naive.
Conclusion:
Impairment in SSTR imaging quality after cSA administration has not been demonstrated. On the contrary, the administration of cSAs seems to improve the contrast between tumoral lesions and the surroundings.
... The main mechanism of absorption of the PRRT radiation dose by the kidney is partial reabsorption of the radiopeptide in the proximal tubules after glomerular filtration and retention in the renal interstitium. This process is mediated by cubilin-dependent megalin receptor endocytosis at the proximal tubules (6). Renal radiopeptide retention can lead to excessive renal irradiation to the radiosensitive glomeruli, with potential subsequent deterioration in kidney function. ...
Purpose: To assess efficacy and safety of 177Lu-DOTATATE in patients with neuroendocrine tumours (NETs) with reduced renal function i.e., eGFR below 60 ml/min/1.73 m2. Methods: A single-centre retrospective analysis was performed in 33 patients with eGFR less than 60 ml/min/1.73 m2. Of these 33 patients, 26 patients had chronic kidney disease (CKD) stage 3a (eGFR between 45-60 ml/min/1.73 m2) and 7 patients had CKD stage 3b (eGFR between 30-45 ml/min/1.73 m2). Renal toxicity and temporal changes in eGFR were recorded. Association of potential risk factors and any kidney function deterioration (>10% reduction of eGFR) was evaluated. Survival, radiological response assessment and quality of life data was collected. Results: The incidence of permanent grade 3/4 nephrotoxicity was 3% (single patient with grade 4 nephrotoxicity). The mean annual reduction of eGFR estimated at 2.5%. Permanent decline of >10% eGFR of any grade was recorded in 45% of patients (n = 15). Nine patients moved into higher CKD categories (eight patients who moved from CKD 3a to CKD 3b and one patient who moved from CKD3b to CKD 5). No significant relationship was found between renal risk factors and permanent reduction of renal function. Grade 3/4 bone marrow toxicity was observed in 9% of patients. The estimated median progression-free survival (PFS) was 42 months and median overall survival (OS) was 47 months. At the end of the treatment, the radiological assessment showed partial response in 33%, stable disease in 55%, and progressive disease in 12%. There was an improvement in global quality of life and endocrine score (EORTC QLQ-GI-NET21) (p value: 0.046 and 0.041 respectively). Conclusion: 177Lu-DOTATATE appears to be generally well-tolerated in patients with pre-existing CKD stage 3 with a low incidence of permanent major nephrotoxicity. 177Lu-DOTATATE appears to have a good therapeutic effect; with most patients reporting improvement in quality of life.
... Although SSTR 2 receptors are expressed in vasa recta [32], glomeruli, tubular cells of the cortex and the ascending limb of Henle's [33], the tracer excretion and reabsorption most probably mask the specific binding on the various cells in the kidney. This is also described in the report by Rolleman et al. in which two out of eight patients showed similar renal activity on 111 In-DTPA 0 -octreotide scintigraphy, whether they were with or without SSA medication [34]. Forrer et al. recognize that although cells from the bone marrow express SSTR, the receptor density is so low that the uptake primarily reflects the blood content and is unaffected by the cellular tracer accumulation [35]. ...
Abstract Background Low-grade neuroendocrine tumors (NETs) are characterized by an abundance of somatostatin receptors (SSTR) that can be targeted with somatostatin analogs (SSA). When activated with a single dose of SSA, the receptor-ligand complex is internalized, and the receptor is by default recycled within 24 h. Ongoing medication with long-acting SSAs at 68Ga-DOTA-SSA-PET has been shown to increase the tumor-to-normal organ contrast. This study was performed to investigate the time-dependent extended effect (7 h) of a single intravenous dose of 400 µg short-acting octreotide on the tumor versus normal tissue uptake of 68Ga-DOTATOC. Methods Patients with small-intestinal NETs received a single intravenous dose of 400 µg octreotide and underwent dynamic abdominal 68Ga-DOTATOC-PET/CT at three sessions (0, 3 and 6 h) plus static whole-body (WB) PET/CT (1, 4 and 7 h), starting each PET/CT session by administering 167 ± 21 MBq, 23.5 ± 4.2 µg (mean ± SD, n = 12) of 68Ga-DOTATOC. A previously acquired clinical whole-body 68Ga-DOTATOC scan was used as baseline. SUV and net uptake rate Ki were calculated in tumors, and SUV in healthy organs. Results Tumor SUV decreased significantly from baseline to 1 h post-injection but subsequently increased over time and became similar to baseline at 4 h and 7 h. The tumor net uptake rate, Ki, similarly increased significantly over time and showed a linear correlation both with SUV and tumor-to-blood ratio. By contrast, the uptake in liver, spleen and pancreas remained significantly below baseline levels also at 7 h and the receptor turn-over in tumors thus exceeded that in the normal tissue, with restitution of tumor 68Ga-DOTATOC uptake mainly completed at 7 h. These results however differed depending on tumor size, with significant increases in Ki and SUV between the 1st and 2nd PET, in large tumors (≥ 4 mL) but not in small (> 1 to
... More specifically, SSTR 2 is expressed in the glomeruli and all SSTR subtypes are expressed in the tubuli (both distal and proximal convoluted tubules and loop of Henle) [20,24,25]. While proximal tubular reabsorption covers the major part of renal uptake, binding to SSTR 2 can contribute to the total renal uptake of radiolabelled SSA [21]. Interestingly, a recent study showed that treatment with unlabelled long-acting SSA prior to injection of [ 68 Ga]Ga-DOTA-TATE did not change the uptake in tumour tissue, but did reduce uptake in normal liver leading to an increased tumour-to-liver ratio. ...
Peptide receptor radionuclide therapy (PRRT) is used for the treatment of patients with unresectable or metastasized somatostatin receptor type 2 (SSTR2)-expressing gastroenteropancreatic neuroendocrine tumours (GEP-NETs). The radiolabelled somatostatin analogue [¹⁷⁷Lu]Lu-DOTA-TATE delivers its radiation dose to SSTR2-overexpressing tumour cells, resulting in selective cell killing during radioactive decay. While tumour control can be achieved in many patients, complete remissions remain rare, causing the majority of patients to relapse after a certain period of time. This raises the question whether the currently fixed treatment regime (4 × 7.4 GBq) leaves room for dose escalation as a means of improving therapy efficacy. The kidneys have shown to play an important role in defining a patient's tolerability to PRRT. As a consequence of the proximal tubular reabsorption of [¹⁷⁷Lu]Lu-DOTA-TATE, via the endocytic megalin/cubilin receptor complex, the radionuclides are retained in the renal interstitium. This results in extended retention of radioactivity in the kidneys, generating a risk for the development of radiation nephropathy. In addition, a decreased kidney function has shown to be associated with a prolonged circulation of [¹⁷⁷Lu]Lu-DOTA-TATE, causing increased irradiation to the bone marrow. This can on its turn lead to myelosuppression and haematological toxicity, owing to the marked radio sensitivity of the rapidly proliferating cells in the bone marrow. In contrast to external beam radiotherapy (EBRT), the exact absorbed dose limits for these critical organs (kidneys and bone marrow) in PRRT with [¹⁷⁷Lu]Lu-DOTA-TATE are still unclear. Better insights into these uncertainties, can help in optimizing PRRT to reach its maximum therapeutic potential, while avoiding severe adverse events, like nephropathy and hematologic toxicities. In this review we focus on the nephrotoxic effects of PRRT with [¹⁷⁷Lu]Lu-DOTA-TATE for the treatment of GEP-NETs. If the absorbed dose to the kidneys can be lowered, higher activities can be administered, enlarging the therapeutic window for PRRT. Therefore, we evaluated the renal protective potential of current and promising future strategies and discuss the importance of (renal) dosimetry in PRRT.
... Consequently, 177 Lu-DOTA-EB-TATE delivered 7.9-fold higher dose to tumor than 177 Lu-DOTATATE. Prolonged blood retention of 177 Lu-DOTA-EB-TATE led to significant increase of dose delivery to the kidneys and red marrow, which is 3.2 and 18.2-fold, respectively more than those of 177 Lu-DOTATATE [10], but still far less than the general accepted maximum absorbed doses [12,20,21]. ...
Purpose:
To evaluate the safety and efficacy of 177Lu-DOTA-EB-TATE, a radiolabeled somatostatin analog modified by Evans blue, at escalating doses, was used to increase tumor retention in patients with progressive metastatic neuroendocrine tumors (NETs).
Methods:
Thirty-three patients with metastatic NETs were prospectively enrolled into four groups: group A (n = 6, 43 ± 12 years) administered approximately 3.7 GBq (100 mCi) 177Lu-DOTATATE as controls; group B (n = 7, 55 ± 7 years) administered approximately 1.11 GBq (30 mCi) 177Lu-DOTA-EB-TATE; group C (n = 6, 55 ± 10 years) administered approximately 1.85 GBq (50 mCi) 177Lu-DOTA-EB-TATE; group D (n = 14, 50 ± 10 years) administered approximately 3.7 GBq (100 mCi) 177Lu-DOTA-EB-TATE. Treatment-related adverse events were graded according to the CTCAE v.5.0. 68Ga-DOTATATE PET/CT were performed at baseline and 2-3 months after treatment for response evaluation.
Results:
Administration was well tolerated. No CTC 3/4 hematotoxicity, nephrotoxicity, or hepatotoxicity was observed during or after treatment in groups A-C. In group D, CTC-3 hematotoxicity was recorded in 2 patients with multicourse chemotherapy previously. After one-cycle treatment, the SUVmax decreased in group C (Δ% = - 17.4 ± 29.3%) and group D (Δ% = - 15.1 ± 39.1%), but greatly increased in group B (Δ% = 30.0 ± 68.0%) and mildly increased in group A (Δ% = 5.4 ± 45.9%). Referring to EORTC criteria, 16.7% (1/6), 0% (0/7), 50% (3/6), and 50% (7/14) were evaluated as partial response in groups A, B, C, and D, respectively. When selecting lesions with comparable baseline SUVmax ranging from 15 to 40, SUVmax showed no significant decrease in group B (Δ% = - 7.3 ± 24.5%) (P = 0.214), significant decrease in group C (Δ% = - 34.9 ± 12.4%) (P = 0.001), and in group D (Δ% = - 17.9 ± 19.7%) (P = 0.012) as compared with group A with increased SUVmax (Δ% = 8.4 ± 48.8%). SUVmax significantly decreased in the EBTATE groups (groups B-D combined) (Δ% = - 19.0 ± 21.5%) as compared with the TATE group (P = 0.045).
Conclusion:
177Lu-DOTA-EB-TATE is well tolerated and is more effective than 177Lu-DOTATATE. Both 1.85 GBq (50 mCi) and 3.7 GBq (100 mCi) doses appear to be more effective than 1.11 GBq (30 mCi) dose. Further investigation with more cycles of 177Lu-DOTA-EB-TATE treatment and longer follow-up is warranted.
Trial registration:
Treatment Using 177Lu-DOTA-EB-TATE in Patients with Advanced Neuroendocrine Tumors (NCT03478358). URL: https://register.clinicaltrials.gov/prs/app/action/ViewOrUnrelease?uid=U0001JRW&ts=13&sid=S0007RNX&cx=y3yqv4.
... and a cumulative radiation dose of 15 Gy [271,274]. Compared with 177 Lu-Dotatate excreted via the kidney, excretion of 131 I-hypericin by liver-bile duct-intestine, organs with a higher tolerance dose than that of the kidney, appears to be safer [275][276][277][278][279]. Moreover, targetability of OncoCiDia seems superior to that of 177 Lu-Dotatate, which may go 'off target' in the kidney and spleen due to the expression of somatostatin receptors [271,280,281]. ...
Cancer remains a major cause of death globally. Given its relapsing and fatal features, curing cancer seems to be something hardly possible for the majority of patients. In view of the development in cancer therapies, this article summarizes currently available cancer therapeutics and cure potential by cancer type and stage at diagnosis, based on literature and database reviews. Currently common cancer therapeutics include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, treatment with curative intent by these methods are mainly eligible for patients with localized disease or treatment-sensitive cancers and therefore their contributions to cancer curability are relatively limited. The prognosis for cancer patients varies among different cancer types with a five-year relative survival rate (RSR) of more than 80% in thyroid cancer, melanoma, breast cancer, and Hodgkin’s lymphoma. The most dismal prognosis is observed in patients with small-cell lung cancer, pancreatic cancer, hepatocellular carcinoma, oesophagal cancer, acute myeloid leukemia, non-small cell lung cancer, and gastric cancer with a five-year RSR ranging between 7% and 28%. The current review is intended to provide a general view about how much we have achieved in curing cancer as regards to different therapies and cancer types. Finally, we propose a small molecule dual-targeting broad-spectrum anticancer strategy called OncoCiDia, in combination with emerging highly sensitive liquid biopsy, with theoretical curative potential for the management of solid malignancies, especially at the micro-cancer stage.
... Renal irradiation is mainly caused by reabsorption of radiolabeled peptides in the proximal tubule. SSTR also plays a role in the total renal uptake of radiolabeled somatostatin analogs (13), because vasa recta, tubular cells of the cortex, and distal tubule cells express SSTR (14,15). The fast clearance of the peptide also affects the accumulation of radioactivity within the tumor, which means radiolabeled DOTATATE needs to be given by adding intravenous infusion dose and treatment cycles. ...
... Plus, radiation exposure of the spleen may also affect the development of hematologic toxicity (37). Both 177 Lu-DOTA-EB-TATE and 177 Lu-DOTATATE showed high spleen accumulation, which may be explained by SSTR2 expression in this organ (13). ...
... Renal irradiation is mainly caused by reabsorption of radiolabeled peptides in the proximal tubule. SSTR also plays a role in the total renal uptake of radiolabeled somatostatin analogs (13), because endogenous expression of SSTR2s was found in vasa recta, tubular cells of the cortex, and distal tubule cells (14,15). Different from 177 Lu-DOTA-TATE, which showed high dose rate within the early time period, 177 Lu-DOTA-EB-TATE showed rather steady and extended kidney accumulation over time. ...
Radiolabeled somatostatin analogue therapy has become an established treatment method for patients with well to moderately differentiated unresectable or metastatic neuroendocrine tumors (NETs). The most frequently used somatostatin analogues in clinical practice are octreotide and octreotate. However, both peptides showed suboptimal retention within tumors. The aim of this first-in-human study is to explore the safety and dosimetry of a long-acting radiolabeled somatostatin analogue, lutetium-177-1, 4, 7, 10-tetra-azacyclododecane-1, 4, 7, 10-tetraacetic acid-Evans blue-octreotate (177Lu-DOTA-EB-TATE). Methods: Eight patients (6 males and 2 females; age range, 27-61 y) with advanced metastatic neuroendocrine tumors were recruited. Five patients received a single dose 0.35-0.70 GBq (9.5-18.9 mCi) of 177Lu-DOTA-EB-TATE and underwent serial whole body planar and single-photon emission computed tomography-computed tomography (SPECT-CT) scans at 2, 24, 72, 120 and 168 h after injection. The other 3 patients received intravenous injection of 0.28-0.41 GBq (7.5-11.1 mCi) of 177Lu-DOTATATE for the same imaging acquisition procedures at 1, 3, 4, 24 and 72 h after injection. The dosimetry was calculated using the OLINDA/EXM 1.1 software. Results: Administration of 177Lu-DOTA-EB-TATE was well tolerated, with no adverse symptoms being noticed or reported in any of the patients. Compared with 177Lu-DOTATATE, 177Lu-DOTA-EB-TATE showed extended circulation in the blood and achieved 7.9-fold increase of tumor dose delivery. The total body effective doses were 0.205 ± 0.161 mSv/MBq for 177Lu-DOTA-EB-TATE and 0.174 ± 0.072 mSv/MBq for 177Lu-DOTATATE. Significant dose delivery increases to the kidneys and bone marrow were also observed in patients receiving 177Lu-DOTA-EB-TATE than those receiving 177Lu-DOTATATE (3.2 and 18.2-fold, respectively). Conclusion: By introducing an albumin binding moiety, 177Lu-DOTA-EB-TATE showed remarkably higher uptake and retention in NET tumors as well as significantly increased accumulation in the kidneys and red marrow. It has great potential to be used in PRRT for NET tumors with lower dose and less frequency of administration.
... Rolleman et al. [48] do not support this theory. They wanted to establish the nephrotoxicity of radiolabelled SSTA. ...
