Methods for preparation and administration of lutetium-177 oxodotreotide 3.7 GBq: proceedings from an Italian advisory board (original) (raw)
Related papers
European Journal of Nuclear Medicine and Molecular Imaging, 2013
Purpose Somatostatin-based radiopeptide treatment is generally performed using the β-emitting radionuclides 90 Y or 177 Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. Methods In a comparative cohort study, patients with advanced neuroendocrine tumours underwent repeated cycles of [ 90 Y-DOTA]-TOC or [ 177 Lu-DOTA]-TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were employed to examine predictors of survival and adverse events for both treatment groups. Results Overall, 910 patients underwent 1,804 cycles of [ 90 Y-DOTA]-TOC and 141 patients underwent 259 cycles of [ 177 Lu-DOTA]-TOC. The median survival after [ 177 Lu-DOTA]-TOC and after [ 90 Y-DOTA]-TOC was comparable (45.5 months versus 35.9 months, hazard ratio 0.91, 95 % confidence interval 0.63-1.30, p =0.49). Subgroup analyses revealed a significantly longer survival for [ 177 Lu-DOTA]-TOC over [ 90 Y-DOTA]-TOC in patients with low tumour uptake, solitary lesions and extra-hepatic lesions. The rate of severe transient haematotoxicities was lower after [ 177 Lu-DOTA]-TOC treatment (1.4 vs 10.1 %, p =0.001), while the rate of severe permanent renal toxicities was similar in both treatment groups (9.2 vs 7.8 %, p =0.32). Conclusion The present results revealed no difference in median overall survival after [ 177 Lu-DOTA]-TOC and [ 90 Y-DOTA]-TOC. Furthermore, [ 177 Lu-DOTA]-TOC was less haematotoxic than [ 90 Y-DOTA]-TOC. A. Romer and D. Seiler contributed equally to this work.
EJNMMI Physics, 2019
Background: 177 Lu-DOTATATE peptide receptor radionuclide therapy is administered to patients on an inpatient and outpatient basis for the treatment of welldifferentiated, metastatic neuroendocrine tumours. Following administration, these patients present an external radiation hazard due to the gamma emissions of lutetium-177. The purpose of this study was to determine precautions to be observed by 177 Lu-DOTATATE patients to restrict the dose received by patients' family members to less than 5 mSv in 5 years and members of the public to less than 1 mSv per year in line with the current UK legislation. Retrospective data from therapeutic administrations of 177 Lu-DOTATATE (Mallinckrodt Pharmaceuticals) and Lutathera® (Advanced Accelerator Applications) were analysed to measure activity retention at discharge. Patient dose rate measurements were assumed to follow the same activity decay curve as that derived from a least squares fit of geometric mean counts in planar whole-body scans performed at four time points postadministration. Combining this with social contact times, the cumulative dose received through contact with the patient was estimated and an iterative process used to determine the length of contact restrictions to ensure the relevant dose constraints are not exceeded. Results: On average, 36% of the administered activity was retained at the time of discharge for inpatients receiving 177 Lu-DOTATATE (Mallinckrodt). Retentions of 24% and 38% were measured for Lutathera® inpatients and outpatients respectively. Inpatients should restrict day contact and sleep separately from their partner for 15 days and remain off work for 5 days post-therapy. Contact with children for whom the patient is the main carer should be restricted for 16, 13 and 9 days for children below 2, 2-5 and 5-11 years respectively. One additional day is added to outpatient restriction periods, except for children aged 2-5 years which remains 13 days. No private transport restrictions are required. Patients should limit travel by public transport to 1 h on the day of discharge. Conclusion: Restrictions are necessary to limit radiation dose to members of patients' household and the public. Proposed precautions for inpatient and outpatient 177 Lu-DOTATATE therapy protocols restrict the dose received to less than the limit imposed by the UK legislation.
Journal of Translational Medicine, 2013
Background: We describe the long-term outcome after clinical introduction and dose escalation of somatostatin receptor targeted therapy with [ 90 Y-DOTA]-TOC in patients with metastasized neuroendocrine tumors. Methods: In a clinical phase I dose escalation study we treated patients with increasing [ 90 Y-DOTA]-TOC activities. Multivariable Cox regression and competing risk regression were used to compare efficacy and toxicities of the different dosage protocols. Results: Overall, 359 patients were recruited; 60 patients were enrolled for low dose (median: 2.4 GBq/cycle, range 0.9-7.8 GBq/cycle), 77 patients were enrolled for intermediate dose (median: 3.3 GBq/cycle, range: 2.0-7.4 GBq/cycle) and 222 patients were enrolled for high dose (median: 6.7 GBq/cycle, range: 3.7-8.1 GBq/cycle) [ 90 Y-DOTA]-TOC treatment. The incidences of hematotoxicities grade 1-4 were 65.0%, 64.9% and 74.8%; the incidences of grade 4/5 kidney toxicities were 8.4%, 6.5% and 14.0%, and the median survival was 39 (range: 1-158) months, 34 (range: 1-118) months and 29 (range: 1-113) months. The high dose protocol was associated with an increased risk of kidney toxicity (Hazard Ratio: 3.12 (1.13-8.59) vs. intermediate dose, p = 0.03) and a shorter overall survival (Hazard Ratio: 2.50 (1.08-5.79) vs. low dose, p = 0.03). Conclusions: Increasing [ 90 Y-DOTA]-TOC activities may be associated with increasing hematological toxicities. The dose related hematotoxicity profile of [ 90 Y-DOTA]-TOC could facilitate tailoring [ 90 Y-DOTA]-TOC in patients with preexisting hematotoxicities. The results of the long-term outcome suggest that fractionated [ 90 Y-DOTA]-TOC treatment might allow to reduce renal toxicity and to improve overall survival. Trial registration: ClinicalTrials.gov number: NCT00978211
Journal of nuclear medicine technology, 2018
Lu-DOTATATE is a radiolabeled somatostatin analog that has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors in adults. Radionuclide therapies have been administered for many years within nuclear medicine departments in North America. However, in comparison to other radiotherapies, Lu-DOTATATE peptide receptor radionuclide therapy involves more planning, coordination, concomitant medication administration (antiemetic medications and amino acids), and direct patient care. To date, various methods have been used in multiple centers during the NETTER-1 trial and the provision of patient care. As participants in the phase 3 NETTER-1 trial and the subsequent expanded-access program for the administration of Lu-DOTATATE studies, as well as recently starting postapproval clinical care, we have administered 61 Lu-DOTATATE therapies at the time of this manuscript submission (13 in the ...
Journal of Clinical Oncology, 2008
Despite the fact that most gastroenteropancreatic neuroendocrine tumors (GEPNETs) are slowgrowing, median overall survival (OS) in patients with liver metastases is 2 to 4 years. In metastatic disease, cytoreductive therapeutic options are limited. A relatively new therapy is peptide receptor radionuclide therapy with the radiolabeled somatostatin analog [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate. Here we report on the toxicity and efficacy of this treatment, performed in over 500 patients.
Peptide receptor radionuclide therapy with 177Lu-DOTATATE: the IEO phase I-II study
European Journal of Nuclear Medicine and Molecular Imaging, 2011
Peptide receptor radionuclide therapy (PRRT) is used in tumours expressing type 2 somatostatin receptors (sst(2)), mainly neuroendocrine. The aim of this prospective phase I-II study was to evaluate the toxicity and efficacy of (177)Lu-DOTATATE in multiple cycles. Fifty-one consecutive patients with unresectable/metastatic sst(2)-positive tumours, divided into two groups, received escalating activities (3.7-5.18 GBq/cycle, group 1; 5.18-7.4 GBq/cycle, group 2) of (177)Lu-DOTATATE. Cumulative activities ranged from 3.7 to 29.2 GBq (median 26.4 GBq in median 6 cycles, group 1, 21 patients) and 5.55 to 28.9 GBq (median 25.2 GBq in 4 cycles, group 2, 30 patients), based on dosimetry. No major acute or delayed renal or haematological toxicity occurred (one grade 3 leukopenia and thrombocytopenia). Cumulative renal absorbed doses were 8-37 Gy (9-41 Gy bioeffective doses). A median decrease of creatinine clearance of 21.7% 6 months after PRRT, 23.9% after 1 year and 27.6% after 2 years was observed. Higher losses (>20%) occurred in patients with risk factors for renal toxicity, particularly hypertension and diabetes. Cumulative bone marrow doses were <1.5 Gy. Blood elements showed a progressive mild drop during cycles and recovered during follow-up (median 30 months). Thirty-nine patients were progressive at enrolment. Partial and complete responses occurred in 15 of 46 (32.6%) assessable patients. The median time to progression was 36 months. Overall survival was 68% at 36 months. Non-responders and patients with extensive tumour involvement had lower survival. (177)Lu-DOTATATE was well tolerated up to 29 GBq cumulative activity (up to 7.4 GBq/cycle). The maximum tolerated dose/cycle was not reached. However, considering the individual bone marrow function and the presence of risk factors for kidney toxicity, it seems safer to divide cumulative activities into lower activity cycles.
Physica Medica
Peptide receptor radionuclide therapy with 177 Lu-DOTATATE has become a standard treatment modality in neuroendocrine tumours (NETs). No consensus has yet been reached however regarding the absorbed dose threshold for lesion response, the absorbed dose limit to organs-at-risk, and the optimal fractionation and activity to be administered. This is partly due to a lack of uniform and comparable dosimetry protocols. The present article details the development of an organ-at-risk dosimetry procedure, which could be implemented and used routinely in a clinical context. Methods: Forty-seven patients with NETs underwent 177 Lu-DOTATATE therapy. Three SPECT/CT images were acquired at 4, 24 and 144-192 h post-injection. Three blood samples were obtained together with the SPECT/CT acquisitions and 2 additional samples were obtained around 30 min and 1 h post-injection. A bi-exponential fit was used to compute the source organ time-integrated activity coefficients. Coefficients were introduced into OLINDA/EXM software to compute organ-at-risk absorbed doses. Median values for all patients were computed for absorbed dose coefficient D A / 0 and for late effective half-life T 1/2eff for kidneys, spleen and red marrow. Results: Dosimetry resulted in a median[interquartile range] of 0.78[0.35], 1.07[0.58] and 0.028[0.010] Gy/ GBq for D A / 0 and of 55[9], 71[9] and 52[18] h for T 1/2eff for kidneys, spleen and red marrow respectively. Conclusions: A dosimetry procedure for organs-at-risk in 177 Lu-DOTATATE therapy based on serial SPECT/CT images and blood samples can be implemented routinely in a clinical context with limited patient burden. The results obtained were in accordance with those of other centres.
Towards tailored radiopeptide therapy
European Journal of Nuclear Medicine and Molecular Imaging, 2015
Purpose Somatostatin receptor-targeted radiopeptide therapy is commonly performed using single radioisotopes. We evaluated the benefits and harms of combining radioisotopes in radiopeptide therapy in patients with neuroendocrine tumor. Methods Using multivariable-adjusted survival analyses and competing risk analyses we evaluated outcomes in patients with neuroendocrine tumor receiving 90 Y-DOTATOC, 177 Lu-DOTATOC or their combination. Results 90 Y-DOTATOC plus 177 Lu-DOTATOC treatment was associated with longer survival than 90 Y-DOTATOC (66.1 vs. 47.5 months; n=1,358; p<0.001) or 177 Lu-DOTATOC alone (66.1 vs. 45.5 months; n=390; p<0.001). 177 Lu-DOTATOC was associated with longer survival than 90 Y-DOTATOC in patients with solitary lesions (HR 0.3, range 0.1-0.7; n=153; p=0.005), extrahepatic metastases (HR 0.5, range 0.3-0.9; n=256; p=0.029) and metastases with low uptake (HR 0.1, range 0.05-0.4; n=113; p=0.001). 90 Y-DOTATOC induced higher hematotoxicity rates than combined treatment (9.5 % vs. 4.0 %, p=0.005) or 177 Lu-DOTATOC (9.5 % vs. 1.4 %, p=0.002). Renal toxicity was similar among the treatments. Conclusions Using 90 Y and 177 Lu might facilitate tailoring radiopeptide therapy and improve survival in patients with neuroendocrine tumors.
European Journal of Nuclear Medicine and Molecular Imaging
Purpose Peptide receptor radionuclide therapy in patients with neuroendocrine tumours has yielded promising results. This prospective study investigated the feasibility of dosimetry of the kidneys and bone marrow during therapy and its impact on efficacy and outcome. Methods The study group comprised 200 consecutive patients with metastasized somatostatin receptor-positive neuroendocrine tumours progressing on standard therapy or not suitable for other therapeutic options. A treatment cycle consisted of 7.4 GBq 177 Lu-DOTA-octreotate with co-infusion of a mixed amino acid solution, and cycles were repeated until the absorbed dose to the kidneys reached 23 Gy or there were other reasons for stopping therapy. The Ki-67 index was ≤2% in 47 patients (23.5%), 3-20% in 121 (60.5%) and >20% in 16 (8%). Results In 123 patients (61.5%) the absorbed dose to the kidneys reached 23 Gy with three to nine cycles during first-line therapy; in no patient was a dose to the bone marrow of 2 Gy reached. The best responses (according to RECIST 1.1) were a complete response (CR) in 1 patient (0.5%), a partial response (PR) in 47 (23.5%), stable disease (SD) in 135 (67.5%) and progressive disease (PD) in 7 (3.5%). Median progression-free survival was 27 months (95% CI 22-30 months) in all patients, 33 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 15 months in those in whom it did not. Median overall survival (OS) was 43 months (95% CI 39-53 months) in all patients, 54 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 25 months in those in whom it did not. Median OS was 60 months in patients with a best response of PR or CR, 42 months in those with SD and 16 months in those with PD. Three patients (1.5%) developed acute leukaemia, 1 patient (0.5%) chronic leukaemia (unconfirmed) and 30 patients (15%) grade 3 or 4 bone marrow toxicity. Eight patients (4%) developed grade 2 kidney toxicity and one patient (0.5%) grade 4 kidney toxicity. Conclusions Dosimetry-based therapy with 177 Lu-DOTA-octreotate is feasible. Patients in whom the absorbed dose to the kidneys reached 23 Gy had a longer OS than those in whom it did not. Patients with CR/PR had a longer OS than those with SD. Bone marrow dosimetry did not predict toxicity.
Minor changes in effective half-life during fractionated 177 Lu-Octreotate therapy
Acta Oncologica, 2012
Aims. Fractionated 177 Lu-DOTA-octreotate therapy has been reported to be an effective treatment option for patients with generalized neuroendocrine tumors. In our clinic, full individual dosimetry is performed during the fi rst therapy cycle, while dosimetry at later cycles is based on the 24 h uptake measurement assuming an unchanged effective half-life. Our aim was to evaluate this assumption and the variation in the 24 h uptake during therapy. Patients. Thirty patients, 13 women and 17 men, were included in the study. Methods. During the fi rst therapy cycle the 177 Lu-concentration was measured with SPECT/CT over the abdomen at 24 h, 96 h and 168 h after infusion. The effective half-life was determined for the kidneys, liver and spleen. The procedure was repeated at cycle 4 or 5. Results . The median ratio between the effective halflives of the latter and the fi rst cycle was 0.97 and 1.01 for the right and left kidney, with a range of 0.89 -1.01 (1st -3rd quartile) and 0.93 -1.05, respectively. Discussion. The mean value of the ratios was slightly lower than one, indicating a tendency towards increased activity elimination during therapy. In individual patients, signifi cant changes were found for all organs, often when a large tumor burden reduction occurred during treatment. Possible contributing factors appeared to be larger amounts of non-tumor bound tracer, improved organ function (kidneys), decrease of vessel obstruction (spleen), less scatter from large tumors and reduction of small metastases (liver and spleen). Conclusion. With most patients it is safe to estimate absorbed doses to kidneys, liver and spleen from 24 h activity concentration assuming an unchanged effective half-life during therapy. Patients with risk factors for kidney dysfunction need to be monitored in more detail. Simplifi ed dosimetry based on the assumption of unchanged effective half-life can function as guidance to the number of therapy cycles an individual patient can tolerate. Acta Oncol Downloaded from informahealthcare.com by University Of Uppsala on 03/28/12