Nephrotoxicity after PRRT with (177)Lu-DOTA-octreotate.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Subacute haematotoxicity after PRRT with (177)Lu-DOTA-octreotate: prognostic factors, incidence and course.

PURPOSE: In peptide receptor radionuclide therapy (PRRT), the bone marrow (BM) is one of the dose-limiting organs. The accepted dose limit for BM is 2 Gy, adopted from (131)I treatment. We investigated the incidence and duration of haematological toxicity and its risk factors in patients treated with PRRT with (177)Lu-DOTA(0)-Tyr(3)-octreotate ((177)Lu-DOTATATE). Also, absorbed BM dose estimates were evaluated and compared with the accepted 2 Gy dose limit. METHODS: The incidence and duration of grade 3 or 4 haematological toxicity (according to CTCAE v3.0) and risk factors were analysed. Mean BM dose per unit (gigabecquerels) of administered radioactivity was calculated and the correlations between doses to the BM and haematological risk factors were determined. RESULTS: Haematological toxicity (grade 3/4) occurred in 34 (11 %) of 320 patients. In 15 of the 34 patients, this lasted more than 6 months or blood transfusions were required. Risk factors significantly associated with haematological toxicity were: poor renal function, white blood cell (WBC) count <4.0 × 10(9)/l, age over 70 years, extensive tumour mass and high tumour uptake on the OctreoScan. Previous chemotherapy was not associated. The mean BM dose per administered activity in 23 evaluable patients was 67 ± 7 mGy/GBq, resulting in a mean BM dose of 2 Gy in patients who received four cycles of 7.4 GBq (177)Lu-DOTATATE. Significant correlations between (cumulative) BM dose and platelet and WBC counts were found in a selected group of patients. CONCLUSION: The incidence of subacute haematological toxicity after PRRT with (177)Lu-DOTATATE is acceptable (11 %). Patients with impaired renal function, low WBC count, extensive tumour mass, high tumour uptake on the OctreoScan and/or advanced age are more likely to develop grade 3/4 haematological toxicity. The BM dose limit of 2 Gy, adopted from (131)I, seems not to be valid for PRRT with (177)Lu-DOTATATE.

Comparison of three radiolabelled peptide analogues for CCK-2 receptor scintigraphy in medullary thyroid carcinoma.

PURPOSE: Cholecystokinin 2 (CCK-2) receptor overexpression has been demonstrated in a high percentage of medullary thyroid carcinomas (MTC). Analogous to somatostatin receptors, CCK-2 receptors might be viable targets for radionuclide scintigraphy and/or radionuclide therapy. Several CCK-2 receptor-binding radiopeptides have been developed, and some have been carried through into clinical studies. However, these studies are mostly limited and difficult to compare. The aim of this study was to evaluate the diagnostic and therapeutic potential of three promising CCK-2 receptor-binding radiopeptides in patients with MTC. METHODS: (111)In-DOTA-(D: )Asp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH(2) ((111)In-DOTA-CCK), a CCK analogue, and the gastrin-based ligands (99m)Tc-N(4)-Gly-(D: )Glu-(Glu)(5)-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH(2) ((99m)Tc-demogastrin 2) and (111)In-DOTA-(D: )Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH(2) ((111)In-DOTA-MG11) were each administered to the same group of six patients. Planar images made at 3-5, 7 and 24 h p.i. were used for comparison of tumour visualisation and renal uptake. RESULTS: (99m)Tc-demogastrin 2 scintigraphy visualised all known lesions and new lesions in four of six patients. (111)In-DOTA-CCK and (111)In-DOTA-MG11 on the other hand missed several lesions; tumour uptake of these two radiopharmaceuticals was quite low. Comparison of retention of renal activity showed no major differences between the three radiopeptides. CONCLUSION: (99m)Tc-demogastrin 2 scintigraphy appeared most promising as a diagnostic tool in patients with MTC. Further studies are required to evaluate its value in patient management. Direct comparisons of the compounds studied strongly suggests that (111)In-DOTA-CCK and (111)In-DOTA-MG11 have less potential as imaging agents than (99m)Tc-demogastrin 2. These DOTA-linked compounds are considered unlikely to be useful for radionuclide therapy because of low tumour uptake.

Bone marrow dosimetry in peptide receptor radionuclide therapy with [177Lu-DOTA(0),Tyr(3)]octreotate.

PURPOSE: Adequate 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. METHODS: Bone marrow aspirates were drawn in 15 patients after treatment with [(177)Lu-DOTA(0),Tyr(3)]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 6 weeks after treatment. RESULTS: A 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 [(177)Lu-DOTA(0),Tyr(3)]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.

Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival.

PURPOSE: Despite the fact that most gastroenteropancreatic neuroendocrine tumors (GEPNETs) are slow-growing, median overall survival (OS) in patients with liver metastases is 2 to 4 years. In metastatic disease, cytoreductive therapeutic options are limited. A relatively new therapy is peptide receptor radionuclide therapy with the radiolabeled somatostatin analog [(177)Lu-DOTA(0),Tyr(3)]octreotate. Here we report on the toxicity and efficacy of this treatment, performed in over 500 patients. PATIENTS AND METHODS: Patients were treated up to a cumulative dose of 750 to 800 mCi (27.8-29.6 GBq), usually in four treatment cycles, with treatment intervals of 6 to 10 weeks. Toxicity analysis was done in 504 patients, and efficacy analysis in 310 patients. RESULTS: Any hematologic toxicity grade 3 or 4 occurred after 3.6% of administrations. Serious adverse events that were likely attributable to the treatment were myelodysplastic syndrome in three patients, and temporary, nonfatal, liver toxicity in two patients. Complete and partial tumor remissions occurred in 2% and 28% of 310 GEPNET patients, respectively. Minor tumor response (decrease in size > 25% and < 50%) occurred in 16%. Median time to progression was 40 months. Median OS from start of treatment was 46 months, median OS from diagnosis was 128 months. Compared with historical controls, there was a survival benefit of 40 to 72 months from diagnosis. CONCLUSION: Treatment with [(177)Lu-DOTA(0),Tyr(3)]octreotate has few adverse effects. Tumor response rates and progression-free survival compare favorably to the limited number of alternative treatment modalities. Compared with historical controls, there is a benefit in OS from time of diagnosis of several years.

Somatostatin receptor subtype 2-mediated uptake of radiolabelled somatostatin analogues in the human kidney.

PURPOSE: 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 what extent these receptors contribute to the total kidney radioactivity uptake. METHODS: Retrospectively, [(111)In-DTPA(0)]octreotide scans of ten selected patients with carcinoids (well-differentiated gastrointestinal endocrine tumour) with liver metastases were evaluated. For each patient, two scans were obtained: one scan was performed without (control) and one during treatment with unlabelled octreotide. Kidney, tumour, spleen and liver uptake was measured in both scans. RESULTS: The interval between the two scans per patient varied from 50 to 397 days. Octreotide treatment substantially lowered kidney [(111)In-DTPA(0)]octreotide uptake in eight out of ten patients. Kidney uptake in all patients was reduced to 82%+/-15% of control, (p < 0.01). A correlation between kidney uptake and spleen uptake was found (r=0.67, p < 0.05). Serum creatinine was unchanged. Surprisingly, tumour and liver [(111)In-DTPA(0)]octreotide uptake was not significantly influenced by unlabelled octreotide therapy, but spleen uptake was significantly lowered by treatment (30.6% of control, p < 0.002). CONCLUSION: We conclude that the somatostatin receptor plays a role in the total renal uptake of radiolabelled somatostatin analogues. The long interval between scans might explain the finding that tumour and liver metastasis uptake of [(111)In-DTPA(0)]octreotide was unchanged. Further studies are needed to confirm and eludicate the results of this study.

Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma.

UNLABELLED: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors.

PURPOSE: 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). PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Long-term follow-up of renal function after peptide receptor radiation therapy with (90)Y-DOTA(0),Tyr(3)-octreotide and (177)Lu-DOTA(0), Tyr(3)-octreotate.

UNLABELLED: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Peptide receptor radionuclide therapy for non-radioiodine-avid differentiated thyroid carcinoma.

UNLABELLED: 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. METHODS: 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). RESULTS: 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. CONCLUSION: (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.

Safe and effective inhibition of renal uptake of radiolabelled octreotide by a combination of lysine and arginine.

As scintigraphy with [(111)In-DTPA(0)]octreotide has become a standard technique in analysing somatostatin receptor-receptor positive lesions such as neuroendocrine tumours, a logical next step is peptide receptor radionuclide therapy (PRRT). Initial studies on PRRT were performed with high doses of [(111)In-DTPA(0)]octreotide, and recently other radionuclides coupled to other somatostatin analogues have been used for this purpose. However, the dose delivered to the kidney is a major dose-limiting factor. Amino acid solutions have previously been used to reduce renal uptake of radioactivity, but these solutions have some disadvantages, i.e. their hyperosmolarity and their propensity to cause vomiting and metabolic changes. In this study we tested various amino acid solutions in patients receiving [(111)In-DTPA(0)]octreotide PRRT in order to assess their safety and their capacity to inhibit the renal uptake of radioactivity. Patients served as their own non-infused control. Renal radioactivity at 24 h following the injection of [(111)In-DTPA(0)]octreotide was inhibited by (1) a commercially available amino acid solution (AA) (21%+/-14%, P<0.02), (2) by 25 g (17%+/-9%, P<0.04), 50 g (15%+/-13%, P<0.04) or 75 g of lysine (44%+/-11%, P<0.001) and (3) by a combination of 25 g of lysine plus 25 g of arginine (LysArg) (33%+/-23%, P<0.01). Fluid infusion alone (500, 1,000 or 2,000 ml of saline/glucose) did not change renal uptake of radioactivity. In patients studied with 75 g of lysine (Lys75) and LysArg, serum potassium levels rose significantly. Maximal potassium levels were within the toxic range (6.3, 6.7 and 6.8 mmol/l) in three out of six patients infused with Lys75, whereas with LysArg the highest concentration measured was 6.0 mmol/l. Electrocardiographic analysis did not reveal significant changes in any of the patients. Vomiting occurred in 50% of patients infused with AA, but in only 6% of patients receiving no amino acid infusion (controls) and 9% of patients receiving LysArg. We conclude that co-infusion of Lys75 or LysArg results in a significant inhibition of renal radioactivity in PRRT, allowing higher treatment doses and thus resulting in higher tumour radiation doses. Because Lys75 produced serious hyperkalaemia, it is not suitable for clinical use. LysArg, however, is effective in offering renal protection in PRRT and is safe.

Phase I study of peptide receptor radionuclide therapy with [In-DTPA]octreotide: the Rotterdam experience.

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.