177Lu-DOTATATE Peptide Receptor Radionuclide Therapy Research Articles

Broadening Horizons with 225Ac-DOTATATE Targeted Alpha Therapy for Gastroenteropancreatic-Neuroendocrine Tumor Patients Stable or Refractory to 177Lu-DOTATATE PRRT: First Clinical Experience on the Efficacy and Safety

Background: The curative option for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is surgery, but as the majority of the patients are diagnosed at the late stage with metastasis and require systemic treatment. Currently available systemic therapies are inadequate and produce only symptomatic relief or at the best stable disease. Therefore, there is an increasing need for novel therapeutic options in the treatment of metastatic GEP-NETs. Although beta-emitting peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE is one of the FDA approved standard treatment options, alpha therapy on the radiobiological basis is considered superior to beta-emitting 177Lutetium (177Lu) based PRRT. This is due to the double-stranded DNA breaks by alpha particles causing high cytotoxic activity on the cellular level with minimal bystander effects. However, clinical evidence in this context is sparse, hence, the objective of this study was to investigate and present the early results on the efficacy, safety, and quality of life of 225Ac-DOTATATE targeted alpha therapy (TAT) in patients with advanced, progressive, 177Lu-DOTATATE refractory, and somatostatin receptor (SSTR) expressing metastatic GEP-NETs. Methods: In this prospective study, we recruited patients with metastatic GEP-NETs who were stable or progressive disease on 177Lu-DOTATATE therapy. We offered 225Ac-DOTATATE therapy as an experimental treatment option after obtaining institutional review board approval. All patients underwent 68Ga-DOTANOC PET/CT scan to ensure high SSTR expression even after repeated 177Lu-DOTATATE therapy cycles. Systemic TAT was performed in all the patients with 225Ac-DOTATATE (100 KBq/Kg body weight) at an interval of 8 weeks. The primary end-point was to assess the objective response (measured by RECIST 1.1 and functional M. D. Anderson criteria). The secondary end-points included biochemical response assessment as per the Italian Trials in Medical Oncology (ITMO), adverse-event profile as per CTCAE v5.0, and clinical response assessment by the quality of life (assessed with EORTC QLQ-GI.NET21 patient-based questionnaire). The renal, hepatic, and haematological evaluation were performed before and after every cycle of 225Ac-DOTATATE TAT at 2, 4 and 8-week intervals. Findings: Between April 2018 and February 2019, 21 patients (9 females, 12 males, median age 54 years, IQR: 50 - 60 years) with either stable disease after completing 177Lu-DOTATATE therapy (12, 57%) or progressive disease on 177Lu-DOTATATE therapy (9, 43%) were included in the study. The mean administered cumulative 225Ac-DOTATATE therapy was 20794 ± 6660 KBq over a median of 3 cycles. The morphological response was assessed in 20/21 patients that revealed partial remission in 10 and stable disease in 10. There were no documented disease progression or deaths in the median follow-up of 9 months (range: 2 - 12 months). There was a significant decrease in the plasma chromogranin level post-225Ac-DOTATATE therapy (P=0·0019). While a significant decrease in the endocrine (P=0·0011) and gastrointestinal symptoms (P=0·0002) were noted, there was a significant improvement in the functional scale: disease-related worries (P<0·0001). The most common adverse effects (AEs) were loss of appetite, nausea, and vomiting, however, were limited to grade 1 or 2 toxicities. Majority of the patients experienced these AEs at the time of amino acid infusion which was co-administered with 225Ac-DOTATATE therapy and was resolved after a few hours of amino acid infusion. Interpretation: Our short-term clinical results indicate 225Ac-DOTATATE TAT as a promising treatment option which adds a new dimension in patients who are refractory to 177Lu-DOTATATE therapy, or have reached the maximum prescribed cycles of 177Lu-DOTATATE therapy. However, Longterm clinical data are in the process of collection for the assessment of sustained tumor response with 225Ac-DOTATATE TAT. Funding Statement: The authors state: None. Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: Ethical clearance received Ref. No IEC-517

Resistant functioning and/or progressive symptomatic metastatic gastroenteropancreatic neuroendocrine tumors: efficacy of 177Lu-DOTATATE peptide receptor radionuclide therapy in this setting.

Functioning and symptomatic disease resistant to conventional therapies constitutes a subset amongst neuroendocrine tumors (NETs) that are commonly considered for peptide receptor radionuclide therapy (PRRT). The aim of this study was to evaluate the efficacy of Lu-DOTATATE PRRT in this group with objective assessment criteria. A total of 46 patients with refractory or progressive symptomatic GEP-NETs (previously treated at various stages with long-acting octreotide, chemotherapy, multikinase inhibitors, etc.) who had undergone treatment with PRRT were retrospectively analyzed. These patients were evaluated for response on three scales: clinical, biochemical parameters (tumor marker levels), and imaging (functional molecular and contrast enhanced anatomic). They were classified as complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD) on each scale. Furthermore, the patients were classified as (a) those who gained benefit from PRRT and (b) those who were nonresponders using predefined criteria. Ninety-one percent of the patient population had liver metastases, with a mean serum chromograninA level of 3307 U/ml, consistent with high volume tumor burden and refractory symptoms. Clinical symptomatic response on an analogue scale showed 54% CR, 35% PR, and 6% SD, whereas 4% showed worsening of symptoms. Biochemically, 17% CR, 28% PR, and 28% SD were observed, whereas 12% showed PD. On evaluation by imaging (PERCIST and RECIST 1.1 criteria), we observed 4% CR, 39% PR, and 36% SD, whereas 19% showed PD. The clinical scale showed the highest overall benefit of 95.6% in the population studied. The data support the evidence that PRRT could be potentially beneficial in resistant, refractory, and progressive symptomatic groups of GEP-NETs with functional disease burden. The use of a multidimensional response evaluation should be adopted (rather than only anatomical-functional imaging) and needs to be considered while managing this subset of patients.

Effects of adding an albumin binder chain on [177Lu]Lu-DOTATATE

Introduction[177Lu]Lu-DOTATATE peptide receptor radionuclide therapy is used for treatment of neuroendocrine tumours. We investigated whether prolonging blood residence time of [177Lu]Lu-DOTATATE with albumin binders could increase tumour accumulation and tumour-to-kidney ratios for improved therapeutic efficacy. MethodsDOTATATE and its derivatives with an albumin-binder motif (GluAB-DOTATATE and AspAB-DOTATATE) were prepared by solid-phase peptide synthesis. Binding affinities of the Lu-labeled peptides for human somatostatin receptor 2 (SSTR2) were measured with membrane competition binding assays. Compounds were radiolabeled with [177Lu]LuCl3 and purified by HPLC. SPECT imaging and biodistribution studies (1, 4, 24, 72, and 120 h) were performed in immunodeficient mice bearing AR42J pancreatic tumour xenografts. ResultsGluAB-DOTATATE and AspAB-DOTATATE were synthesized in 18.8% and 14.3% yields, while Lu-GluAB-DOTATATE and Lu-AspAB-DOTATATE were obtained in 86.5% and 50.0% yields, respectively. The compounds exhibited nanomolar binding affinity (Ki: 8.72–8.95 nM) for SSTR2. The 177Lu-labeled peptides were obtained in non-decay-corrected isolated yields of ≥41%, with >96% radiochemical purity, and molar activities in the range of 314–497 GBq/μmol. In vivo, [177Lu]Lu-GluAB-DOTATATE and [177Lu]Lu-AspAB-DOTATATE had significantly higher blood activity at 1, 4 and 24 h compared to [177Lu]Lu-DOTATATE. Tumour uptake of [177Lu]Lu-DOTATATE was 21.35 ± 5.90%ID/g at 1 h and decreased to 10.10 ± 5.78%ID/g at 120 h. For [177Lu]Lu-GluAB-DOTATATE tumour uptake increased from 21.89 ± 6.86%ID/g at 1 h to 24.44 ± 5.84%ID/g at 4 h, before decreasing to 12.02 ± 1.84%ID/g at 120 h. For [177Lu]Lu-AspAB-DOTATATE tumour uptake was 11.12 ± 3.18%ID/g at 1 h, 18.41 ± 4.36%ID/g at 24 h, and decreased to 16.90 ± 8.97%ID/g at 120 h. Renal uptake was 7.49 ± 1.62%ID/g for [177Lu]Lu-DOTATATE, 31.14 ± 7.06%ID/g for [177Lu]Lu-GluAB-DOTATATE, and 28.82 ± 13.82%ID/g for [177Lu]Lu-AspAB-DOTATATE at 1 h and decreased thereafter. ConclusionThe addition of albumin binder motifs to [177Lu]Lu-DOTATATE enhanced mean residence time in blood. Increased tumour uptake was observed for [177Lu]Lu-AspAB-DOTATATE compared to [177Lu]Lu-DOTATATE at later time points, but its higher kidney uptake diminished the therapeutic index.

Guidance on 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy from the Experience of a Single Nuclear Medicine Division.

177Lu-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, 177Lu-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 177Lu-DOTATATE studies, as well as recently starting postapproval clinical care, we have administered 61 177Lu-DOTATATE therapies at the time of this manuscript submission (13 in the NETTER-1 trial, 39 in the expanded-access program, and 9 clinically) at the Dana-Farber Cancer Institute and here share our procedures, personnel training, and workflow to help other centers establish programs for this FDA-approved 177Lu-DOTATATE peptide receptor radionuclide therapy.

177Lu-DOTATATE Peptide Receptor Radionuclide Therapy.

The peptide receptor radionuclide therapy (PRRT) 177Lu-DOTATATE binds to somatostatin receptors ([1][1]). A multidisciplinary team should be involved when treating patients with 177Lu-DOTATATE PRRT, including medical oncologists, nuclear medicine physicians and technologists, nurses, radiation

P086] Impact of modality (2D planar, 2D/3D hybrid, 3D SPECT) on kidneys absorbed dose in lu-177-based PRRT

Purpose In peptide receptor radionuclide therapy (PRRT) the kidneys are considered an organ at risk for radiation-induced damage. Thus the absorbed dose to the kidneys is one important safety parameter with the potential to influence treatment regimen and therefore treatment outcome. Dosimetry can be performed using planar, hybrid (planar/SPECT) or SPECT imaging. The choice of modality is expected to impact the results. In this work we aimed to compare (1) the different modalities and (2) different planar correction/calibration methods. Methods Retrospective planar, hybrid and 3D dosimetry analysis was performed using the internal dosimetry software suite QDOSE. Five patients with neuroendocrine tumours, who received 177Lu-Dotatate PRRT and were imaged at time points at 0.5 h, 4 h, 24 h and 96 h post-injection, were analyzed. SPECT data were reconstructed with 3D OSEM including attenuation and scatter correction. Planar corrections included attenuation correction using a broad beam μ and background correction. The activity calibration of the planar data was performed either using the activity in the whole body (WB) or a reference vial. Phantom-based dose calculations were performed using IDAC-Dose 2.1. Results Comparing modalities, using 3D SPECT as reference, the absorbed dose to the kidneys was overestimated by 95% when calculated with planar methodology and by 13% when hybrid dosimetry was applied. Regarding planar corrections, there was only a moderate difference between vial and WB calibration of −14% when all corrections were applied. However, vial calibration without attenuation correction resulted in a large deviation of −58% compared to full correction. When WB calibration was applied, no correction performed slightly better (−8% deviation) than only attenuation correction (+9%) or only background correction (−14%) compared to full correction. Conclusions For quantitative accuracy 3D SPECT dosimetry is preferable. If planar imaging is used, overlapping activity can cause significant overestimation of activity and hence absorbed dose for the kidneys. As absorbed dose limits (23Gy–29Gy) are commonly applied to the kidneys, dosimetry results based on planar imaging could potentially impede treatment efficacy by artificially restricting the administered therapeutic activity. Hybrid dosimetry provided a sufficiently accurate compromise between the higher acquisition time demands of 3D dosimetry and limited accuracy of planar dosimetry.

177Lu-DOTATATE Peptide Receptor Radionuclide Therapy in Patients with Borderline Low and Discordant Renal Parameters: Treatment Feasibility Assessment by Sequential Estimation of Triple Parameters and Filtration Fraction.

The aim was to assess the effect of standard fixed-dose protocol of 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in patients with borderline low renal function of one parameter (glomerular filtration rate [GFR], effective renal plasma flow [ERPF] or serum creatinine), that was discordant with the remaining parameters and determine the feasibility of this procedure in this group of patients. Renal toxicity of PRRT is a routine issue or concern for such cases. We compared different renal parameters used for pretherapy assessment in patients with borderline low single parameter at baseline and their potential significance with regards to deterioration of renal function subsequently. A retrospective analysis was performed in patients of metastatic neuroendocrine tumors who received therapeutic 177Lu-DOTATATE (using standard fixed-dose protocol) and had borderline compromised renal parameter values (either of GFR/ERPF/serum creatinine). Filtration fraction (FF) was also estimated in each case and all renal parameters were correlated using kappa statistics. The characteristics of cases showing progressive worsening of renal function in the follow-ups were also studied. A total of 15 patients (11 males, 4 females; age range: 32–75 years) were selected among a population of 450 patients. The follow-up duration ranged from 10 to 48 months and administered cumulative activity ranged 9.9–31.3 GBq (2–5 cycles). Based on the parameter characteristics, the study population was divided into following four groups: (a) patients with reduced GFR and maintained ERPF and normal serum creatinine (n = 3); (b) patients with reduced ERPF with maintained GFR and borderline elevated/normal serum creatinine (n = 3); (c) patients with both reduced GFR and ERPF and maintained serum creatinine (n = 1); (d) patients with compromised single kidney function (n = 5). A total of four patients were found who had normal baseline renal function values but showed progressive worsening in the subsequent period. There was no significant change in renal parameters during the follow-up in both Groups a and c. Two patients of Group b demonstrated well-maintained other renal parameters, whereas in 1 patient, there was the evidence of renal toxicity with gradual fall of GFR and ERPF and progressive increase in serum creatinine level. In patients with compromised single kidney function at baseline (Group d), there was overall maintained normal renal parameters, whereas 3 of 5 (60%) showed the increase of FF of the affected kidney. Interestingly, a compensatory hyperfunction was noted in the contralateral kidney. PRRT with 177Lu-DOTATATE is feasible and can be considered in patients with reduced GFR and with maintained ERPF and normal serum creatinine and also in the presence of single compromised parameter if the other two are normal; however, these patients need critical monitoring.

177Lu-DOTATATE peptide receptor radionuclide therapy in metastatic or advanced and inoperable primary neuroendocrine tumors of rare sites

The present study aimed at exploring the patient and imaging characteristics of primary neuroendocrine tumors (NETs) of rare sites who presented with metastatic and/or advanced inoperable stages and therefore was considered for peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE. A retrospective analysis was undertaken of these patients focusing on the aforementioned aspects. All patients underwent dual-tracer molecular functional imaging with somatostatin receptor (SSTR)-based imaging (with either 99mTc-HYNIC-TOC or 68Ga-DOTATATE) and 18fluorine fludeoxyglucose positron emission tomography-computed tomography as the pretherapy assessment. Based on the qualitative uptake of tracer in SSTR imaging, the lesions were divided into four categories Grade 0–III. The response was assessed post-PRRT by three parameters: (i) symptomatic response, (ii) biochemical response (serum tumor marker), and (iii) objective imaging response. The response profiles under each of these scales were assessed utilizing predefined criteria (detailed in methods). The overall response classification into partial response, stable disease, and progressive disease was done based on documentation of similar scale/category of at least two parameters among the triple parametric assessment. A total of nine patients (7 males, 2 females; age range: 33–59 years) with rare site primary NET were found: The primary sites included ureter (n = 1), sacrococcygeal (n = 1), esophagus (n = 1), thymus (n = 3), and mediastinum (n = 3). Treatment response assessment was undertaken in eight patients who received more than 2 cycles of PRRT with 177Lu-DOTATATE. In this response assessment group (n = 8), the patients received 2–5 cycles and follow-up duration ranged from 5 to 48 months. Symptomatic responses and better quality of life were observed in 4/8 (50%) patients, stable symptomatic disease in 3/8 (37.5%), and progression in 1/8 patients (12.5%). Biochemically, partial response was seen in 3/8 (37.5%), stable values was seen in 3/8 (37.5%), and progression of tumor marker was seen in 2/8 (25%) patients. Morphologically, partial response was seen in 2/8 (25%), stable disease in 5/8 (62.5%), and progressive disease in 1/8 (12.5%) patients. On overall assessment, 2/8 patients (25%) demonstrated partial response, 4/8 stable disease (50%), and 2/8 progressive disease (25%) at the time of assessment. As per the RECIST 1.1, seven patients had stable disease and one patient had progressive disease. No specific correlation could be obtained between dual-tracer molecular imaging features and the response likely due to small population of the study group. Overall, there was evidence of excellent disease stabilization, and symptom palliation with 177Lu-DOTATATE PRRT was documented in these advanced or metastatic NETs of various rare sites.

Clinical Response Profile of Metastatic/Advanced Pulmonary Neuroendocrine Tumors to Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE.

The aims of this study were to perform multiparametric response assessment of metastatic/advanced pulmonary neuroendocrine tumors (NETs) to Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) (clinical, biochemical, molecular/structural imaging, and survival assessment) and to study the relationship between response, mortality, and overall survival with dual-tracer molecular imaging parameters. Twenty-two patients (6 women, 16 men; median age, 44 years; range, 16-72 years) of histopathologically proven pulmonary NETs with metastatic/advanced disease were included and analyzed retrospectively. Lu-DOTATATE PRRT was administered using standardized protocol (150 mCi [5.55 GBq] per cycle, cycles repeated at 12-16 weeks' intervals [range, 1-5 cycles; average, 4 cycles]) with amino acid-based renal protection. Assessment with Tc-HYNIC-TOC (in the initial years of PRRT development, n = 11)/Ga-DOTATATE PET/CT (presently, n = 11) and F-FDG PET/CT (n = 22), symptomatic and biochemical parameters (serum CgA and urinary 5-HIAA levels), and anatomical response using contrast-enhanced CT (after 3 cycles) was part of routine pretreatment and response evaluation. The patients were designated as responders and nonresponders based on predefined response assessment criteria. Kaplan-Meier product-limit method was calculated for overall survival (OS) curve after the first PRRT, and corresponding 95% confidence intervals (95% CIs) were estimated for annual survival at 1, 2, 3, and 4 years. The various prognostic variables were also investigated for association with mortality, OS, and treatment response following PRRT. Of 22 patients, 6 had undergone surgical resection of primary tumors. All patients were symptomatic before start of PRRT. Two patients did not qualify for PRRT, and 1 received single cycle with follow-up less than 3 months, hence excluded from the present analysis. Thus, a total 19 patients were analyzed in our study. Symptomatic response following PRRT was observed in 15 (79%) of 19 patients. Based on predefined 3-scale response evaluation criteria, of 19 patients, 12 patients (63%) were finally characterized as responders, and 7 patients (37%) were overall nonresponder to PRRT. All 7 nonresponders had moderate to intense FDG-avid primary lung lesion (SUVmax >5 in 4 of 7 patients), and 5 had FDG-avid metastatic liver disease (SUVmax >5). Peptide receptor radionuclide therapy was well tolerated in all with no major hematologic and renal toxicity (except for 2 patients showing mild grade I renal and hematologic toxicity in the initial cycles and recovery in subsequent follow-up). Seven (37%) of 19 died at the time of analysis. The observed annual OS rates were as follows: 1 year: 94.7% (95% CI, 68.1%-99.2%), 2 years: 66% (95% CI, 35.5%-84.5%), 3 years: 57.7% (95% CI, 28-78.9%), and 4 years: 38.5% (95% CI, 8.1%-69.5%); median OS was 40 months with 39% (95% CI, 13.1%-64.8%). In conclusion, Lu-DOTATATE PRRT was found safe and well tolerated in receptor-positive pulmonary NET. FDG positivity appeared to forecast aggressive tumor behavior.

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors

The landscape of treatment options in neuroendocrine tumors (NET) has changed in the last 5 years. Novel targeted drugs have been introduced and approved for distinct types of NET. Furthermore, with the first randomized trial on ¹⁷⁷Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in midgut NET, not only is approval of this treatment awaited but also its more widespread use. Techniques and choices of radionuclides have changed over time as well as imaging tools. Recognition of well-differentiated NET G3 within the group of neuroendocrine neoplasms G3 has widened the spectrum of chemotherapeutic drugs used in this field. Even more so, it has become important to provide recommendations for daily clinical practice on how to safely use novel drugs, chemotherapeutic agents, and PRRT. The updated ENETS consensus guidelines for the standards of care in NET provide a tool to accurately assess the diagnosis of NET as well as practical recommendations for the use of surgery, and the different systemic therapeutic options that are available for the management of NET.

Performance of 177Lu-DOTATATE-based peptide receptor radionuclide therapy in metastatic gastroenteropancreatic neuroendocrine tumor: a multiparametric response evaluation correlating with primary tumor site, tumor proliferation index, and dual tracer imaging characteristics.

To assess the performance of Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in metastatic gastroenteropancreatic neuroendocrine tumor (GEP-NET) and correlate it with primary tumor site, tumor proliferation index, and dual tracer imaging characteristics. Fifty patients (M : F 33 : 17, age: 26-71 years) with histopathologically confirmed metastatic/inoperable NETs who had undergone at least three cycles of PRRT with Lu-DOTATATE were included in the analysis. As part of the pretreatment evaluation, they underwent either Tc-HYNIC TOC (n=40)/Ga-DOTATATE PET (n=10) or fluorine-18-fluorodeoxyglucose (F-FDG) PET-computed tomography (CT). Response was assessed after three and five cycles PRRT on the basis of three parameters: (a) symptomatic and subjective scale, (b) biochemical tumor marker level, and (c) objective imaging (F-FDG/Ga DOTATATE PET/CT, Tc-HYNIC TOC, ceCT), and was categorized using predefined criteria (detailed in methods). Stable disease on imaging assessment with response on symptomatic or biochemical tumor marker scales or both were included in the responder group. The study population was broadly classified into (a) metastatic GEP-NET with known primary (n=43 i.e. 86%), which was further subclassified according to the site of primary and (b) those with unknown primary (n=7 i.e. 14%). Symptomatic response: 96% of patients showed a symptomatic response or improvement in health-related quality of life, irrespective of tumor proliferation index, dual tracer imaging characteristics, and response or progression of disease in the scan. Biochemical tumor marker response: 83% of scan responders showed a decrease, 10% showed a stable value, and 7% showed an increase in tumor marker levels. Among the scan nonresponders, 67% patients showed a corresponding increase in the tumor marker level, 22% patient showed a decrease, whereas 11% showed stable values. Scan response: 31 out of total 50 patients (62%) showed a partial scan response with either a decrease in the number of somatostatin receptor (SSTR)-positive lesions or metabolic activity in F-FDG/Ga-DOTATATE PET-CT or both, 10 patients (20%) showed stable disease, and nine patients (18%) showed progressive disease. The higher objective partial scan response documented can be explained by the introduction of the F-FDG-PET/CT parameter as a determinant criterion. Among the responders category (n=41), 32 (78.04%) showed discordance between F-FDG-PET/CT-based and SSTR-based imaging, whereas eight out of nine patients with nonresponse category (88.89%) showed concordance between SSTR-based imaging and F-FDG-PET/CT. Conversely, 32 of 33 patients (96.97%) with SSTR/F-FDG discordance and nine out of 17 (52.94%) with concordance were finally classified as responders, whereas the remaining, that is, 1/33 (3.03%) in the 'discordant' category and 8/17 (47.06%) with imaging concordance were classified as nonresponders, respectively. Our data show that high pretherapy F-FDG maximum standardized uptake values were associated with increased chances of treatment refractoriness in GEP-NETs. However, symptomatic improvement was observed in most cases irrespective of grade and F-FDG uptake. High pretherapy F-FDG maximum standardized uptake value in both low-grade and high-grade NET predicted a poor outcome and was associated with disease progression. Introduction of F-FDG-PET/CT parameter as a determinant of response classification increases the percentage of objective scan responders among patients with grades I and II GEP-NETs as F-FDG activity was observed to decrease before SSTR-based imaging and more frequently compared with the latter.

Peptide receptor radionuclide therapy for metastatic paragangliomas.

There is little evidence to direct the management of malignant paragangliomas (mPGL) beyond initial surgical treatment. Peptide receptor radionuclide therapy (PRRT), using somatostatin analogues, is effective in other neuroendocrine tumours, but data on its efficacy in treating mPGL are scarce. We report safety and efficacy outcomes from a case series of five patients with advanced mPGLs treated with (177)Lu-DOTATATE PRRT. The mean age of our cohort was 34years (range 16-47); 4 patients were male with bone disease being the most prevalent metastatic site. PRRT scheme varied between 1 and 4 cycles, with premature cessation due to suspected pneumonitis in one case and disease progression in another. Three patients with previously documented progressive disease achieved stabilization following treatment; one had partial response and one was treatment refractory. Median progression-free survival was 17months (range 0-78months). 177-Lu-DOTATATE is an effective therapy in mPGLs in this molecularly defined patient cohort, warranting further investigation in larger studies including hereditary and sporadic mPGL.

177Lu-DOTATATE PRRT in Patients with Metastatic Neuroendocrine Tumor and a Single Functioning Kidney: Tolerability and Effect on Renal Function.

Our objective was to assess the renal toxicity profile of (177)Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in patients with a metastatic neuroendocrine tumor (NET) and a single functioning kidney. This was a retrospective analysis of NET patients who had undergone (177)Lu-DOTATATE PRRT at a large tertiary-care center. All patients selected for the study had somatostatin receptor-positive NETs, had received at least 3 cycles of (177)Lu-DOTATATE PRRT, and had a documented single functioning kidney. The analyzed parameters included patient characteristics, metastatic burden, renal characteristics at diagnosis and during therapy, and nephrotoxic factors. For the renal assessment, the following characteristics were studied before each PRRT cycle: glomerular filtration rate (GFR) as estimated by (99m)Tc-diethylenetriamine pentaacetic acid renography, effective renal plasma flow (ERPF) as measured by (99m)Tc-ethylenedicysteine renography, and blood urea and serum creatinine levels. Renal toxicity was evaluated using version 4.0 of the Common Terminology Criteria for Adverse Events (NCI-CTCAE score). The percentage reduction in GFR and ERPF was also assessed. Filtration fraction was calculated to clarify whether there was a relatively greater reduction in one index of renal function than in the other. At the time of analysis, 6 patients met the inclusion criteria, having received between 3 and 5 cycles of therapy with a cumulative activity of 16.6-36.2 GBq. The duration of follow-up ranged from 12 to 56 mo. The overall toxicity profile (as per the NCI-CTCAE score) showed no acute renal toxicity in any patient. Regarding overall chronic renal toxicity, 3 patients had none, 1 patient had grade II, and 2 patients had grade I. All patients with overall chronic renal toxicity showed compromised renal function at the outset (baseline). The 2 patients with grade I chronic renal toxicity after PRRT had grade II at baseline and gradual improvement over the subsequent cycles. One patient with grade II at baseline showed transient worsening to grade III after the first cycle followed by gradual improvement and a return to baseline after the second cycle. Only 2 patients showed a reduction in GFR (5.3% in one and 13.84% in the other). Four patients showed a reduction in ERPF (31.4% in the patient with the greatest reduction), and all had a rise in filtration fraction signifying that tubular parameters were more affected than glomerular parameters. With proper renal protection and dose fractionation, it is feasible to use (177)Lu-DOTATATE PRRT in patients with NET and a single functioning kidney. Further studies are required to assess the long-term renal consequences of changes in ERPF and filtration fraction in these patients.

Pharmacokinetic digital phantoms for accuracy assessment of image-based dosimetry in 177Lu-DOTATATE peptide receptor radionuclide therapy

Patient-specific image-based dosimetry is considered to be a useful tool to limit toxicity associated with peptide receptor radionuclide therapy (PRRT). To facilitate the establishment and reliability of absorbed-dose response relationships, it is essential to assess the accuracy of dosimetry in clinically realistic scenarios. To this end, we developed pharmacokinetic digital phantoms corresponding to patients treated with 177Lu-DOTATATE. Three individual voxel phantoms from the XCAT population were generated and assigned a dynamic activity distribution based on a compartment model for 177Lu-DOTATATE, designed specifically for this purpose. The compartment model was fitted to time-activity data from 10 patients, primarily acquired using quantitative scintillation camera imaging. S values for all phantom source-target combinations were calculated based on Monte-Carlo simulations. Combining the S values and time-activity curves, reference values of the absorbed dose to the phantom kidneys, liver, spleen, tumours and whole-body were calculated. The phantoms were used in a virtual dosimetry study, using Monte-Carlo simulated gamma-camera images and conventional methods for absorbed-dose calculations. The characteristics of the SPECT and WB planar images were found to well represent those of real patient images, capturing the difficulties present in image-based dosimetry. The phantoms are expected to be useful for further studies and optimisation of clinical dosimetry in 177Lu PRRT.

177 Lu-Dota-octreotate radionuclide therapy of advanced gastrointestinal neuroendocrine tumors: results from a phase II study

We evaluated the activity and safety profile of (177)Lu-Dotatate peptide receptor radionuclide therapy (Lu-PRRT) in patients with advanced, well-differentiated (G1-G2) gastrointestinal neuroendocrine tumors (GI-NETs). Forty-three patients with radiological tumor progression at baseline and a positive Octreoscan® completed the treatment with Lu-PRRT, resulting in the cumulative activity of 18.5 or 27.8 GBq in five cycles. Total activity was scheduled on the basis of kidney function or bone marrow reserve. Twenty-five (58 %) patients were treated with a "standard" Lu-PRRT full dosage (FD) of 25.7 GBq (range 22.2-27.8), while the remaining 18 patients (42 %) who, at enrolment, showed a higher probability of developing kidney or bone marrow toxicity received a reduced dosage (RD) of 18.4 GBq (range 14.4-20.4). According to SWOG criteria, the overall response was complete response (CR) in (7 %) cases and stable disease (SD) in 33 (77 %), with a disease control rate (DCR) of 84 %. Median response duration was 25 months (range 7-50). Median progression-free survival (PFS) was 36 months (95 % CI 24-nr), and median overall survival (OS) has not yet been reached. Remarkably, none of the patients, including those at a higher risk of toxicity, showed side-effects after either dosage of Lu-PRRT. Lu-PRRT was shown to be an effective therapeutic option in our patients with advanced progressive GI-NETs, showing an 84 % DCR (95 % CI 73-95) that lasted for 25 months and a PFS of 36 months. Both activities of 27.8 GBq and 18.5 GBq proved safe and effective in all patients, including those with a higher probability of developing kidney or bone marrow toxicity.

Induction of Anti-Tumor Immune Responses by Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE in a Murine Model of a Human Neuroendocrine Tumor

Peptide receptor radionuclide therapy (PRRT) is a relatively new mode of internally targeted radiotherapy currently in clinical trials. In PRRT, ionizing radioisotopes conjugated to somatostatin analogues are targeted to neuroendocrine tumors (NETs) via somatostatin receptors. Despite promising clinical results, very little is known about the mechanism of tumor control. By using NCI-H727 cells in an in vivo murine xenograft model of human NETs, we showed that 177Lu-DOTATATE PRRT led to increased infiltration of CD86+ antigen presenting cells into tumor tissue. We also found that following treatment with PRRT, there was significantly increased tumor infiltration by CD49b+/FasL+ NK cells potentially capable of tumor killing. Further investigation into the immunomodulatory effects of PRRT will be essential in improving treatment efficacy.

Role of 18FDG PET/CT in patients treated with 177Lu-DOTATATE for advanced differentiated neuroendocrine tumours

The prognostic value of FDG PET for neuroendocrine tumours (NETs) has been reported. In this study we evaluated the role of FDG PET in predicting response and progression-free survival (PFS) after (177)Lu-DOTATATE peptide receptor radionuclide therapy (Lu-PRRT) in patients with advanced well-differentiated grade 1/2 NETs. We retrospectively evaluated 52 patients with progressive advanced NETs overexpressing somatostatin receptors and treated with Lu-PRRT with a cumulative activity up to 27.7 GBq divided into five courses. According to WHO 2010/ENETS classification, patients were stratified into two groups: those with grade 1 tumour (Ki-67 index ≤2 %, 19 patients), and those with grade 2 tumour (Ki-67 index >3 % to <20 %, 33 patients). On the basis of the FDG PET scan, 33 patients were classified as PET-positive (PET+) and 19 as PET-negative (PET-). FDG PET was positive in 57 % of patients with grade 1 NET and in 66 % of patients with grade 2 NET, and the rates of disease control (DC, i.e. complete response + partial response + stable disease) in grade 1 and grade 2 patients were 95 % and 79 %, respectively (P = 0.232). In PET- and PET+ patients, the DC rates were 100 % and 76 % (P = 0.020) with a PFS of 32 and 20 months, respectively (P = 0.033). Of the PET+ patients with grade 1 NET, 91 % showed disease control, whereas about one in three PET+ patients with grade 2 NET (32 %) progressed after Lu-PRRT (DC rate 68 %). These results suggest that FDG PET evaluation is useful for predicting response to Lu-PRRT in patients with grade 1/2 advanced NETs. Notably, none of PET- patients had progressed at the first follow-up examination after Lu-PRRT. Grade 2 NET and PET+ (arbitrary SUV cutoff >2.5) were frequently associated with more aggressive disease. PET+ patients with grade 2 NET, 32 % of whom did not respond to Lu-PRRT monotherapy, might benefit from more intensive therapy protocols, such as the combination of chemotherapy and PRRT.

Can the Standardized Uptake Values derived from Diagnostic 68Ga-DOTATATE PET/CT Imaging Predict the Radiation Dose delivered to the Metastatic Liver NET Lesions on 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy?

ABSTRACT Introduction Neuroendocrine neoplasms express somatostatin receptors, enabling the use of somatostatin analogs for molecular imaging, when labeled with the positron-emitter 68Ga for receptor positron emission tomography/computed tomography (PET/CT), and targeted radionuclide therapy, when labeled with beta-emitters, e.g. 90Y and 177Lu. Aim To investigate if 68Ga-DOTATATE PET-derived standardized uptake values (SUV) correlate with the dose delivered to the liver lesions following 177Lu-DOTATATE radionuclide therapy in patients with neuroendocrine neoplasms. Materials and methods Twelve adult (8M: 4F; mean age: 55.9 ± 14.5 years; range: 23-78 years) patients with documented neuroendocrine tumor (NET) disease and liver metastases were enrolled in the study. Ten patients were subjected to 68Ga-DOTATATE and one patient each underwent 68Ga-DOTATOC and 68Ga-DOTANOC diagnostic PET/CT imaging. Subsequently, on the basis of positive PET/CT scan findings for the metastatic NET disease, all these patients were subjected to peptide receptor radionuclide therapy (PRRNT) with 177Lu-DOTATATE. The reconstructed PET/CT data was used to calculate the SUVs on the identifiable liver lesions. The scintigraphic data acquired (anterior and posterior whole body images) following therapeutic doses of 177Lu-DOTATATE were subjected to the quantitative analysis (HERMES workstation and OLINDA/EXM software) to calculate the dose delivered to the hepatic lesions. Results The initial results of this preliminary study indicate poor correlation between SUV and the tumor dose and the linear regression analysis provided R2 values which explained only a small fraction of the total variance. Conclusion The SUVs derived from 68Ga-DOTA-peptide PET/CT images should be used with caution for the prediction of tumor dose on 177Lu-DOTA-peptide therapy as there are large intra- and interpatient variability. Further studies with large numbers of patients are warranted to establish such a correlation between SUV, tumor dose and the response assessment. How to cite this article Singh B, Prasad V, Schuchardt C, Kulkarni H, Baum RP. Can the Standardized Uptake Values derived from Diagnostic 68Ga-DOTATATE PET/CT Imaging Predict the Radiation Dose delivered to the Metastatic Liver NET Lesions on 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy? J Postgrad Med Edu Res 2013;47(1):7-13.