Biokinetics and dosimetry in patients administered with 111In-DOTA-Tyr3-octreotide: implications for internal radiotherapy with 90Y-DOTATOC

Recent advances in receptor-mediated tumour imaging have resulted in the development of a new somatostatin analogue, DOTA-dPhe¹-Tyr³-octreotide. This new compound, named DOTATOC, has shown high affinity for somatostatin receptors, ease of labelling and stability with yttrium-90 and favourable biodistribution in animal models. The aim of this work was to evaluate the biodistribution and dosimetry of DOTATOC radiolabelled with indium-111, in anticipation of therapy trials with ⁹⁰Y-DOTATOC in patients. Eighteen patients were injected with DOTATOC (10 μg), labelled with 150–185 MBq of ¹¹¹In. Blood and urine samples were collected throughout the duration of the study (0–2 days). Planar and single-photon emission tomography images were acquired at 0.5, 3–4, 24 and 48 h and time-activity curves were obtained for organs and tumours. A compartmental model was used to determine the kinetic parameters for each organ. Dose calculations were performed according to the MIRD formalism. Specific activities of >37 GBq/ μmol were routinely achieved. Patients showed no acute or delayed adverse reactions. The residence time for ¹¹¹In-DOTATOC in blood was 0.9±0.4 h. The injected activity excreted in the urine in the first 24 h was 73%±11%. The agent localized primarily in spleen, kidneys and liver. The residence times in source organs were: 2.2±1.8 h in spleen, 1.7±1.2 h in kidneys, 2.4±1.9 h in liver, 1.5±0.3 h in urinary bladder and 9.4±5.5 h in the remainder of the body; the mean residence time in tumour was 0.47 h (range: 0.03–6.50 h). Based on our findings, the predicted absorbed doses for ⁹⁰Y-DOTATOC would be 7.6±6.3 (spleen), 3.3±2.2 (kidneys), 0.7±0.6 (liver), 2.2±0.3 (bladder), 0.03±0.01 (red marrow) and 10.1 (range: 1.4–31.0) (tumour) mGy/MBq. These results indicate that high activities of ⁹⁰Y-DOTATOC can be administered with low risk of myelotoxicity, although with potentially high radiation doses to the spleen and kidneys. Tumour doses were high enough in most cases to make it likely that the disired therapeutic response desired would be obtained. Received 17 February and in revised form 22 April 1999     

Preliminary data on biodistribution and dosimetry for therapy planning of somatostatin receptor positive tumours: comparison of (86)Y-DOTATOC and (111)In-DTPA-octreotide.

The somatostatin analogue (90)Y-DOTATOC (yttrium-90 DOTA- D-Phe(1)-Tyr(3)-octreotide) is used for treatment of patients with neuroendocrine tumours. Accurate pretherapeutic dosimetry would allow for individual planning of the optimal therapeutic strategy. In this study, the biodistribution and resulting dosimetric calculation for therapeutic exposure of critical organs and tumour masses based on the positron emission tomography (PET) tracer (86)Y-DOTATOC, which is chemically identical to the therapeutic agent, were compared with results based on the tracer commonly used for somatostatin receptor scintigraphy, (111)In-DTPA-octreotide (indium-111 DTPA- D-Phe(1)-octreotide, OctreoScan). Three patients with metastatic carcinoid tumours were investigated. Dynamic and static PET studies with 77-186 MBq (86)Y-DOTATOC were performed up to 48 h after injection. Serum and urinary activity were measured simultaneously. Within 1 week, but not sooner than 5 days, patients were re-investigated by conventional scintigraphy with (111)In-DTPA-octreotide (110-187 MBq) using an equivalent protocol. Based on the regional tissue uptake kinetics, residence times were calculated and doses for potential therapy with (90)Y-DOTATOC were estimated. Serum kinetics and urinary excretion of both tracers showed no relevant differences. Estimated liver doses were similar for both tracers. Dose estimation for organs with the highest level of radiation exposure, the kidneys and spleen, showed differences of 10.5%-20.1% depending on the tracer. The largest discrepancies in dose estimation, ranging from 23.1% to 85.9%, were found in tumour masses. Furthermore, there was a wide inter-subject variability in the organ kinetics. Residence times (tau(organs)) for (90)Y-DOTATOC therapy were: tau(liver) 1.59-2.79 h; tau(spleen) 0.07-1.68 h; and tau(kidneys) 0.55-2.46 h (based on (86)Y-DOTATOC). These data suggest that dosimetry based on (86)Y-DOTATOC and (111)In-DTPA-octreotide yields similar organ doses, whereas there are relevant differences in estimated tumour doses. Individual pretherapeutic dosimetry for (90)Y-DOTATOC therapy appears necessary considering the large differences in organ doses between individual patients. If possible, the dosimetry should be performed with the chemically identical tracer (86)Y-DOTATOC.     

Preliminary data on biodistribution and dosimetry for therapy planning of somatostatin receptor positive tumours: comparison of 86Y-DOTATOC and 111In-DTPA-octreotide

The somatostatin analogue ⁹⁰Y-DOTATOC (yttrium-90 DOTA-D-Phe¹-Tyr³-octreotide) is used for treatment of patients with neuroendocrine tumours. Accurate pretherapeutic dosimetry would allow for individual planning of the optimal therapeutic strategy. In this study, the biodistribution and resulting dosimetric calculation for therapeutic exposure of critical organs and tumour masses based on the positron emission tomography (PET) tracer ⁸⁶Y-DOTATOC, which is chemically identical to the therapeutic agent, were compared with results based on the tracer commonly used for somatostatin receptor scintigraphy, ¹¹¹In-DTPA-octreotide (indium-111 DTPA-D-Phe¹-octreotide, OctreoScan). Three patients with metastatic carcinoid tumours were investigated. Dynamic and static PET studies with 77-186 MBq ⁸⁶Y-DOTATOC were performed up to 48 h after injection. Serum and urinary activity were measured simultaneously. Within 1 week, but not sooner than 5 days, patients were re-investigated by conventional scintigraphy with ¹¹¹In-DTPA-octreotide (110-187 MBq) using an equivalent protocol. Based on the regional tissue uptake kinetics, residence times were calculated and doses for potential therapy with ⁹⁰Y-DOTATOC were estimated. Serum kinetics and urinary excretion of both tracers showed no relevant differences. Estimated liver doses were similar for both tracers. Dose estimation for organs with the highest level of radiation exposure, the kidneys and spleen, showed differences of 10.5%-20.1% depending on the tracer. The largest discrepancies in dose estimation, ranging from 23.1% to 85.9%, were found in tumour masses. Furthermore, there was a wide inter-subject variability in the organ kinetics. Residence times (F_organs) for ⁹⁰Y-DOTATOC therapy were: F_liver 1.59-2.79 h; F_spleen 0.07-1.68 h; and F_kidneys 0.55-2.46 h (based on ⁸⁶Y-DOTATOC). These data suggest that dosimetry based on ⁸⁶Y-DOTATOC and ¹¹¹In-DTPA-octreotide yields similar organ doses, whereas there are relevant differences in estimated tumour doses. Individual pretherapeutic dosimetry for ⁹⁰Y-DOTATOC therapy appears necessary considering the large differences in organ doses between individual patients. If possible, the dosimetry should be performed with the chemically identical tracer ⁸⁶Y-DOTATOC.     

Treatment with 177Lu-DOTATOC of patients with relapse of neuroendocrine tumors after treatment with 90Y-DOTATOC.

Therapy with [(90)Y-DOTA(0), Tyr(3)]-octreotide (DOTATOC, where DOTA = tetraazacyclododecane tetraacetic acid and TOC = D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr(ol)) is established for the treatment of metastatic neuroendocrine tumors. Nevertheless, many patients experience disease relapse, and further treatment may cause renal failure. Trials with (177)Lu-labeled somatostatin analogs showed less nephrotoxicity. We initiated a prospective study with (177)Lu-DOTATOC in patients with relapsed neuroendocrine tumors after (90)Y-DOTATOC treatment. METHODS: Twenty-seven patients, pretreated with (90)Y-DOTATOC, were included. The mean time between the last treatment with (90)Y-DOTATOC and (177)Lu-DOTATOC was 15.4 +/- 7.8 mo (SD). All patients were injected with 7,400 MBq of (177)Lu-DOTATOC. Restaging was performed after 8-12 wk. Hematotoxicity or renal toxicity of World Health Organization grade 1 or 2 was not an exclusion criterion. RESULTS: Creatinine levels increased significantly, from 66 +/- 14 micromol/L to 100 +/- 44 micromol/L (P < 0.0001), after (90)Y-DOTATOC therapy. The mean hemoglobin level dropped from 131 +/- 14 to 117 +/- 13 g/L (P < 0.0001) after (90)Y-DOTATOC therapy. (177)Lu-DOTATOC therapy was well tolerated. No serious adverse events occurred. The mean absorbed doses were 413 +/- 159 mGy for the whole body, 3.1 +/- 1.5 Gy for the kidneys, and 61 +/- 5 mGy for the red marrow. After restaging, we found a partial remission in 2 patients, a minor response in 5 patients, stable disease in 12 patients, and progressive disease in 8 patients. Mean hemoglobin and creatinine levels did not change significantly. CONCLUSION: (177)Lu-DOTATOC therapy in patients with relapse after (90)Y-DOTATOC treatment is feasible, safe, and efficacious. No serious adverse events occurred.     

Yttrium-90 DOTATOC: first clinical results.

In a pilot study, DOTA-d-Phe(1)-Tyr(3)-octreotide (DOTATOC), which can be labelled with the beta-emitting radioisotope yttrium-90, has recently been used for the treatment of patients with advanced somatostatin receptor-positive tumours who had no other treatment option. The aim of the present study was to elucidate the therapeutic potential of (90)Y-DOTATOC in a larger number of patients employing a standardized treatment protocol. Careful attention was paid to any side-effects (renal and/or haematological toxicity). Of 44 patients with advanced somatostatin receptor-positive tumours of different histology, 29 could be included in the study. The 15 patients who were excluded from the study protocol were assigned to our institution for purely compassionate reasons. The 29 patients who were included received four or more single doses of (90)Y-DOTATOC with ascending activity at intervals of approximately 6 weeks (cumulative dose 6120+/-1347 MBq/m(2)) with the aim of performing an intra-patient dose escalation study. In total, 127 single treatments were given. In eight of these 127 single treatments, total doses of > or = 3700 MBq were administered. In an effort to prevent renal toxicity, two patients received Hartmann-Hepa 8% solution during all therapy cycles, while 13 patients did so during some but not all therapy cycles; in 14 patients no solution was administered during the therapy cycles. The treatment was monitored by computed tomography and indium-111 DOTATOC scintigraphy. Blood parameters were controlled weekly, while tumour markers and liver enzymes were controlled 6-weekly. Of the 29 patients, 24 patients showed no severe renal or haematological toxicity (toxicity < or = grade 2 according to the National Cancer Institute grading criteria). These 24 patients received a cumulative dose of < or = 7400 MBq/m(2). Five patients developed renal and/or haematological toxicity. All of these five patients received a cumulative dose of >7400 MBq/m(2) and had received no Hartmann-Hepa 8% solution during the therapy cycles. Four of the five patients developed renal toxicity; two of these patients showed stable renal insufficiency and two require haemodialysis. Two of the five patients exhibited anaemia (both grade 3) and thrombopenia (grade 2 and 4, respectively). To date, 20 of the 29 patients have shown a disease stabilization, two a partial remission, four a reduction of tumour mass <50% and three a progression of tumour growth. (90)Y-DOTATOC could be a powerful and promising new therapeutic agent for anti-cancer treatment - at least in terms of an adjuvant starting point of the disease. However, problems with toxicity have to be solved. Evaluation of the effect of amino acid infusions (e.g. Hartmann-Hepa 8% solution) during (90)Y-DOTATOC treatments with the aim of reducing renal toxicity is ongoing.     

Receptor-mediated radiotherapy with Y-DOTA-DPhe-Tyr-octreotide: the experience of the European Institute of Oncology Group

High concentrations of subtype 2 somatostatin tumor receptors (sst(2)) are expressed in numerous tumors, enabling primary and metastatic masses to be localized by scintigraphy after injecting (111)In-labeled somatostatin analogue octreotide. In addition to neuroendocrine tumors, somatostatin receptors have been identified on cancers of the central nervous system, breast, lung, and lymphatic tissue, and the use of radionuclide-labeled somatostatin analogues appeared promising for therapy as well as for diagnosis of such malignancies. The somatostatin analogue [DOTA-(D)Phe(1)-Tyr(3)] octreotide (DOTATOC) possesses favorable characteristics for its potential therapeutic use in that it shows high affinity for sst(2), moderately high affinity for sst(5), and intermediate affinity for sst(3), high hydrophilicity, stable and facile labeling with (111)In and (90)Y. We began to investigate the potential therapeutic applications of (90)Y DOTATOC in 1997 by performing a thorough dosimetric study in 18 patients who were administered (111)In DOTATOC to estimate the absorbed doses during(90)Y-DOTATOC therapy. Then, we moved on and treated an overall number of 256 patients, mostly recruited in 2 distinct protocols with and without the administration of kidney protecting agents, with (90)Y DOTATOC. No major acute reactions were observed up to the activity of 5.55 GBq per cycle. The MTD per cycle was defined as 5.18 GBq. Objective therapeutic responses were documented in more than 20% of patients in terms of partial and complete responses. The present article reports in details our clinical experience (still ongoing) and outcomes with the use of (90)Y DOTATOC.     

Receptor-mediated radiotherapy with 90Y-DOTA-D-Phe1-Tyr3-octreotide

A newly developed somatostatin radioligand, DOTA-[D-Phe1-Tyr3]-octreotide (DOTATOC), has been synthesised for therapeutic purposes, because of its stable and easy labelling with yttrium-90. The aim of this study was to determine the dosage, safety profile and therapeutic efficacy of 90Y-DOTATOC in patients with cancers expressing somatostatin receptors. We recruited 30 patients with histologically confirmed cancer. The main inclusion criterion was the presence of somatostatin receptors as documented by 111In-DOTATOC scintigraphy. 90Y-DOTATOC was injected intravenously using a horizontal protocol: patients received equivalent-activity doses in each of three cycles over 6 months. The first six patients received 1.11 GBq per cycle and the four successive groups of six patients received doses increasing in 0.37-GBq steps. Toxicity was evaluated according to WHO criteria. No patient had acute or delayed adverse reactions up to 2.59 GBq 90Y-DOTATOC per cycle (total 7.77 GBq). After a total dose of 3.33 GBq, one patient developed grade II renal toxicity 6 months later. The maximum tolerated dose per cycle has not yet been reached, although transient lymphocytopenia has been observed. Total injectable activity is limited by the fact that the maximum dose tolerated by the kidneys has been estimated at 20-25 Gy. Complete or partial tumour mass reduction occurred in 23% of patients; 64% had stable and 13% progressive disease. It is concluded that high activities of 90Y-DOTATOC can be administered with a low risk of myelotoxicity, although the cumulative radiation dose to the kidneys is a limiting factor and requires careful evaluation. Objective therapeutic responses have been observed.     

End-stage renal disease after treatment with 90Y-DOTATOC.

DOTA-D-Phe1-Tyr3-octreotide (DOTATOC), a newly developed somatostatin analogue which can be stably labelled with the beta-emitter yttrium-90, can be used for receptor-mediated internal radiotherapy. A 78-year-old woman suffering from a carcinoid of the small intestine with multiple metastases in the liver as well as mesenteric and supraclavicular lymph node metastases was treated with this therapy after the disease had progressed under other chemotherapy options employed years previously. The patient received four single doses of 90Y-DOTATOC at 6-week intervals, yielding a cumulative dose of 9,620 MBq (5,659 MBq/m2). Restaging revealed stable metastatic disease. Serum creatinine and urea nitrogen levels were within the normal range prior to starting and during DOTATOC therapy. However, 15 months after cessation of DOTATOC therapy, a progressive deterioration of renal function occurred, leading to end-stage renal disease. Urinalysis revealed a slight proteinuria of 700 mg/day without haematuria, leucocyturia or casts. There was no obvious risk factor for chronic renal insufficiency except DOTATOC therapy. However, it was not feasible to use kidney biopsy to prove the presence of radiation-induced nephritis. Intermittent haemodialysis was started as the creatinine clearance declined to below 10 ml/min. Diuresis was not affected. The presented case shows delayed renal insufficiency after a relatively low cumulative dose of 90Y-DOTATOC (5,659 MBq/m2). This serious adverse event indicates that further studies are needed to evaluate which dose of 90Y-DOTATOC, under which renal protection regimen, will provide optimal management, balancing risks and benefits.     

Yttrium-90 DOTATOC: first clinical results

In a pilot study, DOTA-d-Phe¹-Tyr³-octreotide (DOTATOC), which can be labelled with the β-emitting radioisotope yttrium-90, has recently been used for the treatment of patients with advanced somatostatin receptor-positive tumours who had no other treatment option. The aim of the present study was to elucidate the therapeutic potential of ⁹⁰Y-DOTATOC in a larger number of patients employing a standardized treatment protocol. Careful attention was paid to any side-effects (renal and/or haematological toxicity). Of 44 patients with advanced somatostatin receptor-positive tumours of different histology, 29 could be included in the study. The 15 patients who were excluded from the study protocol were assigned to our institution for purely compassionate reasons. The 29 patients who were included received four or more single doses of ⁹⁰Y-DOTATOC with ascending activity at intervals of approximately 6 weeks (cumulative dose 6120±1347 MBq/m²) with the aim of performing an intra-patient dose escalation study. In total, 127 single treatments were given. In eight of these 127 single treatments, total doses of ≥3700 MBq were administered. In an effort to prevent renal toxicity, two patients received Hartmann-Hepa 8% solution during all therapy cycles, while 13 patients did so during some but not all therapy cycles; in 14 patients no solution was administered during the therapy cycles. The treatment was monitored by computed tomography and indium-111 DOTATOC scintigraphy. Blood parameters were controlled weekly, while tumour markers and liver enzymes were controlled 6-weekly. Of the 29 patients, 24 patients showed no severe renal or haematological toxicity (toxicity ≤ grade 2 according to the National Cancer Institute grading criteria). These 24 patients received a cumulative dose of ≤7400 MBq/m². Five patients developed renal and/or haematological toxicity. All of these five patients received a cumulative dose of >7400 MBq/m² and had received no Hartmann-Hepa 8% solution during the therapy cycles. Four of the five patients developed renal toxicity; two of these patients showed stable renal insufficiency and two require haemodialysis. Two of the five patients exhibited anaemia (both grade 3) and thrombopenia (grade 2 and 4, respectively). To date, 20 of the 29 patients have shown a disease stabilization, two a partial remission, four a reduction of tumour mass <50% and three a progression of tumour growth. ⁹⁰Y-DOTATOC could be a powerful and promising new therapeutic agent for anti-cancer treatment – at least in terms of an adjuvant starting point of the disease. However, problems with toxicity have to be solved. Evaluation of the effect of amino acid infusions (e.g. Hartmann-Hepa 8% solution) during ⁹⁰Y-DOTATOC treatments with the aim of reducing renal toxicity is ongoing. Received 12 February and in revised form 16 May 1999     

End-stage renal disease after treatment with 90Y-DOTATOC

DOTA-D-Phe¹-Tyr³-octreotide (DOTATOC), a newly developed somatostatin analogue which can be stably labelled with the #-emitter yttrium-90, can be used for receptor-mediated internal radiotherapy. A 78-year-old woman suffering from a carcinoid of the small intestine with multiple metastases in the liver as well as mesenteric and supraclavicular lymph node metastases was treated with this therapy after the disease had progressed under other chemotherapy options employed years previously. The patient received four single doses of ⁹⁰Y-DOTATOC at 6-week intervals, yielding a cumulative dose of 9,620 MBq (5,659 MBq/m²). Restaging revealed stable metastatic disease. Serum creatinine and urea nitrogen levels were within the normal range prior to starting and during DOTATOC therapy. However, 15 months after cessation of DOTATOC therapy, a progressive deterioration of renal function occurred, leading to end-stage renal disease. Urinalysis revealed a slight proteinuria of 700 mg/day without haematuria, leucocyturia or casts. There was no obvious risk factor for chronic renal insufficiency except DOTATOC therapy. However, it was not feasible to use kidney biopsy to prove the presence of radiation-induced nephritis. Intermittent haemodialysis was started as the creatinine clearance declined to below 10 ml/min. Diuresis was not affected. The presented case shows delayed renal insufficiency after a relatively low cumulative dose of ⁹⁰Y-DOTATOC (5,659 MBq/m²). This serious adverse event indicates that further studies are needed to evaluate which dose of ⁹⁰Y-DOTATOC, under which renal protection regimen, will provide optimal management, balancing risks and benefits.     

Radioimmunotherapy of non-Hodgkin's lymphoma with 90Y-DOTA humanized anti-CD22 IgG (90Y-Epratuzumab): do tumor targeting and dosimetry predict therapeutic response?

A DOTA (1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid)-conjugated, (111)In- and (90)Y-labeled humanized antibody to CD22, epratuzumab, was studied in patients with non-Hodgkin's lymphoma (NHL) to assess biodistribution and tumor targeting, pharmacokinetics, dosimetry, and anti-antibody response. Of particular interest was to evaluate whether pretherapy targeting and tumor dosimetry could predict therapeutic responses. METHODS: Patients received a pretherapy imaging study with (111)In-DOTA-epratuzumab IgG (0.75 mg/kg), followed about 1 wk later with (90)Y-DOTA-epratuzumab starting at a dose level of 0.185 GBq/m(2) (5 mCi/m(2)) in patients who had prior high-dose chemotherapy (group 2), and at 0.370 GBq/m(2) in patients who did not have a prior transplant (group 1), with escalation in 0.185-GBq/m(2) increments. RESULTS: The effective blood half-life for (111)In-DOTA epratuzumab was 36.1 +/- 7.9 h (n = 25) compared with 35.2 +/- 7.0 h for (90)Y-DOTA-epratuzumab (n = 22). The whole-body half-life for (90)Y-DOTA-epratuzumab estimated from (111)In-DOTA-epratuzumab scintigraphy was 58.3 +/- 4.7 h (n = 20), with urine collection confirming the loss of between 2.2% and 15.9% of the injected activity over 3 d (n = 3). One-hundred sixteen of 165 CT-confirmed lesions were visualized with (111)In-DOTA-epratuzumab. Radiation-absorbed doses to liver, lungs, and kidneys averaged 0.55 +/- 0.13 (n = 17), 0.28 +/- 0.06 (n = 17), and 0.38 +/- 0.07 mGy/MBq (n = 10), respectively, with 0.14 +/- 0.02 and 0.23 +/- 0.04 mGy/MBq delivered to the whole-body and red marrow, respectively. Tumor doses (n = 14 lesions in 10 patients) ranged from 1.0 to as much as 83 mGy/MBq for a 0.5-g lesion (median, 7.15 mGy/MBq). Group 2 patients were more likely to experience significant hematologic toxicities, but doses of up to 0.370 GBq/m(2) of (90)Y-DOTA-epratuzumab were tolerated with standard support measures, whereas patients in group 1 tolerated doses of up to 0.740 GBq/m(2) with the potential for further escalation. Anti-tumor effects were seen in both indolent and aggressive NHL. The data also suggest that anti-tumor responses of potentially equal magnitude can occur irrespective of tumor targeting and tumor size. Hence, tumor response did not correlate with the radiation dose delivered or with the tumor being visualized by external imaging. An anti-antibody response to epratuzumab was detected by an enzyme-linked immunosorbent assay in only 2 of 16 patients. CONCLUSION: These results suggest that (90)Y-DOTA-epratuzmab is a promising agent for the treatment of NHL and warrants further study. There was evidence suggesting that in this system, factors other than tumor radiation dose and targeting may be involved in the success of radioimmunotherapy.     

Dosimetry in radionuclide therapies with 90Y-conjugates: the IEO experience.

The basis for a successful radionuclide therapy is a high and stable uptake of the radiopharmaceutical in the target tissue along with low activity concentration in other normal organs. The contribution of dosimetry in radionuclide therapy is to predict before the treatment the absorbed doses in tumor and normal organs, to identify the critical organs, to minimize any possible toxicity and to evaluate the maximum tolerated dose. We report our experience concerning pharmacokinetics and dosimetry of two 90Y-therapeutic protocols: 3-step pretargeting radioimmunotherapy (RIT) according to the biotin-avidin system and receptor mediated radionuclide therapy with the somatostatin analogue [DOTA-D-Phe1-Tyr3] octreotide named DOTATOC. For the dosimetric analysis, analogous approaches for the two radiolabeled compounds due to the similar pharmacokinetic characteristics were adopted; the MIRD formalism was applied, taking into account both the physical and the biological characteristics of the radioconjugate and patients' metabolism. In order to determine biological clearance, serial blood samples and complete urine collection were obtained up to 48 hours after injection; to evaluate biodistribution, several whole body scans were acquired. Both therapies showed the advantageous characteristics of a fast blood clearance and a predominantly renal excretion of the radiopharmaceuticals thus lowering the irradiation of the total body. Although pharmacokinetic characteristis were similar, different critical organs were found for the two therapies; in particular, some considerations regarding red marrow, spleen and kidneys were required. The results of our studies indicate that high activities of 90Y-biotin (3-step RIT) and 90Y-DOTATOC can be administered with acceptable radiation doses to normal organs.     

Safety, biodistribution, and dosimetry of 99mTc-HYNIC-annexin V, a novel human recombinant annexin V for human application.

99mTc-hydrazinonicotinamido (HYNIC)-annexin V is a novel tracer for in vivo imaging of apoptosis. The present study on humans was performed to investigate the safety of (99m)Tc-HYNIC-annexin V and to quantify the biodistribution and radiation dose. METHODS: Six healthy, male volunteers participated in the study. A dual-head gamma camera was used to acquire conjugate anterior and posterior views. Imaging started with a transmission scan using a (57)Co-flood source to obtain a map of the local thickness of the volunteer. Approximately 250 MBq of (99m)Tc-HYNIC-annexin V were injected intravenously, directly followed by a 30-min dynamic study. Whole-body scans were obtained at about 30 min, 3 h, 6 h, and 24 h after injection. Organ uptake was determined after correction for background, scatter, and attenuation. The MIRDOSE3.1 program was used to calculate organ-absorbed doses and effective dose. Signs of adverse effects were investigated by monitoring renal and liver function, hematology, blood coagulation, and vital signs (blood pressure, pulse, respiration rate, temperature, and electrocardiogram). RESULTS: The kidneys accumulated 49.7 +/- 8.1 percentage injected dose (%ID) at 3 h after injection; the liver, 13.1 +/- 1.0 %ID; the red marrow, 9.2 +/- 1.8 %ID; and the spleen, 4.6 +/- 1.6 %ID. More than 90% of the blood activity was cleared with a half-life of 24 +/- 3 min. The biologic half-life of the activity registered over the total body was long (69 +/- 7 h). Excretion of the activity was almost exclusively through the urine (22.5 +/- 3.5 %ID at 24 h), and hardly any activity was seen in the bowel or feces. Absorbed doses were found to be 196 +/- 31 micro Gy/MBq for the kidneys, 41 +/- 12 micro Gy/MBq for the spleen, 16.9 +/- 1.3 micro Gy/MBq for the liver, and 8.4 +/- 0.9 micro Gy/MBq for the red marrow. The effective dose was 11.0 +/- 0.8 micro Sv/MBq, or 2.8 +/- 0.2 mSv for the average injected activity of 250 MBq. No adverse effects were observed. CONCLUSION: (99m)Tc-HYNIC-annexin V is a safe radiopharmaceutical, having a favorable biodistribution for imaging of apoptosis in the abdominal as well as thoracic area with an acceptable radiation dose.     

Radiation dosimetry of a 99mTc-labeled IgM murine antibody to CD15 antigens on human granulocytes.

99mTc-labeled anti-stage specific embryonic antigen-1 (anti-SSEA-1) is an injectable IgM antibody derived from mice. It binds to CD15 antigens on some granulocytic subpopulations of human white blood cells in vivo after systemic administration. The purpose of this study was to measure biodistribution of 99mTc-labeled anti-SSEA-1 and perform radiation dosimetry in 10 healthy human volunteers. METHODS: Transmission scans and whole-body images were acquired sequentially on a dual-head camera for 32 h after the intravenous administration of about 370 MBq (10.0 mCi) of the radiopharmaceutical. Renal excretion fractions were measured from 10 to 14 discrete urine specimens voided over 27.9 +/- 2.0 h. Multiexponential functions were fit iteratively to the time-activity curves for 17 regions of interest using a nonlinear least squares regression algorithm. The curves were integrated numerically to yield source organ residence times. Gender-specific radiation doses were then estimated individually for each subject, using the MIRD technique, before any results were averaged. RESULTS: Quantification showed that the kidneys excreted 39.5% +/- 6.5% of the administered dose during the first 24 h after administration. Image analysis showed that 10%-14% of the radioactivity went to the spleen, while more than 40% went to the liver. Residence times were longest in the liver (3.37 h), followed by the bone marrow (1.09 h), kidneys (0.84 h) and the spleen (0.65 h). The dose-limiting organ in both men and women was the spleen, which received an average of 0.062 mGy/MBq (0.23 rad/mCi, range 0.08-0.30 rad/mCi), followed by the kidneys (0.051 mGy/MBq), liver (0.048 mGy/MBq) and urinary bladder (0.032 mGy/MBq). The effective dose equivalent was 0.018 mSv/MBq (0.068 rem/mCi). CONCLUSION: The findings suggest that the radiation dosimetry profile for this new infection imaging agent is highly favorable.     

Anti-CD45 monoclonal antibody YAML568: A promising radioimmunoconjugate for targeted therapy of acute leukemia.

The outcome of hematopoietic cell transplantation for hematologic malignancies may be improved by delivering targeted radiation to hematopoietic organs while relatively sparing nontarget organs. We evaluated the biodistribution of 111In-labeled anti-CD45 antibody in humans using the rat IgG2a monoclonal antibody YAML568 that recognizes a common CD45 epitope present on all human leukocytes. METHODS: Eight patients undergoing bone marrow transplantation received YAML568 labeled with 122 +/- 16 MBq of 111In intravenously followed by serial blood sampling, urine collection, and conjugated view planar gamma-camera imaging up to 144 h after injection. Time-activity curves were obtained using region-of-interest analysis in the accumulating organs and residence times were calculated. An estimate for the radiation-absorbed doses for each organ per unit of administered activity of 90Y was calculated using software for internal dose assessment. The first patient received no unlabeled antibody preloading. The second 2 patients received a preloading dose of 10 mg (0.15 mg/kg). The last 5 patients received a preloading dose of 30-47 mg (0.5 mg/kg). RESULTS: No significant administration-related side effects were seen. The 3 patients receiving no antibody or low antibody preloading had an unfavorable biodistribution with a high initial accumulation of activity in the liver (37%) and the spleen (34%). For the patients receiving 0.5-mg/kg antibody preloading, the estimated radiation-absorbed doses for red bone marrow, spleen, liver, kidney, and total body were 6.4 +/- 1.2, 19 +/- 5, 3.9 +/- 1.4, 1.1 +/- 0.4, and 0.6 +/- 0.1 mGy/MBq, respectively, demonstrating preferential red marrow targeting. A linear regression model showed that the amount of unlabeled antibody preloading per body weight has a strong influence on the estimated red marrow absorbed dose (P = 0.003, R2 = 0.80). CONCLUSION: This study shows that the anti-CD45 monoclonal antibody YAML568 is suitable for delivering selectively radiation to hematopoietic tissues when labeled with 90Y provided that a preloading dose of about 0.5 mg/kg unlabeled antibody is given.     

Dosimetric model for locoregional treatments of brain tumors with 90Y-conjugates: clinical application with 90Y-DOTATOC.

Locoregional (LR) administration of (90)Y-conjugates after surgical debulking is a promising therapeutic option of gliomas. Dosimetry is highly recommended, as patient-specific parameters influence the absorbed dose to target and normal tissues. After tumor resection, the absorbed dose must be carefully evaluated in the rim of tissue surrounding the resected area. The aim of this study was to calculate and provide the S values, according to the MIRD concept, for dosimetry of LR brain treatments with several (90)Y-labeled compounds. The S values thus obtained have been clinically applied in 12 patients treated with (90)Y-labeled [DOTA(0),D-Phe(1),Tyr(3)]octreotide ((90)Y-DOTATOC). METHODS: An anthropomorphic model for Monte Carlo simulations was developed to evaluate absorbed doses in brain-adjacent tissue (BAT) and in normal brain. To adapt the model to single patients, S values were evaluated taking into account (i) different surgical resection cavity (SRC) volumes, (ii) different percentages of conjugate binding to the cavity wall, and (iii) different depths of percolation of the conjugate trough the cavity wall. BAT was divided into 1-mm-thick consecutive adjacent shells to evaluate the dose distribution around the cavity. Corresponding S values were obtained to allow dosimetric evaluation in brain LR therapy with (90)Y-conjugates. In the clinical treatments, 0.4-1.1 GBq of (90)Y-DOTATOC were injected into the SRC via an appropriate catheter. The activity in the SRC was assumed to be the difference between the total injected activity and the activity in the blood plus the activity cumulatively eliminated with the urine. RESULTS: Assuming no diffusion, with a mean residence time in SRC of 60 +/- 8 h, absorbed doses to shell II were 0.25 and 0.03 Gy/MBq for SRC volumes of 7.2 and 65.4 mL, respectively. Assuming a slight diffusion of 1 mm with a 7.2-mL SRC, absorbed dose to shells I, II, and VI were consistently different: 5.32, 2.53, and 0.12 Gy/MBq, respectively. Mean doses to normal brain, red marrow, bladder wall, and total body were 0.015, 0.03, 1.22, and 0.006 MGy/MBq. CONCLUSION: The model proved to be suitable for the dosimetry of several LR therapies with (90)Y-conjugates. According to our results, LR treatment with (90)Y-DOTATOC can safely deliver very high doses to target tissue, sparing normal organs including brain.     

A comparison of <Superscript>111</Superscript>In-DOTATOC and <Superscript>111</Superscript>In-DOTATATE: biodistribution and dosimetry in the same patients with metastatic neuroendocrine tumours

[Yttrium-90-DOTA-Tyr³]-octreotide (DOTATOC) and [¹⁷⁷Lu-DOTA-Tyr³-Thr⁸]-octreotide (DOTATATE) are used for peptide receptor-mediated radionuclide therapy (PRMRT) in neuroendocrine tumours. No human data comparing these two compounds are available so far. We used ¹¹¹In as a surrogate for ⁹⁰Y and ¹⁷⁷Lu and examined whether one of the ¹¹¹In-labelled peptides had a more favourable biodistribution in patients with neuroendocrine tumours. Special emphasis was given to kidney uptake and tumour-to-kidney ratio since kidney toxicity is usually the dose-limiting factor. Five patients with metastatic neuroendocrine tumours were injected with 222 MBq ¹¹¹In-DOTATOC and ¹¹¹In-DOTATATE within 2 weeks. Up to 48 h after injection, whole-body scans were performed and blood and urine samples were collected. The mean absorbed dose was calculated for tumours, kidney, liver, spleen and bone marrow. In all cases ¹¹¹In-DOTATATE showed a higher uptake (%IA) in kidney and liver. The amount of ¹¹¹In-DOTATOC excreted into the urine was significantly higher than for ¹¹¹In-DOTATATE. The mean absorbed dose to the red marrow was nearly identical. ¹¹¹In-DOTATOC showed a higher tumour-to-kidney absorbed dose ratio in seven of nine evaluated tumours. The variability of the tumour-to-kidney ratio was high and the significance level in favour of ¹¹¹In-DOTATOC was P=0.065. In five patients the pharmacokinetics of ¹¹¹In-DOTATOC and ¹¹¹In-DOTATATE was found to be comparable. The two peptides appear to be nearly equivalent for PRMRT in neuroendocrine tumours, with minor advantages for ¹¹¹In/⁹⁰Y-DOTATOC; on this basis, we shall continue to use ⁹⁰Y-DOTATOC for PRMRT in patients with metastatic neuroendocrine tumours.     

Pharmacokinetics and Biodistribution of (86)Y-Trastuzumab for (90)Y dosimetry in an ovarian carcinoma model: correlative MicroPET and MRI.

Preclinical biodistribution and pharmacokinetics of investigational radiopharmaceuticals are typically obtained by longitudinal animal studies. These have required the sacrifice of multiple animals at each time point. Advances in small-animal imaging have made it possible to evaluate the biodistribution of radiopharmaceuticals across time in individual animals, in vivo. MicroPET and MRI-based preclinical biodistribution and localization data were obtained and used to assess the therapeutic potential of (90)Y-trastuzumab monoclonal antibody (mAb) (anti-HER2/neu) against ovarian carcinoma. METHODS: Female nude mice were inoculated intraperitoneally with 5.10(6) ovarian carcinoma cells (SKOV3). Fourteen days after inoculation, 12-18 MBq (86)Y-labeled trastuzumab mAb was injected intraperitoneally. Tumor-free mice, injected with (86)Y-trastuzumab, and tumor-bearing mice injected with labeled, irrelevant mAb or (86)Y-trastuzumab + 100-fold excess unlabeled trastuzumab were used as controls. Eight microPET studies per animal were collected over 72 h. Standard and background images were collected for calibration. MicroPET images were registered with MR images acquired on a 1.5-T whole-body MR scanner. For selected time points, 4.7-T small-animal MR images were also obtained. Images were analyzed and registered using software developed in-house. At completion of imaging, suspected tumor lesions were dissected for histopathologic confirmation. Blood, excised normal organs, and tumor nodules were measured by gamma-counting. Tissue uptake was expressed relative to the blood concentration (percentage of injected activity per gram of tissue [%IA/g]/%IA/g blood). (86)Y-Trastuzumab pharmacokinetics were used to perform (90)Y-trastuzumab dosimetry. RESULTS: Intraperitoneal injection of mAb led to rapid blood-pool uptake (5-9 h) followed by tumor localization (26-32 h), as confirmed by registered MR images. Tumor uptake was greatest for (86)Y-trastuzumab (7 +/- 1); excess unlabeled trastuzumab yielded a 70% reduction. Tumor uptake for the irrelevant mAb was 0.4 +/- 0.1. The concentration in normal organs relative to blood ranged from 0 to 1.4 across all studies, with maximum uptake in spleen. The absorbed dose to the kidneys was 0.31 Gy/MBq (90)Y-trastuzumab. The liver received 0.48 Gy/MBq, and the spleen received 0.56 Gy/MBq. Absorbed dose to tumors varied from 0.10 Gy/MBq for radius = 0.1 mm to 3.7 Gy/MBq for radius = 5 mm. CONCLUSION: For all injected compounds, the relative microPET image intensity of the tumor matched the subsequently determined (86)Y uptake. Coregistration with MR images confirmed the position of (86)Y uptake relative to various organs. Radiolabeled trastuzumab mAb was shown to localize to sites of disease with minimal normal organ uptake. Dosimetry calculations showed a strong dependence on tumor size. These results demonstrate the usefulness of combined microPET and MRI for the evaluation of novel therapeutics.     

Therapy using labelled somatostatin analogues: comparison of the absorbed doses with 111In-DTPA-D-Phe1-octreotide and yttrium-labelled DOTA-D-Phe1-Tyr3-octreotide

OBJECTIVE: We estimated the absorbed doses for (111)In-DTPA-D-Phe(1)-octreotide and (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide in the same patients in order to compare the potential effectiveness (tumour dose) and safety (kidney and red marrow dose) of these drugs for peptide-targeted radiotherapy of somatostatin receptor positive tumours. METHODS: Six patients with neuroendocrine tumours underwent quantitative (111)In-DTPA-D-Phe(1)-octreotide SPECT and (86)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide PET scan at intervals of 1 week. All studies were performed with a co-infusion of amino acids for renal protection. PET and SPECT were reconstructed using iterative algorithms, incorporating attenuation and scatter corrections. Tissue uptakes (IA%) were measured and used to calculate residence times. Absorbed doses to tissues were estimated and the maximal allowed activity, defined as either the activity delivering 23 Gy to the kidneys (MAA(K)) or 2 Gy to the red marrow (MAA(RM)), was calculated and the resulting tumour absorbed doses were computed. RESULTS: For the MAA(K) the mean absorbed dose to the red marrow was lower for (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide than for (111)In-DTPA-D-Phe(1)-octreotide (1.8+/-0.9 Gy vs. 6.4+/-1.6 Gy; P<0.001). The median absorbed dose to tumours for the MAA(K) was two-fold higher for (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide as compared to (111)In-DTPA-D-Phe(1)-octreotide (30.1 vs. 12.6 Gy; P<0.05). The median absorbed dose to tumours estimated for the MAA(RM) was 10-fold higher for (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide than for (111)In-DTPA-D-Phe(1)-octreotide (35.1 Gy vs. 3.9 Gy; P<0.05). CONCLUSIONS: This direct intra-patient comparison confirms that the use of (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide is more appropriate for therapy of somatostatin receptor bearing tumours. When using (111)In-DTPA-D-Phe(1)-octreotide, the red marrow represents the major critical organ; this can result in significant toxicity if high activities have to be administered to obtain efficient tumour irradiation.     

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.