DOTA-D-Phe(1)-Tyr(3)-octreotide Research Articles

Evaluation of the Possible Utilization of 68Ga-DOTATOC in Diagnosis of Adenocarcinoma Breast Cancer.

Objective(s):Studies have indicated advantageous properties of [DOTA-DPhe1, Tyr3] octreotide (DOTATOC) in tumor models and labeling with gallium. Breast cancer is the second leading cause of cancer mortality in women, and most of these cancers are often an adenocarcinoma. Due to the importance of target to non-target ratios in the efficacy of diagnosis, the pharmacokinetic of 68Ga-DOTATOC in an adenocarcinoma breast cancer animal model was studied in this research, and the optimized time for imaging was determined.Methods:68Ga was obtained from 68Ge/68Ga generator. The complex was prepared at optimized conditions. Radiochemical purity of the complex was checked using both HPLC and ITLC methods. Biodistribution of the complex was studied in BALB/c mice bearing adenocarcinoma breast cancer. Also, PET/CT imaging was performed up to 120 min post injection.Results:The complex was produced with radiochemical purity of greater than 98% and specific activity of about 40 GBq/mM at optimized conditions. Biodistribution of the complex was studied in BALB/c mice bearing adenocarcinoma breast cancer indicated fast blood clearance and significant uptake in the tumor. Significant tumor: blood and tumor:muscle uptake ratios were observed even at early times post-injection. PET/CT images were also confirmed the considerable accumulation of the tracer in the tumor.Conclusion:Generally, the results proved the possible application of the radiolabelled complex for the detection of the adenocarcinoma breast cancer and according to the pharmacokenitic data, the suitable time for imaging was determined as at least 30 min after injection.

Impairment of lymphocyte function following yttrium-90 DOTATOC therapy.

The radiolabeled somatostatin analogue, yttrium-90 DOTA-D-Phe(1)-Tyr(3)-octreotide (DOTATOC), is currently applied to treat advanced somatostatin receptor-positive tumors, e.g., neuroendocrine tumors of the pancreas, lung or gut. However, effects of this treatment on antimicrobial immune responses are not yet defined. In 20 patients treated with DOTATOC, cellular in vitro immune function was determined. Their antimicrobial lymphocyte responses were assessed by lymphocyte transformation test and enzyme-linked immunospot-measuring lymphocyte proliferation and on a single cell level production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10)-prior to therapy, at day 1, day 7 and day 90 post-therapy. Proliferative lymphocyte responses and interferon-γ production after in vitro stimulation with microbial antigens were non-significantly suppressed at day 1 and significantly (p<0.05) at day 7 versus pre-therapy. In vitro immune responses did not fully recover until day 90. In contrast, at day 1 interleukin-10 production was significantly (p<0.05) increased. Taken together, we observed a decrease in pro-inflammatory immune responses after DOTATOC therapy. Patients with versus without bone metastases displayed significantly (p<0.05) lower cellular immune responses toward several microbial antigens. Progressive disease and higher tumor burden could also be defined as factors associated with impaired immune function. Spearman correlation analysis indicated that cellular in vitro immunity was positively correlated with kidney function; better kidney function led to stronger immune responses. In conclusion, DOTATOC therapy caused a decrease in in vitro immune responses against microorganisms. The clinical impact needs to be evaluated in further studies.

Somatostatin receptor expression in Merkel cell carcinoma as target for molecular imaging.

BackgroundMerkel cell carcinoma (MCC) is a rare cutaneous neoplasm with increasing incidence, aggressive behavior and poor prognosis. Somatostatin receptors (SSTR) are expressed in MCC and represent a potential target for both imaging and treatment.MethodsTo non-invasively assess SSTR expression in MCC using PET and the radiotracers [68Ga]DOTA-D-Phe1-Tyr3-octreotide (DOTATOC) or -octreotate (DOTATATE) as surrogate for tumor burden. In 24 patients with histologically proven MCC SSTR-PET was performed and compared to results of computed tomography (CT).ResultsSSTR-PET detected primary and metastatic MCC lesions. On a patient-based analysis, sensitivity of SSTR-PET was 73% for nodal metastases, 100% for bone, and 67% for soft-tissue metastases, respectively. Notably, brain metastases were initially detected by SSTR-PET in 2 patients, whereas liver and lung metastases were diagnosed exclusively by CT. SSTR-PET showed concordance to CT results in 20 out of 24 patients. Four patients (17%) were up-staged due to SSTR-PET and patient management was changed in 3 patients (13%).ConclusionSSTR-PET showed high sensitivity for imaging bone, soft tissue and brain metastases, and particularly in combination with CT had a significant impact on clinical stage and patient management.

Radiolabeling of DOTATOC with the long-lived positron emitter 44Sc

The positron-emitting radionuclide 44Sc with a half-life of 3.97h and a β+ branching of 94.3% is of potential interest for clinical PET. As so far it is available from a 44Ti/44Sc generator in Mainz, where long-lived 44Ti decays to no-carrier-added (nca) 44Sc. The 44Sc is a trivalent metal cation and should be suitable for complexation with many well established bifunctional chelators conjugated to peptides or other molecular targeting vectors. Thus, the aim of this work was to investigate the potential of 44Sc for labeling of DOTA-conjugated peptides. DOTA-D-Phe1-Tyr3-octreotide (DOTATOC) was used as a model molecule to study and optimize labeling procedure. Reaction parameters such as buffer conditions, concentration of peptide, pH range, reaction temperature and time were optimized. Addition of 21nmol of DOTATOC to 44Sc in ammonium acetate buffer pH 4.0 provided labeling yields >98% within 25min of heating in an oil-bath at 95°C. This time can be reduced to 3min only by applying microwave supported heating. 44Sc-DOTATOC was found to be stable in 0.9% NaCl, PBS pH 7.4, fetal calf and human serums, and also in the presence of competing metal cations (Fe3+, Ca2+, Cu2+, Mg2+), as well as other ligand competitors, like EDTA and DTPA, even after almost 25h incubation at 37°C. Present study shows that nca 44Sc forms stable complexes with the macrocyclic ligand DOTA and that 44Sc-DOTATOC and analog targeting vectors may be synthesized for further preclinical and clinical investigations.

Association of Somatostatin Receptor 2 Immunohistochemical Expression with [111In]-DTPA Octreotide Scintigraphy and [68Ga]-DOTATOC PET/CT in Neuroendocrine Tumors

In the absence of preoperative somatostatin receptor ( SST) scans, knowledge of immunohistochemical SST2 tumor expression may help predicting the success of somatostatin analogue-based follow-up studies and treatment of neuroendocrine tumors (NET). We studied the association between SST immunostaining and tracer uptake in [(111)In]-DTPA octreotide (DTPAOC) scintigraphy and [(68)Ga]-DOTA-D-Phe(1)-Tyr(3)-octreotide (DOTATOC) positron emission tomography (PET)/computed tomography (CT). Retrospective analy-sis of 36 NET patients was carried out. In 40 tumors, immunohistochemical SST2, SST3, and SST5 expressions were analyzed using a pathological scoring, applying monoclonal ( SST2) or polyclonal antibodies (SST3, SST5). In 14 lesions, [(111)In]-DTPAOC uptake was assessed by a semiquantitative score. In 26 tumors, [(68)Ga]-DOTATOC PET/CT was quantified using an uptake score and maximal standard uptake value (SUV(max)). Combined and separate qualitative analysis of SST scans revealed significant associations between increased tracer uptake and immunohistochemical SST2 detection (combined: rho=0.56, p=0.0002, [(111)In]-DTPAOC: rho=0.63, p=0.0152, and [(68)Ga]-DOTATOC: rho=0.52, p=0.0065, respectively). In contrast, SST3 and SST5 immunostaining was not associated with tracer uptake (all p>0.14). The semiquantitative immunohistochemical score for SST2 was associated with the [(68)Ga]-DOTATOC uptake score and SUV (max) values (rho=0.67, p=0.0002 and rho=0.63, p=0.0010, respectively), but not with the [(111)In]-DTPAOC uptake score (rho=0.24, p=0.4). In patients without preoperative SST scans, knowledge of immunohistochemical SST2 expression may help estimating the value of SST imaging in the clinical follow-up, in particular in those lesions with positive SST2 immunostaining. Negativity for SST2, however, does not rule out tracer uptake in some patients, with heterogeneous SST2 expression within the tumor as a potential explanation.

68Ga]-DOTATOC-PET/CT for meningioma IMRT treatment planning

PurposeThe observation that human meningioma cells strongly express somatostatin receptor (SSTR 2) was the rationale to analyze retrospectively in how far DOTATOC PET/CT is helpful to improve target volume delineation for intensity modulated radiotherapy (IMRT).Patients and MethodsIn 26 consecutive patients with preferentially skull base meningioma, diagnostic magnetic resonance imaging (MRI) and planning-computed tomography (CT) was complemented with data from [68Ga]-DOTA-D Phe1-Tyr3-Octreotide (DOTATOC)-PET/CT. Image fusion of PET/CT, diagnostic computed tomography, MRI and radiotherapy planning CT as well as target volume delineation was performed with OTP-Masterplan®. Initial gross tumor volume (GTV) definition was based on MRI data only and was secondarily complemented with DOTATOC-PET information. Irradiation was performed as EUD based IMRT, using the Hyperion Software package.ResultsThe integration of the DOTATOC data led to additional information concerning tumor extension in 17 of 26 patients (65%). There were major changes of the clinical target volume (CTV) which modify the PTV in 14 patients, minor changes were realized in 3 patients. Overall the GTV-MRI/CT was larger than the GTV-PET in 10 patients (38%), smaller in 13 patients (50%) and almost the same in 3 patients (12%). Most of the adaptations were performed in close vicinity to bony skull base structures or after complex surgery. Median GTV based on MRI was 18.1 cc, based on PET 25.3 cc and subsequently the CTV was 37.4 cc. Radiation planning and treatment of the DOTATOC-adapted volumes was feasible.ConclusionDOTATOC-PET/CT information may strongly complement patho-anatomical data from MRI and CT in cases with complex meningioma and is thus helpful for improved target volume delineation especially for skull base manifestations and recurrent disease after surgery.

Staged surgery with neoadjuvant 90Y-DOTATOC therapy for down-sizing synchronous bilobular hepatic metastases from a neuroendocrine pancreatic tumor

Treatment with DOTA-d-Phe(1)-Tyr(3)-octreotide (DOTATOC), labeled with beta-emitting radioisotope yttrium-90 ((90)Y-DOTATOC), has successfully been used for the palliative treatment of patients with advanced somatostatin receptor-expressing neuroendocrine tumors (NETs). However, controversy persists as to whether patients with metastatic NETs of the pancreas should undergo radical (salvage) surgery or receive palliative therapy. We proposed that (90)Y-DOTATOC could be used in a neoadjuvant intention for improving therapy of hepatic NET metastases. We investigated a novel therapy concept in a 49-year-old patient presenting with a neuroendocrine tumor of the pancreatic tail and synchronous multiple bilobular hepatic metastases. After surgical removal of the large primary tumor by extended left en bloc resection of the pancreatic tail, the patient received neoadjuvant (90)Y-DOTATOC for therapy of primarily non-resectable bilobular hepatic metastases. The (90)Y-DOTATOC therapy resulted in an impressive regression of hepatic lesions, thus facilitating surgical removal of all remaining liver metastases in a second operation (staged surgery). In addition, one lesion was ablated using radiofrequency ablation (RFA). At 1-year of follow-up after hepatic R0 resection/RFA, there was no evidence of tumor recurrence or extrahepatic metastasis. The neoadjuvant use of (90)Y-DOTATOC therapy could prove valuable for treatment of advanced pancreatic NETs metastatic to the liver in terms of facilitating R0 resection by applying staged surgery concepts.

Evaluation of Positron Emission Tomography Imaging Using [ 68Ga]-DOTA-D Phe 1-Tyr 3-Octreotide in Comparison to [ 111In]-DTPAOC SPECT. First Results in Patients with Neuroendocrine Tumors

PURPOSE: [ 111In]-DTPAOC (Octreoscan®) has been shown to be very useful in the detection of somatostatin receptor (SSTR) positive tumors and their metastases using either conventional scintigraphy or single photon emission computed tomography (SPECT). The main drawback of this method is the limited spatial resolution and a somewhat low receptor affinity of the radiopeptide. Due to the increased spatial resolution and the ability of quantification, an agent for positron emission tomography (PET) imaging of SSTR is desirable. This communication shows our initial experience using [ 68Ga]-DOTA-D-Phe 1-Tyr 3-Octreotide (DOTATOC) in comparison to [ 111In]-DTPAOC-SPECT in patients with neuroendocrine tumors. PROCEDURES: Four patients, two male and two female (46–55 years old) have been examined by [ 111In]-DTPAOC scintigraphy and within one month by [ 68Ga]-DOTATOC-PET. All of them suffered from neuroendocrine tumors and/or their metastases. DOTATOC has been labeled using the positron-emitting generator-nuclide 68Ga (t 1/2 68 minutes). In two patients with previously known localization of tumor, dynamic PET scans after intravenous bolus-injection of 181±17 MBq [ 68Ga]-DOTATOC until 120 minutes post-injection were acquired. In all patients, the static PET-scans have been acquired after 45 or 60 minutes post-injection (SUV1) and 140 minutes post-injection (SUV2). RESULTS: Similar to [ 111In]-DTPAOC, [ 68Ga]-DOTATOC showed the highest uptake in the spleen, followed by the kidneys and the liver. A clear delineation of the pituitary gland could only be achieved by PET. The highest SUVs were found at a plateau between 45 and 90 minutes with a maximum 60 minutes post-injection. Due to the fast tracer accumulation in the tumor and the rapid clearance of the compound, resulting in high tumor to background ratios even 40 minutes after injection, the short half life of 68Ga is reasonable. In two patients more findings have been revealed by [ 68Ga]-DOTATOC-PET as compared to the [ 111In]-DTPAOC-SPECT. In comparison to the [ 111In]-DTPAOC-SPECT [ 68Ga]-DOTATOC-PET seems to be superior especially concerning small findings with low tracer uptake. Both [ 111In]-DTPAOC-SPECT and [ 68Ga]-DOTATOC-PET were less sensitive in the detection of liver metastases of neuroendocrine tumors compared to computerized tomography CT because they showed a lower uptake than the surrounding liver tissue. CONCLUSIONS: According to our initial experiences in a limited number of patients, [ 68Ga]-DOTATOC is a promising PET tracer for imaging neuroendocrine tumors and their metastases. In comparison to the [ 111In]-DTPAOC-scan it seems to be superior especially in detecting small tumors or tumors bearing only a low density of SSTRs. It offers excellent imaging properties and very high tumor to background ratios. Further evaluation of [ 68Ga]-DOTATOC in a larger number of patients is certainly justified.

Ga-66 labeled somatostatin analogue DOTA-DPhe1-Tyr3-octreotide as a potential agent for positron emission tomography imaging and receptor mediated internal radiotherapy of somatostatin receptor positive tumors

Radionuclide labeled somatostatin analogues selectively target somatostatin receptor (SSTR)-expressing tumors as a basis for diagnosis and treatment of these tumors. Recently, a DOTA-functionalized somatostatin analogue, DOTATOC (DOTA-DPhe1-Tyr3-octreotide) has been developed. This compound has been shown to be superior to the other somatostatin analogues as indicated by its uniquely high tumor-to-non-target tissue ratio. DOTATOC can be labeled with a variety of radiometals including gallium radioisotopes. Gallium-66 is a positron emitting radionuclide (T1/2 =9.5 hr; β+=56%), that can be produced in carrier free form by a low-beam energy cyclotron. In this study we investigated SSTR targeting characteristics of 66Ga-DOTATOC in AR42J rat pancreas tumor implanted nude mice as a potential agent for diagnosis and receptor-mediated internal radiotherapy of SSTR-expressing tumors. We compared our results with 67Ga- and 68Ga- labeled DOTATOC. The radiolabeling procedure gave labeling yield ranged from 85–95% and radiochemical and chemical purity was > 95%. In-vitro competitive binding curves and in-vivo competitive displacement studies with an excess of unlabeled peptide indicates that there is specific binding of the radioligand to SSTR. Animal biodistribution data and serial microPET™ images demonstrated rapid tumor uptake and rapid clearance from the blood and all tissues except kidney. Maximum % ID/g values for tumor were 10.0 ± 0.7, 13.2 ± 2.1 and 9.8 ± 1.5 for 66Ga-, 67Ga-, and 68Ga-DOTATOC, respectively. Calculated tumor, kidney and bone marrow doses for 66Ga-DOTATOC based on biodistribution data were 178, 109 and 1.2 cGy/MBq, respectively.We conclude that 66Ga labeled DOTATOC can be used for PET diagnosis and quantitative imaging-based dosimetry of SSTR positive tumors. 66Ga-DOTATOC may also be used in higher doses for ablation of these tumors. However, kidney is the critical organ for toxicity (tumor/kidney ratio = 1.64), and high kidney uptake must be eliminated before devising a therapy protocol.

A new cause of renal thrombotic microangiopathy: Yttrium 90-DOTATOC internal radiotherapy

The chelator somatostatin analogue dota-d-phe1-tyr3-octreotide (DOTATOC), which is stably labeled with the β-emitting radioisotope yttrium 90 (90Y), is used as internal radiotherapy for the treatment of patients with advanced neuroendocrine tumors. We report 5 patients who developed chronic renal failure, caused in 3 patients by biopsy-proven thrombotic microangiopathy (TMA). Twenty-nine patients (14 men, 15 women) with normal renal function before therapy were treated with divided intravenous doses of 90Y-DOTATOC approximately 6 weeks apart (mean normalized cumulative dose, 165.4 ± 36.4 mCi/m2). Twenty-two of 29 patients were administered a normalized cumulative dose of 200 mCi/m2 without side effects. Among the 7 patients (6 women, 1 man) administered a normalized cumulative dose greater than 200 mCi/m2, 5 patients (4 women, 1 man) developed renal failure. Increasing serum creatinine levels were observed within 3 months after the last 90Y-DOTATOC injection. The evolution was rapidly progressive in 3 patients, resulting in end-stage renal failure within 6 months. The remaining 2 patients developed chronic renal insufficiency (mean serum creatinine level, 300 μmol/L an average 16 months after the end of treatment). Renal biopsies performed in 3 patients showed typical signs of TMA involving glomeruli, arterioles, and small arteries. Patients treated with high-dose 90Y-DOTATOC internal radiotherapy (cumulative dose > 200 mCi/m2) are at high risk to develop severe renal failure caused by TMA lesions. The histopathologic lesions are identical to those found after external radiotherapy, which suggests a causal relationship between 90Y-DOTATOC and renal TMA.

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.