[68Ga]Ga-Pentixafor for PET Imaging of Vascular Expression of CXCR-4 as a Marker of Arterial Inflammation in HIV-Infected Patients: A Comparison with 18F[FDG] PET Imaging.

People living with human immunodeficiency virus (PLHIV) have excess risk of atherosclerotic cardiovascular disease (ASCVD). Arterial inflammation is the hallmark of atherogenesis and its complications. In this study we aimed to perform a head-to-head comparison of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) and Gallium-68 pentixafor positron emission tomography/computed tomography [68Ga]Ga-pentixafor PET/CT for quantification of arterial inflammation in PLHIV. We prospectively recruited human immunodeficiency virus (HIV)-infected patients to undergo [18F]FDG PET/CT and [68Ga]Ga-pentixafor PET/CT within two weeks of each other. We quantified the levels of arterial tracer uptake on both scans using maximum standardized uptake value (SUVmax) and target-background ratio. We used Bland and Altman plots to measure the level of agreement between tracer quantification parameters obtained on both scans. A total of 12 patients were included with a mean age of 44.67 ± 7.62 years. The mean duration of HIV infection and mean CD+ T-cell count of the study population were 71.08 ± 37 months and 522.17 ± 260.33 cells/µL, respectively. We found a high level of agreement in the quantification variables obtained using [18F]FDG PET and [68Ga]Ga-pentixafor PET. There is a good level of agreement in the arterial tracer quantification variables obtained using [18F]FDG PET/CT and [68Ga]Ga-pentixafor PET/CT in PLHIV. This suggests that [68Ga]Ga-pentixafor may be applied in the place of [18F]FDG PET/CT for the quantification of arterial inflammation.

Sensitivity Comparison of 68Ga-OPS202 and 68Ga-DOTATOC PET/CT in Patients with Gastroenteropancreatic Neuroendocrine Tumors: A Prospective Phase II Imaging Study.

Radiolabeled somatostatin (sst) receptor agonists are integral to the diagnosis of gastroenteropancreatic neuroendocrine tumors (NETs), but detection rates, especially of liver metastases, remain limited even with PET/CT. 68Ga-OPS202 (68Ga-NODAGA-JR11; NODAGA = 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid and JR11 = Cpa-c(dCys-Aph(Hor)-dAph(Cbm)-Lys-Thr-Cys)-dTyr-NH2)), a novel radiolabeled sst receptor antagonist with a high affinity for the sst2 receptor, has the potential to perform better than sst receptor agonists. Here, we present the results of the phase II component of a phase I/II study that evaluated the sensitivity of 68Ga-OPS202, compared with the reference compound, 68Ga-DOTATOC (an sst receptor agonist), in PET imaging. Methods: Patients received a single 150-MBq intravenous injection of 68Ga-DOTATOC (15 µg of peptide) and 2 single 150-MBq intravenous injections of 68Ga-OPS202 (15 µg of peptide at visit 1 and 50 µg at visit 2). Whole-body PET/CT acquisitions were performed 1 h after injection on the same calibrated PET/CT scanner. Diagnostic efficacy measures were compared against contrast medium-enhanced CT or MRI as the gold standard. Two independent masked experts read the scans, and both outcomes were combined for analysis. Results: Twelve consecutive patients with low- or intermediate-grade gastroenteropancreatic NETs took part in this prospective study. Image contrast for matched malignant liver lesions was significantly higher for the 68Ga-OPS202 scans than for the 68Ga-DOTATOC scan: the median of the mean tumor-to-background SUVmax ratios were significantly higher for 15 and 50 µg of 68Ga-OPS202 (5.3 and 4.3, with interquartile ranges of 2.9-5.7 and 3.4-6.3 and P values of 0.004 and 0.008) than for 68Ga-DOTATOC (1.9, with an interquartile range of 1.4-2.9). The higher tumor-to-background ratio of 68Ga-OPS202 resulted not only in a higher detection rate of liver metastases but also in a significantly higher lesion-based overall sensitivity with the antagonist than with 68Ga-DOTATOC: 94% and 88% for 50 and 15 µg of 68Ga-OPS202, respectively, and 59% for 15 µg of 68Ga-DOTATOC (P < 0.001). Positive predictive values for 68Ga-OPS202 PET/CT and 68Ga-DOTATOC PET/CT were similar (∼98%). There were no significant differences in image contrast, sensitivity, or positive predictive values between the 2 68Ga-OPS202 peptide doses, indicating a high reproducibility. Conclusion: Preliminary diagnostic efficacy data from this phase II study indicate that 68Ga-OPS202 has high sensitivity for the detection of gastroenteropancreatic NETs. Further studies in larger patient populations are warranted.

Safety, Biodistribution, and Radiation Dosimetry of 68Ga-OPS202 in Patients with Gastroenteropancreatic Neuroendocrine Tumors: A Prospective Phase I Imaging Study.

Preclinical and preliminary clinical evidence indicates that radiolabeled somatostatin (sst) receptor antagonists perform better than agonists in detecting neuroendocrine tumors (NETs). We performed a prospective phase I/II study to evaluate the sst receptor antagonist 68Ga-OPS202 (68Ga-NODAGA-JR11; NODAGA = 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid and JR11 = Cpa-c(dCys-Aph(Hor)-dAph(Cbm)-Lys-Thr-Cys)-dTyr-NH2)) for PET imaging. Here, we report the results of phase I of the study. Methods: Patients received 2 single 150-MBq intravenous injections of 68Ga-OPS202 3-4 wk apart (15 µg of peptide at visit 1 and 50 µg at visit 2). At visit 1, a dynamic PET/CT scan over the kidney was obtained during the first 30 min after injection, and static whole-body scans were obtained at 0.5, 1, 2, and 4 h after injection; at visit 2, a static whole-body scan was obtained at 1 h. Blood samples and urine were collected at regular intervals to determine 68Ga-OPS202 pharmacokinetics. Safety, biodistribution, radiation dosimetry, and the most appropriate imaging time point for 68Ga-OPS202 were assessed. Results: Twelve patients with well-differentiated gastroenteropancreatic (GEP) NETs took part in the study. 68Ga-OPS202 cleared rapidly from the blood, with a mean residence time of 2.4 ± 1.1 min/L. The organs with the highest mean dose coefficients were the urinary bladder wall, kidneys, and spleen. The calculated effective dose was 2.4E-02 ± 0.2E-02 mSv/MBq, corresponding to 3.6 mSv, for a reference activity of 150 MBq. Based on total numbers of detected malignant lesions, the optimal time window for the scan was between 1 and 2 h. For malignant liver lesions, the time point at which most patients had the highest mean tumor contrast was 1 h. 68Ga-OPS202 was well tolerated; adverse events were grade 1 or 2, and there were no signals of concern from laboratory blood or urinalysis tests. Conclusion:68Ga-OPS202 showed favorable biodistribution and imaging properties, with optimal tumor contrast between 1 and 2 h after injection. Dosimetry analysis revealed that the dose delivered by 68Ga-OPS202 to organs is similar to that delivered by other 68Ga-labeled sst analogs. Further evaluation of 68Ga-OPS202 for PET/CT imaging of NETs is therefore warranted.

Biodistribution, Pharmacokinetics, and Dosimetry of 177Lu-, 90Y-, and 111In-Labeled Somatostatin Receptor Antagonist OPS201 in Comparison to the Agonist 177Lu-DOTATATE: The Mass Effect.

Radiolabeled somatostatin receptor (SSTR) antagonists have shown in vivo higher uptake in SSTR-expressing tumors than agonists. In this preclinical study, the SSTR2 antagonist OPS201 (DOTA-JR11; DOTA-[Cpa-c(DCys-Aph(Hor)-DAph(Cbm)-Lys-Thr-Cys)-DTyr-NH2]) labeled with 177Lu, 90Y, and 111In was compared with the SSTR2 agonist 177Lu-DOTATATE. Methods: Biodistribution, pharmacokinetics, SPECT/CT, and dosimetry studies were performed to assess the bioequivalence of all radiotracers. Use of escalated peptide mass and nephroprotective agents were systematically investigated. Results: The tumor residence time was 15.6 h (13.4-17.7) for 177Lu-OPS201 (10 pmol) and 6.4 h (5.4-7.3) for 177Lu-DOTATATE, resulting in a 2.5-times-higher tumor dose for the antagonist than for the agonist (0.854 vs. 0.333 mGy/MBq for a 4-cm tumor). The overall tumor-to-kidney dose ratio was approximately 24% and 32% higher for 177Lu-OPS201 than for 90Y-OPS201 and 177Lu-DOTATATE, respectively. 111In-OPS201 had a biodistribution significantly different from 90Y-OPS201 and is therefore not a surrogate for 90Y-OPS201 dosimetry studies. Importantly, and in contrast to 177Lu-DOTATATE, injection of 10, 200, and 2,000 pmol of 177Lu-OPS201 did not cause any relevant tumor saturation, with tumor uptake 4 h after injection: 23.9, 24.9, and 18.8 percentage of injected activity per gram of tissue (%IA/g), respectively, for the antagonist (P > 0.05), as compared with 17.8, 12.0, and 9.9 %IA/g for the agonist (P < 0.05). Increasing the peptide mass of 177Lu-OPS201 from 10 to 200 pmol drastically decreased the effective dose from 0.0908 to 0.0184 mSv/MBq and decreased the uptake in the liver, bone marrow, and all SSTR2-expressing organs; thus, the therapeutic index improved considerably. Lysine and succinylated gelatine, alone or in combination, significantly reduced the renal dose of 177Lu-OPS201 compared with the control group, by 45%, 25%, and 40%, respectively (P < 0.05). The reduction was similar for 10 and 200 pmol, whereas lysine performed better than succinylated gelatine. Conclusion:177Lu-OPS201 exhibits higher tumor uptake, longer tumor residence time, and improved tumor-to-kidney dose ratio compared with 177Lu-DOTATATE and 90Y-OPS201. Importantly, the mass-escalation study indicates that an optimized antagonist mass might further improve the safety window of peptide receptor radionuclide therapy by reducing the liver and bone marrow doses as well as the effective dose. Clinical studies are warranted to confirm the efficacy and advantageous toxicity profile of 177Lu-OPS201.

(177)Lu-OPS201 targeting somatostatin receptors: in vivo biodistribution and dosimetry in a pig model.

BACKGROUND: (177)Lu is used in peptide receptor radionuclide therapies for the treatment of neuroendocrine tumors. Based on the recent literature, SST2 antagonists are superior to agonists in tumor uptake. The compound OPS201 is the novel somatostatin antagonist showing the highest SST2 affinity. The aim of this study was to measure the in vivo biodistribution and dosimetry of (177)Lu-OPS201 in five anesthetized Danish Landrace pigs as an appropriate substitute for humans to quantitatively assess the absorbed doses for future clinical applications. RESULTS: (177)Lu-OPS201 was obtained with a specific activity ranging from 10 to 17 MBq/µg. Prior to administration, the radiochemical purity was measured as s > 99.7 % in all cases. After injection, fast clearance of the compound from the blood stream was observed. Less than 5 % of the injected activity was presented in blood 10 min after injection. A series of SPECT/CT and whole-body scans conducted until 10 days after intravenous injection showed uptake mostly in the liver, spine, and kidneys. There was no visible uptake in the spleen. Blood samples were taken to determine the time-activity curve in the blood. Time-activity curves and time-integrated activity coefficients were calculated for the organs showing visible uptake. Based on these data, the absorbed organ dose coefficients for a 70-kg patient were calculated with OLINDA/EXM. For humans after an injection of 5 GBq (177)Lu-OPS201, the highest predicted absorbed doses are obtained for the kidneys (13.7 Gy), the osteogenic cells (3.9 Gy), the urinary bladder wall (1.8 Gy), and the liver (1.0 Gy). No metabolites of (177)Lu-OPS201 were found by radio HPLC analysis. None of the absorbed doses calculated will exceed organ toxicity levels. CONCLUSIONS: The (177)Lu-OPS201 was well tolerated and caused no abnormal physiological or behavioral signs. In vivo distributions and absorbed doses of pigs are comparable to those observed in other publications. According to the biodistribution data in pigs, presented in this work, the expected radiation exposure in humans will be within the acceptable range.

90Y-edotreotide for metastatic carcinoid refractory to octreotide.

PURPOSE: Metastatic carcinoid is an incurable malignancy whose symptoms, such as diarrhea and flushing, can be debilitating and occasionally life-threatening. Although symptom relief is available with octreotide, the disease eventually becomes refractory to octreotide, leaving no proven treatment options. The goal of this study was to evaluate the clinical effect of using (90)Y-edotreotide to treat symptomatic patients with carcinoid tumors. PATIENTS AND METHODS: Patients enrolled had metastatic carcinoid, at least one sign/symptom refractory to octreotide, and at least one measurable lesion. Study treatment consisted of three cycles of 4.4 GBq (120 mCi) (90)Y-edotreotide each, once every 6 weeks. RESULTS: Ninety patients were enrolled in the study. Using Southwest Oncology Group tumor response criteria, 67 (74.%) of 90 patients (95% CI, 65.4% to 83.4%) were objectively stable or responded. A statistically significant linear trend toward improvement was demonstrated across all 12 symptoms assessed. Median progression-free survival was significantly greater (P = .03) for the 38 patients who had durable diarrhea improvement than the 18 patients who did not (18.2 v 7.9 months, respectively). Adverse events (AEs) were reported in 96.7% (87 of 90) of patients. These AEs consisted primarily of reversible GI events (76 of 90), which could be caused in part by concomitant administration of amino acid solution given to reduce radiation exposure to the kidneys. There was one case each of grade 3 oliguria and grade 4 renal failure, each lasting 6 days. CONCLUSION: (90)Y-edotreotide treatment improved symptoms associated with malignant carcinoid among subjects with no treatment alternatives. Treatment was well-tolerated and had an acceptable expected AE profile.

Octreotide LAR vs. surgery in newly diagnosed patients with acromegaly: a randomized, open-label, multicentre study.

OBJECTIVE: This prospective randomized study evaluated the efficacy and safety of octreotide LAR vs. surgery in newly diagnosed acromegalic patients. METHODS: Totally 104 male and female patients were enrolled in a 50-week, exploratory, open-label and randomized study. Eligible patients were randomized to receive either octreotide LAR 20 mg every 28 days or to undergo surgery. Efficacy was assessed by changes in mean GH and IGF-I serum concentrations, at weeks 12, 24 and 48. Tumour volume was assessed by contrast-enhanced MRI. In both groups, treatment adjustment was performed for patients uncontrolled at week 12 or 24. Octreotide LAR patients received a dose increased to 30 mg or, if already receiving this dose, investigator and patients could decide to cross-over to surgery. Patients uncontrolled after surgery received octreotide LAR 20 mg, increased to 30 mg if acromegaly was still uncontrolled. RESULTS: Overall success rates at weeks 24 and 48 were 25% and 28% for the octreotide LAR group and 49% and 39% for the surgery group. Only the difference observed at week 24 was statistically significant (P = 0.047). Both groups had a significant (> 20%) tumour shrinkage: 73% of patients in the octreotide LAR group and 95% in the surgery group. Major differences between octreotide LAR and surgery group in the occurrence of adverse events were gastrointestinal (71%vs. 27%), hepatobiliary (41%vs. 8%) and respiratory (5%vs. 28%). CONCLUSION: This first randomized study in unselected patients indicates that the 48-week treatment outcome of octreotide LAR as first-line treatment of acromegaly does not significantly differ from surgery. As a complete response to surgery in GH-secreting macro-adenomas can be difficult, first-line therapy with octreotide LAR can be considered as a viable alternative for most patients with acromegaly, due to its low complication rate.

A prospective, multicentre study to investigate the efficacy, safety and tolerability of octreotide LAR (long-acting repeatable octreotide) in the primary therapy of patients with acromegaly.

OBJECTIVE: To evaluate the efficacy, safety and tolerability of octreotide LAR (long-acting repeatable octreotide) in the primary therapy of acromegaly. DESIGN AND PATIENTS: Ninety-eight previously untreated acromegalics were recruited into this prospective multicentre study. A total of 68 patients successfully completed 48 weeks of the study period, received 12 doses of octreotide LAR 10-30 mg every 4 weeks, and constituted the population used for this analysis. MEASUREMENTS AND RESULTS: A clinically relevant reduction (i.e. to < or = 5 microg/l) in mean GH (mGH) was recorded in 72% of patients after 24 weeks of treatment, and 42% reached a 'safe' GH value (< or = 2.5 microg/l). At week 48, 16 more patients were considered partial GH responders (GH > 2.5 microg/l and < or = 5 microg/l) and 44% had reached a GH level < or = 2.5 microg/l. IGF-1 levels normalized in 38% and 34% of patients after 24 and 48 weeks of treatment, respectively. At study completion, 10 patients (14.7%) who had not normalized their IGF-1 levels had achieved at least a 50% decrement in this marker. In eight microadenoma patients, tumour volume decreased from a mean baseline level of 298 +/- 145 mm3 to 139 +/- 94 mm3 after 24 weeks and to 99 +/- 70 mm3 after 48 weeks of therapy. In 60 patients with macroadenoma, the corresponding values were 3885 +/- 5077 mm3 at baseline and 2723 +/- 3435 and 2406 +/- 3207 mm3 after 24 and 48 weeks, respectively. At weeks 24 and 48, a significant (> 20%) tumour volume reduction was reported in 63% and 75% of patients, respectively. A reduction in the severity of symptoms of acromegaly was observed early in treatment and was maintained throughout the study period. CONCLUSION: Octreotide LAR represents a viable alternative to surgery for primary treatment of acromegaly leading to a progressive regression of tumour volume, a sustained control of biochemical abnormalities and an adequate relief of symptoms of the disease.

Survival and response after peptide receptor radionuclide therapy with [90Y-DOTA0,Tyr3]octreotide in patients with advanced gastroenteropancreatic neuroendocrine tumors.

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.

Long-acting octreotide and prolonged-release lanreotide formulations have different pharmacokinetic profiles.

Single-dose pharmacokinetic (PK) profiles and multiple-dose PK modeling were compared for long-acting octreotide (20 or 60 mg) and prolonged-release lanreotide (90 or 120 mg) over 91 days; steady-state profiles were simulated. All treatments were well tolerated. Octreotide 20-mg profile showed increased concentration on day 1, lag from days 2 to 6, then prolonged plateau phase (days 11-41); 60-mg PK was dose proportional. Lanreotide 90-mg profile showed C(max) on day 1 then elimination (apparent t1/2 25.5 days); 120-mg profile was underproportional. Steady-state PK of octreotide 20 mg/28 d suggested a C(mean) of 1216 rhog/mL (range, 1065-1585) with low fluctuation index (43%). Steady-state PK of lanreotide 90 mg/28 d suggested a C(mean) of 4455 rhog/mL (range, 2499-9279) with high fluctuation index (152%). Long-acting octreotide had more predictable PK than prolonged-release lanreotide. Simulated steady-state profiles suggest long-acting octreotide could be optimized to meet individual patient needs. In contrast, prolonged-release lanreotide requires exposure constantly above the therapeutic target to enable monthly long-term therapy.

Metabolic effects of amino acid solutions infused for renal protection during therapy with radiolabelled somatostatin analogues.

BACKGROUND: Infusion of amino acids (AAs) can reduce renal uptake of radiolabelled somatostatin analogues resulting in a lower kidney exposure during peptide radiotherapy of patients with neuroendocrine tumours. In this study, we investigated the metabolic effects related to the infusion of large amounts of amino acids in patients undergoing positron emission tomography (PET) studies with [(86)Y]DOTA(0)-D-Phe(1)-Tyr(3)-octreotide. METHODS: Twenty-four patients, in four consecutive groups of six, received a 4 h infusion of 120 g of mixed AAs and, in addition, either a 4 h infusion of 50 g of L-lysine (n = 6), a 10 h infusion of 240 g of mixed AAs (n = 6), a 4 h infusion of 50 g of L-lysine + L-arginine (Lys-Arg; n = 6) or no infusion (control; n = 6) in randomly ordered crossover studies. A number of clinical and biochemical parameters in blood and urine were measured over 24 h, including calculation of creatinine clearance, tubular reabsorption of inorganic phosphate (TRP) and fractional urate excretion. RESULTS: No clinical side effects occurred during the infusions except for nausea and vomiting under mixed AAs. Patients in the latter group showed an increase in serum urea, whereas patients receiving L-lysine showed an increase in serum potassium and chloride. Inorganic phosphate levels dropped at 2.5 h in all groups except controls, and a significant decrease in TRP was observed with mixed AAs but not with L-lysine or Lys-Arg. CONCLUSION: Although infusion of AA solutions can improve the effect of therapy by allowing the administration of higher doses of radiolabelled somatostatin analogues, each preparation has specific sides effects that should be taken into account with this type of therapy.

Pre-therapeutic dosimetry and biodistribution of 86Y-DOTA-Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advanced neuroendocrine tumours.

PURPOSE: For the internal radiotherapy of neuroendocrine tumours, the somatostatin analogue DOTATOC labelled with 90Y is frequently used [90Y-DOTA-Phe1-Tyr3)-octreotide (SMT487-OctreoTher)]. Radiation exposure to the kidneys is critical in this therapy as it may result in renal failure. The aim of this study was to compare cumulative organ and tumour doses based upon dosimetric data acquired with the chemically identical 86Y-DOTA-Phe1-Tyr3-octreotide (considered as the gold standard) and the commercially available 111In-pentetreotide. METHODS: The cumulative organ and tumour doses for the therapeutic administration of 13.32 GBq 90Y-DOTA-Phe1-Tyr3-octreotide (three cycles, each of 4.44 GBq) were estimated based on the MIRD concept (MIRDOSE 3.1 and IMEDOSE). Patients with a cumulative kidney dose exceeding 27 Gy had to be excluded from subsequent therapy with 90Y-DOTA-Phe1-Tyr3-octreotide, in accordance with the directives of the German radiation protection authorities. RESULTS: The range of doses (mGy/MBq 90Y-DOTA-Phe1-Tyr3-octreotide) for kidneys, spleen, liver and tumour masses was 0.6-2.8, 1.5-4.2, 0.3-1.3 and 2.1-29.5 (86Y-DOTA-Phe1-Tyr3-octreotide), respectively, versus 1.3-3.0, 1.8-4.4, 0.2-0.8 and 1.4-19.7 (111In-pentetreotide), with wide inter-subject variability. Despite renal protection with amino acid infusions, estimated cumulative kidney doses in two patients exceeded 27 Gy. CONCLUSION: Compared with 86Y-DOTA-Phe1-Tyr3-octreotide, dosimetry with 111In-pentetreotide overestimated doses to kidneys and spleen, whereas the radiation dose to the tumour-free liver was underestimated. However, both dosimetric approaches detected the two patients with an exceptionally high radiation burden to the kidneys that carried a potential risk of renal failure following radionuclide therapy.

Effects of intravenous amino acid administration with Y-90 DOTA-Phe1-Tyr3-Octreotide (SMT487[OctreoTher) treatment.

Y-90-DOTA-Phe1-Tyr3-Octreotide (90Y-SMT 487, OctreoTher) has shown potential for effectively treating patients with neuroendocrine tumors. The dose-limiting organ for this agent is the kidney. The purpose of this work is to assess the effectiveness of a commercially available amino acid solution on reducing renal uptake of 90Y-SMT 487 and determine the safety profile of this solution. Subjects with In-111 pentetreotide positive tumors and normal creatinine levels were treated with 3 cycles of 90Y-SMT 487, 120 mCi/cycle, at 6-9 week intervals. During each treatment two liters of an amino acid solution containing arginine and lysine (Aminosyn II 7%, Abbott Laboratories, Abbott Park, IL) were infused IV over 4 hours. Adverse events were recorded. To assess the effect of Aminosyn II on renal uptake of 90Y-SMT 487, a subgroup of subjects underwent bremsstrahlung imaging 24 hours following infusion. Kidney to liver (K/L) count density ratios were generated from the baseline In-111 pentetreotide images (performed without amino acid infusion) and the 90Y bremsstrahlung images. Follow-up creatinine levels were obtained. Thirty-seven subjects received a total of 89 90Y-SMT 487 treatments. The number of amino-acid infusions associated with one or more episodes of emesis was 53 (62%). During 13 (15%) of these infusions, the Aminosyn II rate had to be reduced because of severe nausea and vomiting. Symptomatic flushing occurred during 16 (18%) of the infusions. One subject experienced a near syncopal event shortly after completing the infusion. Creatinine levels remained normal in 34 of 36 subjects during a mean follow-up period of 9.8 months. Fourteen subjects underwent bremsstrahlung imaging following infusion of 90Y-SMT 487. Kidney uptake appeared to decrease with administration of the amino acid solution in 13 of 14 subjects. For the 28 individual kidneys, the mean percent decrease in the Kidney/Liver uptake ratio with the amino acid solution was found to be 32%. We conclude that 2 L of Aminosyn II 7% infused over 4 hours appears to notably reduce renal uptake of 90Y-SMT 487. Aminosyn is generally well tolerated, particularly at lower infusion rates with occasional moderate to severe nausea and vomiting at higher rates.

Evaluating the clinical effectiveness of 90Y-SMT 487 in patients with neuroendocrine tumors.

UNLABELLED: Because of the presence of cell membrane somatostatin receptors (SSTRs), many neuroendocrine tumors will bind analogs of somatostatin. (90)Y-Dodecanetetraacetic acid-Phe1-Tyr3-octreotide (SMT 487) is an SSTR radiopharmaceutical currently under investigation as a therapeutic option for neuroendocrine tumors. Although there are a variety of methods for evaluating response to a given cancer therapy, an important indicator of success is the impact on the clinical status of the patient. The purpose of this work was to develop a semiquantitative method and assess the clinical effectiveness of (90)Y-SMT 487 therapy in patients with neuroendocrine tumors. METHODS: A scoring system was developed to evaluate clinical response that included the following parameters: weight, health status score (determined by the patient), Karnofsky score, and tumor-related symptoms. RESULTS: We applied this scoring system to 21 patients who had completed 3 cycles of therapy with (90)Y-SMT 487. Fourteen of the 21 showed a favorable clinical response, whereas 5 were clinically stable after treatment and 2 showed evidence of clinical progression. There was also a significant reduction in the amount of octreotide being used after completion of (90)Y-SMT 487 therapy in the 20 patients who were on this medication. CONCLUSION: Using this scoring method, (90)Y-SMT 487 appears effective in improving the clinical status of patients with (111)In-pentetreotide-positive neuroendocrine tumors.

Assessment of hepatic toxicity from treatment with 90Y-SMT 487 (OctreoTher(TM)) in patients with diffuse somatostatin receptor positive liver metastases.

The purpose of this study was to determine whether there is evidence for hepatocellular radiation injury following treatment with (90)Y-SMT487 ((90)Y-DOTA-tyr3-octreotide, OctreoTher(TM)) in patients with extensive liver metastases from neuroendocrine tumors. Patients reported in this study participated in a Phase II trial of efficacy and safety of (90)Y-SMT487. The trial design called for three treatment cycles of 120 mCi each (4400 MBq) of (90)Y-SMT487. (111)In-pentetreotide SPECT images were used to determine the extent of liver metastases. Serum AST, ALT, and alkaline phosphatase levels were obtained at baseline and following each cycle of therapy. Least squares fit was applied to the serial liver enzyme measurements in patients with extensive liver metastases. Post-therapy liver enzyme measurements were also evaluated using WHO common toxicity criteria. Repeated-measures ANOVA and paired t-test were applied to the serial enzyme measures. There were 21 subjects. Fifteen of these had hepatic metastases with 12 demonstrating extensive (defined as 25% or more) liver involvement. In only 4 of these 15 did any of the three enzyme levels increase in WHO toxicity grade from baseline to final follow-up. We conclude that patients with diffuse SSTR positive hepatic metastases can be treated with a cumulative administered activity of 360 mCi (90)Y-SMT487 with only a small chance of developing mild acute or subacute hepatic radiation injury.

86Y-DOTA0)-D-Phe1-Tyr3-octreotide (SMT487)--a phase 1 clinical study: pharmacokinetics, biodistribution and renal protective effect of different regimens of amino acid co-infusion.

The pharmacokinetics and dosimetry of (86)Y-DOTA(0)- d-Phe(1)-Tyr(3)-octreotide ((86)Y-SMT487) were evaluated in a phase I positron emission tomography (PET) study of 24 patients with somatostatin receptor-positive neuroendocrine tumours. The effect of amino acid (AA) co-infusion on renal and tumour uptake was assessed in a cross-over randomised setting. Five regimens were tested: no infusion, 4-h infusion of 120 g mixed AA (26.4 g l-lysine + l-arginine), 4 h l-lysine (50 g), 10 h 240 g mixed AA (52.8 g l-lysine + l-arginine) and 4 h Lys-Arg (25 g each). Comparisons were performed on an intra-patient basis. Infusions of AA started 0.5 h prior to injection of (86)Y-SMT487 and PET scans were obtained at 4, 24 and 48 h p.i. Absorbed doses to tissues were computed using the MIRD3 method. (86)Y-SMT487 displayed rapid plasma clearance and exclusive renal excretion; uptake was noted in kidneys, tumours, spleen and, to a lesser extent, liver. The 4-h mixed AA co-infusion significantly ( P<0.05) reduced (86)Y-SMT487 renal uptake by a mean of 21%. This protective effect was significant on the dosimetry data (3.3+/-1.3 vs 4.4+/-1.0 mGy/MBq; P<0.05) and was further enhanced upon prolonging the infusion to 10 h (2.1+/-0.4 vs 1.7+/-0.2 mGy/MBq; P<0.05). Infusion of Lys-Arg but not of l-lysine was more effective in reducing renal uptake than mixed AA. Infusion of AA did not result in reduced tumour uptake. The amount of (90)Y-SMT487 (maximum allowed dose: MAD) that would result in a 23-Gy cut-off dose to kidneys was calculated for each study: MAD was higher with mixed AA co-infusion by a mean of 46% (10-114%, P<0.05 vs no infusion). In comparison with 4 h mixed AA, the MAD was higher by a mean of 23% (9-37%; P<0.05) with prolonged infusion and by a mean of 16% (2-28%; P<0.05) with Lys-Arg. We conclude that infusion of large amounts of AA reduces renal exposure during peptide-based radiotherapy and allows higher absorbed doses to tumours. The prolongation of the infusion from 4 to 10 h further enhances the protective effect on the kidneys.