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Individualised 177Lu-DOTATATE treatment of neuroendocrine tumours based on kidney dosimetry.

ABSTRACT: PURPOSE:To present data from an interim analysis of a Phase II trial designed to determine the feasibility, safety, and efficacy of individualising treatment based on renal dosimetry, by giving as many cycles as possible within a maximum renal biologically effective dose (BED). METHOD:Treatment was given with repeated cycles of 7.4 GBq 177Lu-DOTATATE at 8-12-week intervals. Detailed dosimetry was performed in all patients after each cycle using a hybrid method (SPECT?+?planar imaging). All patients received treatment up to a renal BED of 27?±?2 Gy (?/??=?2.6 Gy) (Step 1). Selected patients were offered further treatment up to a renal BED of 40?±?2 Gy (Step 2). Renal function was followed by estimation and measurement of the glomerular filtration rate (GFR). RESULTS:Fifty-one patients were included in the present analysis. Among the patients who received treatment as planned, the median number of cycles in Step 1 was 5 (range 3-7), and for those who completed Step 2 it was 7 (range 5-8); 73% were able to receive >4 cycles. Although GFR decreased in most patients after the completion of treatment, no grade 3-4 toxicity was observed. Patients with a reduced baseline GFR seemed to have an increased risk of GFR decline. Five patients received treatment in Step 2, none of whom exhibited a significant reduction in renal function. CONCLUSIONS:Individualising PRRT using renal dosimetry seems feasible and safe and leads to an increased number of cycles in the majority of patients. The trial will continue as planned.

SUBMITTER: Sundlov A

PROVIDER: S-EPMC5506097 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Individualised <sup>177</sup>Lu-DOTATATE treatment of neuroendocrine tumours based on kidney dosimetry.

Sundlöv Anna A Sjögreen-Gleisner Katarina K Svensson Johanna J Ljungberg Michael M Olsson Tomas T Bernhardt Peter P Tennvall Jan J

European journal of nuclear medicine and molecular imaging 20170322 9

<h4>Purpose</h4>To present data from an interim analysis of a Phase II trial designed to determine the feasibility, safety, and efficacy of individualising treatment based on renal dosimetry, by giving as many cycles as possible within a maximum renal biologically effective dose (BED).<h4>Method</h4>Treatment was given with repeated cycles of 7.4 GBq <sup>177</sup>Lu-DOTATATE at 8-12-week intervals. Detailed dosimetry was performed in all patients after each cycle using a hybrid method (SPECT + ...[more]

PMID: 28331954

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Project description:BACKGROUND:Radionuclide therapy can be individualized by performing dosimetry. To determine absorbed organ doses in (177)Lu-DOTATATE therapy, three methods based on activity concentrations are currently in use: the small volume of interest (sVOI) method, and two methods based on large VOIs either on anatomical CT (aVOI) or on thresholds on functional images (tVOI). The main aim of the present work was to validate the sVOI in comparison to the other two methods regarding agreement and time efficiency. Secondary aims were to investigate inter-observer variability for the sVOI and the change of functional organ volumes following therapy. METHODS:Thirty patients diagnosed with neuroendocrine tumours undergoing therapy with (177)Lu-DOTATATE were included. Each patient underwent three SPECT/CT scans at 1, 4 and 7 days after the treatment. Three independent observers calculated absorbed doses to the right and left kidney and the spleen using sVOI and one observer used aVOI. For tVOI, the absorbed doses were calculated based on automatically drawn isocontours around the organs at different thresholds (42, 50, 60 and 70 %). The inter-observer difference between the calculated absorbed doses for sVOI was calculated, and the differences between the three methods were computed. Ratios of organ volumes acquired at days 1, 4 and 7 versus the volume at day 1 were calculated for the tVOI method. RESULTS:The differences in results of the absorbed dose calculations using all the sVOI and tVOI were small (<5 %). Absorbed dose calculations using aVOI differed slightly more from these results but were still below 10 %. The differences between the three dose calculation methods varied between <5 and 10 %. The organ volumes derived from the tVOI were independent of time for the spleen while they decreased with time for the kidneys. The fastest analysis was performed with the sVOI method. CONCLUSIONS:All three dose calculation methods rendered comparable results with small inter-observer differences for sVOI. Unlike the spleen, the functional volume of the kidneys decreased over time during therapy, which suggests that the absorbed dose calculation for the kidneys on activity concentrations should be performed for each time point. The sVOI is the preferred method for calculating absorbed doses in solid organs.

Project description:Tumor dosimetry was performed for 177Lu-DOTATATE with the aims of better understanding the range and variation of the tumor-absorbed doses (ADs), how different dosimetric quantities evolve over the treatment cycles, and whether this evolution differs depending on the tumor grade. Such information is important for radiobiologic interpretation and may inform the design of alternative administration schemes. Methods: The data came from 41 patients with neuroendocrine tumors (NETs) of grade 1 (n = 23) or 2 (n = 18) who had received between 2 and 9 treatment cycles. Dosimetry was performed for 182 individual lesions, giving a total of 880 individual AD assessments across all cycles. Hybrid planar-SPECT/CT imaging was used, including quantitative SPECT reconstruction, voxel-based absorbed-dose-rate calculation, semiautomatic image segmentation, and partial-volume correction. Linear mixed-effect models were used to analyze changes in tumor ADs over cycles, absorbed-dose rates and activity concentrations on day 1, effective half-times, and tumor volumes. Tumors smaller than 8 cm3 were excluded from analyses. Results: Tumor ADs ranged between 2 and 77 Gy per cycle. On average, the AD decreased over the cycles, with significantly different rates (P < 0.05) of 6% and 14% per cycle for grade 1 and 2 NETs, respectively. The absorbed-dose rates and activity concentrations on day 1 decreased by similar amounts. The effective half-times were less variable but shorter for grade 2 than for grade 1 (P < 0.001). For grade 2 NETs, the tumor volumes decreased, with a similar tendency in grade 1. Conclusion: The tumor AD, absorbed-dose rate, and activity uptake decrease, in parallel with tumor volumes, between 177Lu-DOTATATE treatment cycles, particularly for grade 2 NETs. The effective half-times vary less but are lower for grade 2 than grade 1 NETs. These results may indicate the development of radiation-induced fibrosis and could have implications for the design of future treatment and dosimetry protocols.

Project description:PurposeFractionated peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE is increasingly applied as an effective treatment for patients with disseminated neuroendocrine tumors. In parallel to dose planning before external beam radiation therapy, dosimetry is also needed to optimize PRRT to the individual patient. Accordingly, absorbed doses to organs at risk need to be calculated during PRRT, based on serial measurements of radioactivity distribution utilizing SPECT/CT. The dosimetry should be based on as few measurements as possible, while still retaining reliable results. The main aim of the present work was to calculate the fractional contribution of the extrapolations of the curve fits for the absorbed dose calculations to the kidneys. The secondary aim was to study agreement between absorbed dose (AD) and the effective half-life (teff) for the kidneys, estimated by means of measurements at one or two time points, in comparison to our current method employing three time points.MethodsIn 777 patients with disseminated neuroendocrine tumors undergoing PRRT, SPECT/CT over the abdomen was acquired at 1, 4, and 7 days after 177Lu-DOTATATE infusion. The absorbed dose to the kidneys was calculated from SPECT/CT radioactivity distribution data, and the teff and fractional contributions of the extrapolations were estimated, utilizing data from one, two, and three time points, respectively.ResultsThe fractional contributions from extrapolations before day 1 measurement and after day 7 measurement were approximately 26% and 11%, respectively. The mean differences in absorbed dose, based on one, two, and three time points were small, but with high method dependence for individual patients. The differences in estimated teff were small when it was based on measurements at days 1 and 7, but high for days 1 and 4 time points.ConclusionWhen assessing simplifications of methods for calculation of the absorbed dose to the kidneys, it was of the uttermost importance to incorporate the fractional contribution for the extrapolations included in the reference method. Measurements at an early and a late time point were found most important. An intermediate measurement contributes with an idea of the goodness of the fit.

Project description:PurposeRadionuclide therapy with 177Lu-DOTATATE is well established for patients with advanced somatostatin receptor-positive neuroendocrine tumors with a standard schedule of 7.4 GBq at four occasions. However, this approach does not consider individual variability affecting the tumor radiation dose or dose to organs at risk. Therefore, it is important to assess more personalized strategies. The aim of this phase II trial was to evaluate individualized 177Lu-DOTATATE for which the number of cycles varied based on renal dosimetry.MethodsPatients were eligible if they had a progressive, somatostatin receptor-positive neuroendocrine tumor with a Ki 67 labeling index < 20%. They received cycles of 7.4 GBq of 177Lu-DOTATATE at 10 ± 2-week intervals until a predefined radiation dose to the kidneys was reached. The primary endpoint was objective tumor response (RECIST v 1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity (CTCAE v. 4.0).ResultsNinety-six patients who had received a median of 5 cycles (range 1-9) were evaluable for efficacy. The objective tumor response was 16% partial response, 66% stable disease, and 19% progressive disease. The median PFS and OS were 29 months and 47 months, respectively, and were significantly associated with kidney dose, performance status, and Ki 67 levels but not with tumor origin. The overall toxicity was mild, and the most common events were grade 1-2 anemia, thrombocytopenia, fatigue, nausea, and diarrhea. Grade 3-4 toxicity occurred in < 10% of patients and was mostly hematological, with no grade 3-4 renal toxicity.ConclusionIndividualized treatment with 177Lu-DOTATATE based on renal dosimetry is clearly feasible with low toxicity and promising efficacy, showing the potential to further improve outcome beyond the standard approach, and should be further assessed in randomized trials.Trial registrationEudraCT 2011-000,240-16. NCT01456078. https://clinicaltrials.gov/ct2/show/NCT01456078.

Project description:BackgroundIndividualized dosimetry is recommended for [177Lu]Lu-PSMA radioligand therapy (RLT) which is resource-intensive and protocols are often not optimized. Therefore, a simulation study was performed focusing on the determination of efficient optimal sampling schedules (OSS) for renal and tumour dosimetry by investigating different numbers of time points (TPs).MethodsSampling schedules with 1-4 TPs were investigated. Time-activity curves of the kidneys and two tumour lesions were generated based on a physiologically based pharmacokinetic (PBPK) model and biokinetic data of 13 patients who have undergone [177Lu]Lu-PSMA I&T therapy. Systematic and stochastic noise of different ratios was considered when modelling time-activity data sets. Time-integrated activity coefficients (TIACs) were estimated by simulating the hybrid planar/SPECT method for schedules comprising at least two TPs. TIACs based on one single SPECT/CT measurement were estimated using an approximation for reducing the number of fitted parameters. For each sampling schedule, the root-mean-squared error (RMSE) of the deviations of the simulated TIACs from the ground truths for 1000 replications was used as a measure for accuracy and precision.ResultsAll determined OSS included a late measurement at 192 h p.i., which was necessary for accurate and precise tumour TIACs. OSS with three TPs were identified to be 3-4, 96-100 and 192 h with an additional SPECT/CT measurement at the penultimate TP. Kidney and tumour RMSE of 6.4 to 7.7% and 6.3 to 7.8% were obtained, respectively. Shortening the total time for dosimetry to e.g. 96 h resulted in kidney and tumour RMSE of 6.8 to 8.3% and 9.1 to 11%, respectively. OSS with four TPs showed similar results as with three TPs. Planar images at 4 and 68 h and a SPECT/CT shortly after the 68 h measurement led to kidney and tumour RMSE of 8.4 to 12% and 12 to 16%, respectively. One single SPECT/CT measurement at 52 h yielded good approximations for the kidney TIACs (RMSE of 7.0%), but led to biased tumour TIACs.ConclusionOSS allow improvements in accuracy and precision of renal and tumour dosimetry for [177Lu]Lu-PSMA therapy with potentially less effort. A late TP is important regarding accurate tumour TIACs.

Project description:177Lu-DOTATATE (Lutathera®) enables targeted radionuclide therapy of neuroendocrine tumors expressing somatostatin receptor type 2. Though patient-specific dosimetry estimates may be clinically important for predicting absorbed dose-effect relationships, there are multiple relevant dosimetry paradigms which are distinct in terms of clinical effort, numerical output and added-value. This work compares three different approaches for177Lu-DOTATATE dosimetry, including 1) an organ-level approach based on reference phantom MIRD S-values scaled to patient-specific organ masses (MIRDcalc), 2) an organ-level approach based on Monte Carlo simulation in a patient-specific mesh phantoms (PARaDIM), and 3) a 3D approach based on Monte Carlo simulation in patient-specific voxel phantoms.Method. Serial quantitative SPECT/CT images for two patients receiving177Lu-DOTATATE therapy were obtained from archive in theDeep Bluedatabase. For each patient, the serial CT images were co-registered to the first time point CT using a deformable registration technique aided by virtual landmarks placed in the kidney pelves and the lesion foci. The co-registered SPECT images were integrated voxel-wise to generate time-integrated activity maps. Lesions, kidneys, liver, spleen, lungs, compact bone, spongiosa, and rest of body were segmented at the first imaging time point and overlaid on co-registered integrated activity maps. The resultant segmentation was used for three purposes: 1) to generate patient-specific phantoms, 2) to determine organ-level time-integrated activities, and 3) to generate dose volume histograms from 3D voxel-based calculations.Results. Mean absorbed doses were computed for lesions and 48 tissues with MIRDcalc software. Mean organ absorbed doses and dose volume histograms were obtained for lesions and 6 tissues with the voxel Monte Carlo approach. Lesion- and organ-level absorbed dose estimates agreed within ±26% for the lesions and ±13% for the critical organs, among the different methods tested. Overall good agreement was observed with the dosimetry estimates from the NETTER-1 trial.Conclusions. For personalized177Lu-DOTATATE dosimetry, a combined approach was determined to be valuable, which utilized two dose calculation methods supported by a single image processing workflow. In the absence of quantitative imaging limitations, the voxel Monte Carlo method likely provides valuable information to guide treatment by considering absorbed dose non-uniformity in lesions and organs at risk. The patient-scaled reference phantom method also provides valuable information, including absorbed dose estimates for non-segmented organs, and more accurate dose estimates for complex radiosensitive organs including the active marrow.

Project description:AimTo evaluate the cost-effectiveness of [177Lu]Lu-DOTA-TATE versus relevant comparators for the treatment of neuroendocrine tumours located in the gastrointestinal tract (GI-NETs) and the pancreas (P-NETs).Materials and methodsA three-state partitioned survival model was developed to perform a cost-utility analysis of [177Lu]Lu-DOTA-TATE versus standard of care (high dose Octreotide LAR), everolimus and sunitinib. Effectiveness data for SoC, everolimus and sunitinib were obtained from published Kaplan-Meier survival curves. Given a lack of head-to-head effectiveness data, matching adjusted indirect comparisons (MAICs) were performed to population-adjust [177Lu]Lu-DOTA-TATE survival data based on prognostic factors and derive estimates of relative effectiveness. Health state utilities were estimated from real-world evidence. Drug acquisition costs were taken from nationally published sources (BNF, NICE), and administration costs were based on treatment protocols in [177Lu]Lu-DOTA-TATE studies, combined with nationally published unit costs (PSSRU, DoH reference costs). Incidence of adverse events were estimated using published sources. A discount rate of 3.5% was applied to both utilities and costs, and deterministic and probabilistic sensitivity analyses were performed. Costs were included from an NHS perspective and presented in 2017/18 GBP (and PPP Euros for base case).ResultsIn GI-NETs, the incremental cost-effectiveness ratio (ICER) of [177Lu]Lu-DOTA-TATE compared to SoC and everolimus was £26,528 (€27,672) and £24,145 (€25,186) per QALY, respectively. In P-NETs, the ICER of [177Lu]Lu-DOTA-TATE compared to SoC was £22,146 (€23,101) or £28,038 (€29,251) dependent on matched population, and £21,827 (€22,766) and £15,768 (€16,445) compared to everolimus and sunitinib, respectively.ConclusionsAt a willingness to pay threshold of £30,000, [177Lu]Lu-DOTA-TATE is likely to be a cost-effective treatment option for GI-NET and P-NET patients versus relevant treatment comparators (NHS perspective).

Dataset Information

Individualised 177Lu-DOTATATE treatment of neuroendocrine tumours based on kidney dosimetry.

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Individualised <sup>177</sup>Lu-DOTATATE treatment of neuroendocrine tumours based on kidney dosimetry.

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