lutetium-lu-177-dotatate and Kidney-Diseases

Peptide receptor radionuclide therapy (PRRT) is used in tumours expressing type 2 somatostatin receptors (sst(2)), mainly neuroendocrine. The aim of this prospective phase I-II study was to evaluate the toxicity and efficacy of (177)Lu-DOTATATE in multiple cycles.. Fifty-one consecutive patients with unresectable/metastatic sst(2)-positive tumours, divided into two groups, received escalating activities (3.7-5.18 GBq/cycle, group 1; 5.18-7.4 GBq/cycle, group 2) of (177)Lu-DOTATATE. Cumulative activities ranged from 3.7 to 29.2 GBq (median 26.4 GBq in median 6 cycles, group 1, 21 patients) and 5.55 to 28.9 GBq (median 25.2 GBq in 4 cycles, group 2, 30 patients), based on dosimetry.. No major acute or delayed renal or haematological toxicity occurred (one grade 3 leukopenia and thrombocytopenia). Cumulative renal absorbed doses were 8-37 Gy (9-41 Gy bioeffective doses). A median decrease of creatinine clearance of 21.7% 6 months after PRRT, 23.9% after 1 year and 27.6% after 2 years was observed. Higher losses (>20%) occurred in patients with risk factors for renal toxicity, particularly hypertension and diabetes. Cumulative bone marrow doses were <1.5 Gy. Blood elements showed a progressive mild drop during cycles and recovered during follow-up (median 30 months). Thirty-nine patients were progressive at enrolment. Partial and complete responses occurred in 15 of 46 (32.6%) assessable patients. The median time to progression was 36 months. Overall survival was 68% at 36 months. Non-responders and patients with extensive tumour involvement had lower survival.. (177)Lu-DOTATATE was well tolerated up to 29 GBq cumulative activity (up to 7.4 GBq/cycle). The maximum tolerated dose/cycle was not reached. However, considering the individual bone marrow function and the presence of risk factors for kidney toxicity, it seems safer to divide cumulative activities into lower activity cycles.

Topics: Adult; Aged; Dose-Response Relationship, Radiation; Female; Humans; Kidney Diseases; Male; Maximum Tolerated Dose; Middle Aged; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Radiation Injuries; Radiopharmaceuticals; Receptors, Somatostatin; Treatment Outcome

Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumours with (90)Y-DOTATOC and (177)Lu-DOTATATE is promising. The kidney is the critical organ and despite renal protection, function loss may become evident years later. The aim of this study was to analyse renal parameters in patients who had undergone dosimetry before PRRT.. Among those in protocols at our institution, 28 patients were considered: 23 received (90)Y-DOTATOC (3.8-29.2 GBq, median 12.2) and five received (177)Lu-DOTATATE (20.7-29.2 GBq, median 23.2). Patients were followed up after therapy for creatinine and creatinine clearance loss (CCL) for 3-97 months (median 30). Renal doses and bio-effective doses (BED) were calculated (MIRD, LQ model).. After (90)Y-DOTATOC toxicity on creatinine according to NCI criteria occurred in nine cases (seven grade 1, one grade 2, one grade 3), CCL at 1 year was >5% in 12 cases and >10% in eight. A 28-Gy BED threshold was observed in patients with risk factors (mainly hypertension and diabetes), while it was 40 Gy in patients without risk factors. Probably due to the low number of patients, despite the absence of severe toxicity after hyper-fractionated PRRT, clear correlations between fractionation and toxicity could not be found. After (177)Lu-DOTATATE, no toxicity occurred in 1-2 year follow-up; CCL at 1 year >5% occurred in three patients and >10% in two.. Our results indicate the importance of clinical screening for risk factors: In this case, a BED <28 Gy is recommended. Fractionation of therapy is important in order to decrease toxicity, and further studies are needed to evaluate its clinical impact.

Topics: Adolescent; Adult; Aged; Body Burden; Female; Humans; Kidney; Kidney Diseases; Longitudinal Studies; Male; Middle Aged; Octreotide; Organometallic Compounds; Radiation Injuries; Radiopharmaceuticals; Receptors, Peptide; Risk Assessment; Risk Factors; Young Adult

After peptide receptor radionuclide therapy (PRRT), renal toxicity may occur, particular in PRRT with (90)Y-labelled somatostatin analogues. Risk factors have been identified for increased probability of developing renal toxicity after PRRT, including hypertension, diabetes and age. We investigated the renal function over time, the incidence of nephrotoxicity and associated risk factors in patients treated with PRRT with [(177)Lu-DOTA(0),Tyr(3)]-Octreotate ((177)Lu-Octreotate). Also, radiation dose to the kidneys was evaluated and compared with the accepted dose limits in external beam radiotherapy and PRRT with (90)Y-radiolabelled somatostatin analogues.. The annual decrease in creatinine clearance (CLR) was determined in 209 Dutch patients and the incidence of grade 3 or 4 renal toxicity (according to CTCAE v4.03) was evaluated in 323 patients. Risk factors were analysed using a nonlinear mixed effects regression model. Also, radiation doses to the kidneys were calculated and their association with high annual decrease in renal function were analysed.. Of the 323 patients, 3 (1 %) developed (subacute) renal toxicity grade 2 (increase in serum creatinine >1.5 - 3.0 times baseline or upper limit of normal). No subacute grade 3 or 4 nephrotoxicity was observed. The estimated average baseline CLR (± SD) was 108 ± 5 ml/min and the estimated average annual decrease in CLR (± SD) was 3.4 ± 0.4 %. None of the risk factors (hypertension, diabetes, high cumulative injected activity, radiation dose to the kidneys and CTCAE grade) at baseline had a significant effect on renal function over time. The mean absorbed kidney dose in 228 patients was 20.1 ± 4.9 Gy.. Nephrotoxicity in patients treated with (177)Lu-octreotate was low. No (sub)acute grade 3 or 4 renal toxicity occurred and none of the patients had an annual decrease in renal function of >20 %. No risk factors for renal toxicity could be identified. Our data support the idea that the radiation dose threshold, adopted from external beam radiotherapy and PRRT with (90)Y-labelled somatostatin analogues, does not seem valid for PRRT with (177)Lu-octreotate.

Topics: Aged; Aged, 80 and over; Comorbidity; Coordination Complexes; Female; Humans; Incidence; Kidney Diseases; Male; Molecular Targeted Therapy; Neoplasms; Netherlands; Octreotide; Radiation Injuries; Radiopharmaceuticals; Radiotherapy; Radiotherapy Dosage; Risk Factors; Survival Rate

Peptide receptor radionuclide therapy (PRRT) with (177)Lu-DOTATATE is an efficient new treatment option in patients with neuroendocrine tumors (NETs), with low risk of toxicity. Since the kidneys are critical organs in PRRT, renal function is known to deteriorate after PRRT. We analyzed the decline in glomerular filtration rate (GFR), increase in serum creatinine (SCr), and changes in hemogram parameters between pretherapy and at least 6 months after last cycle post-therapy with (177)Lu-DOTATATE.. Forty-seven patients with NETs received 2-6 cycles of (177)Lu-DOTATATE, leading to a total renal radiation absorbed dose of 12.5 ± 4.1 Gy. All renal dose estimates were calculated with the help of OLINDA/EXM software. All patients were infused with renal protective amino acids during the administration of the radiopharmaceuticals. In this study, we used GFR that was estimated by in vitro method using (99m)Tc-DTPA and SCr to assess renal toxicity.. The patients were administered a mean cumulative activity of 20.1 ± 6.74 GBq of (177)Lu-DOTATATE. There was a significant decrease in GFR from 86.8 ± 15.4 mL/1.73 m(2)/min to 66.1 ± 14.5 mL/1.73 m(2)/min and rise in SCr from 0.86 ± 0.19 mg/dL to 1.0 ± 0.2 mg/dL with treatment. Patients with WHO grade 1 renal toxicity (group 2) at baseline demonstrated an increase in SCr that was significantly higher compared with patients with normal baseline creatinine levels (group 1). No serious acute or remote adverse events were recorded. Self-limiting serious hematological toxicity was observed in 2 patients.. The decline in renal function as measured by in vitro GFR tends to be of greater magnitude in patients with baseline impaired renal function than in patients with preserved renal function after PRRT. Hematologic toxicity is relatively rare and can be managed conservatively when encountered.

Topics: Female; Hematologic Diseases; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Radiation Injuries; Radiopharmaceuticals; Receptors, Peptide

High kidney radiation doses during clinical peptide receptor radionuclide therapy (PRRT) with β-particle-emitting radiolabeled somatostatin analogs will lead to renal failure several months after treatment, urging the coinfusion of the cationic amino acids lysine and arginine to reduce the renal radiation dose. In rat PRRT studies, renal protection by the coadministration of lysine was confirmed by histologic examination of kidney specimens indicating nephrotoxicity. In the current study, we investigated dedicated small-animal SPECT/CT renal imaging in rats to monitor renal function in vivo during follow-up of PRRT, with and without lysine.. The following 3 groups of rats were imaged using a multipinhole SPECT/CT camera: controls (group 1) and rats at more than 90 d after therapy with 460 MBq (15 μg) of (177)Lu-DOTA-Tyr(3)-octreotate without (group 2) or with (group 3) a 400-mg/kg lysine coinjection as kidney protection (n ≥ 6 per group). At 90 and 140 d after therapy, static kidney scintigraphy was performed at 2 h after injection of 25 MBq of (99m)Tc-dimercaptosuccinic acid ((99m)Tc-DMSA). In addition, dynamic dual-isotope renography was performed using 50 MBq of (111)In-diethylenetriaminepentaacetic acid ((111)In-DTPA) and 50 MBq of (99m)Tc-mercaptoacetyltriglycine ((99m)Tc-MAG3) at 100-120 d after therapy.. (111)In-DTPA and (99m)Tc-MAG3 studies revealed a time-activity pattern comparable to those in patients, with a peak at 2-6 min followed by a decline of renal radioactivity. Reduced (111)In-DTPA, (99m)Tc-MAG3, and (99m)Tc-DMSA uptake indicated renal damage in group 2, whereas group 3 showed only a decrease of (99m)Tc-MAG3 peak activity. These results indicating nephrotoxicity in group 2 and renal protection in group 3 correlated with levels of urinary protein and serum creatinine and urea and were confirmed by renal histology.. Quantitative dynamic dual-isotope imaging using both (111)In-DTPA and (99m)Tc-MAG3 and static (99m)Tc-DMSA imaging in rats is feasible using small-animal SPECT, enabling longitudinal monitoring of renal function. (99m)Tc-MAG3 renography, especially, appears to be a more sensitive marker of tubular function after PRRT than serum chemistry or (99m)Tc-DMSA scintigraphy.

Topics: Albumins; Animals; Autoradiography; Creatinine; Glomerular Filtration Rate; Kidney; Kidney Diseases; Kidney Tubules; Lysine; Male; Octreotide; Organometallic Compounds; Pentetic Acid; Proteinuria; Radiation Injuries; Radioisotope Renography; Radiopharmaceuticals; Rats; Rats, Inbred Lew; Technetium Tc 99m Dimercaptosuccinic Acid; Technetium Tc 99m Mertiatide; Tomography, Emission-Computed, Single-Photon

Studies on peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues have shown promising results with regard to tumour control. The efficacy of PRRT is limited by uptake and retention in the proximal tubules of the kidney, which might lead to radiation nephropathy. We investigated the long-term renal toxicity after different doses of [(177)Lu-DOTA(0),Tyr(3)]octreotate and the effects of dose fractionation and lysine co-injection in two tumour-bearing rat models.. Significant renal toxicity was detected beyond 100 days after start of treatment as shown by elevated serum creatinine and proteinuria. Microscopically, tubules were strongly dilated with flat epithelium, containing protein cylinders. Creatinine levels rose significantly after 555 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate, but were significantly lower after 278 MBq (single injection) or two weekly doses of 278 MBq. Renal damage scores were maximal after 555 MBq and significantly lower in the 278 and 2x278 MBq groups. Three doses of 185 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate with intervals of a day, a week or a month significantly influenced serum creatinine (469+/-18, 134+/-70 and 65+/-15 micromol/l, respectively; p<0.001). Renal histological damage scores were not significantly influenced by dose fractionation. Lysine co-administration with three weekly treatments of 185 MBq significantly lowered serum creatinine and proteinuria.. Injection of high doses of [(177)Lu-DOTA(0),Tyr(3)]octreotate resulted in severe renal damage in rats as indicated by proteinuria, elevated serum creatinine and histological damage. This damage was dose dependent and became overt between 100 and 200 days after treatment. Dose fractionation had significant beneficial effects on kidney function. Also, lysine co-injection successfully prevented functional damage.

Topics: Animals; Bone Marrow; Bone Marrow Diseases; Dose-Response Relationship, Drug; Kidney; Kidney Diseases; Lethal Dose 50; Longitudinal Studies; Male; Octreotide; Organometallic Compounds; Radiation Injuries; Radiopharmaceuticals; Rats; Rats, Inbred Lew