Hypoalbuminemia, but not derived neutrophil to lymphocyte ratio (dNLR), predicts overall survival in neuroendocrine tumours undergoing peptide receptor radionuclide therapy: A retrospective, cohort study of 557 patients.

Several inflammation scores have shown association with survival outcomes for patients with neuroendocrine tumours (NET) treated with peptide receptor radionuclide therapy (PRRT). However, whether these scores add value to established prognostic factors remains unknown. In this retrospective, cohort study of 557 NET patients undergoing PRRT in a tertiary referral centre from 2005 to 2015, we examined inflammatory markers and scores previously associated with cancer outcomes, using Cox proportional hazard models and Akaike's information criterion. Lower albumin (hazard ratio [95% confidence interval], .91 [.87-.95] per unit), as well as higher C-reactive protein (CRP; 1.02 [1.01-1.02]), Glasgow Prognostic Score (GPS; 1 vs. 0: 1.67 [1.14-2.44], 2 vs. 0 3.60 [2.24-5.79]), CRP/albumin ratio (1.84 [1.43-2.37]) and platelet count (Plt) × CRP, but not white blood cell, neutrophil and thrombocyte counts or derived neutrophil to lymphocyte ratio (dNLR), were associated with shorter median overall survival (OS) in an adjusted analysis. The addition of parameters based on albumin and CRP, but not dNLR, to a base model including age, chromogranin A, the cell proliferation marker Ki-67, performance status, tumour site and previous treatments improved the predictive accuracy of the base model. In an exploratory analysis of patients with available erythrocyte sedimentation rate (ESR) and CRP, ESR emerged as the most powerful predictor. When added to a prognostic model for OS in NET patients treated with PRRT, most inflammation scores further improved the model. Albumin was the single marker adding most value to the set of established prognostic markers, whereas dNLR did not seem to improve the model's prognostic ability.

Receptor depletion and recovery in small-intestinal neuroendocrine tumors and normal tissues after administration of a single intravenous dose of octreotide measured by 68Ga-DOTATOC PET/CT.

BACKGROUND: Low-grade neuroendocrine tumors (NETs) are characterized by an abundance of somatostatin receptors (SSTR) that can be targeted with somatostatin analogs (SSA). When activated with a single dose of SSA, the receptor-ligand complex is internalized, and the receptor is by default recycled within 24 h. Ongoing medication with long-acting SSAs at 68Ga-DOTA-SSA-PET has been shown to increase the tumor-to-normal organ contrast. This study was performed to investigate the time-dependent extended effect (7 h) of a single intravenous dose of 400 µg short-acting octreotide on the tumor versus normal tissue uptake of 68Ga-DOTATOC. METHODS: Patients with small-intestinal NETs received a single intravenous dose of 400 µg octreotide and underwent dynamic abdominal 68Ga-DOTATOC-PET/CT at three sessions (0, 3 and 6 h) plus static whole-body (WB) PET/CT (1, 4 and 7 h), starting each PET/CT session by administering 167 ± 21 MBq, 23.5 ± 4.2 µg (mean ± SD, n = 12) of 68Ga-DOTATOC. A previously acquired clinical whole-body 68Ga-DOTATOC scan was used as baseline. SUV and net uptake rate Ki were calculated in tumors, and SUV in healthy organs. RESULTS: Tumor SUV decreased significantly from baseline to 1 h post-injection but subsequently increased over time and became similar to baseline at 4 h and 7 h. The tumor net uptake rate, Ki, similarly increased significantly over time and showed a linear correlation both with SUV and tumor-to-blood ratio. By contrast, the uptake in liver, spleen and pancreas remained significantly below baseline levels also at 7 h and the receptor turn-over in tumors thus exceeded that in the normal tissue, with restitution of tumor 68Ga-DOTATOC uptake mainly completed at 7 h. These results however differed depending on tumor size, with significant increases in Ki and SUV between the 1st and 2nd PET, in large tumors (≥ 4 mL) but not in small (> 1 to < 4 mL) tumors. CONCLUSION: SSTR recycling is faster in small-intestinal NETs than in liver, spleen and pancreas. This opens the possibility to protect normal tissues during PRRT by administering a single dose of cold peptide hours before peptide receptor radionuclide therapy (PRRT), and most likely additionally improve the availability and uptake of the therapeutic preparation in the tumors.

Tumor growth rate in pancreatic neuroendocrine tumor patients undergoing PRRT with 177Lu-DOTATATE.

BACKGROUND: Monitoring of pancreatic neuroendocrine tumors (PanNET) undergoing peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE depends on changes in tumor size, which often occur late. Tumor growth rate (TGR) allows for quantitative assessment of the tumor kinetics expressed as %/month. We explored how TGR changes before and during/after PRRT and evaluated TGR as a biomarker for progression-free survival (PFS). METHODS: In PanNET patients undergoing PRRT with 177Lu-DOTATATE from 2006 to 2018, contrast-enhanced CT or MRI was performed before and during the therapy. Patients with at least one hypervascular liver metastasis were included. TGR was calculated for the period preceding treatment and for two intervals during/after PRRT. Cox regression was used for the survival analysis. RESULTS: Sixty-seven patients (43 men, 24 women), median age 60 years (range 29-77), median Ki-67 10% (range 1-30) were included. TGR before baseline (n = 57) (TGR0) was mean (s.d.) 6.0%/month (s.d. = 8.7). TGR at 4.5 months (n = 56) (TGR4) from baseline was -3.4 (s.d. = 4.2) %/month. TGR at 9.9 months (n = 57) (TGR10) from baseline was -3.0 (s.d. = 2.9) %/month. TGR4 and TGR10 were lower than TGR0 (TGR4 vs TGR0, P < 0.001 and TGR10 vs TGR0, P < 0.001). In the survival analysis, patients with TGR10 ≥ 0.5%/month (vs <0.5%/month) had shorter PFS (median = 16.0 months vs 31.5 months, hazard ratio 2.82; 95% CI 1.05-7.57, P = 0.040). DISCUSSION: TGR in PanNET patients decreases considerably during PRRT with 177Lu-DOTATATE. TGR may be useful as a biomarker to identify patients with the shortest PFS.

177Lu-DOTATATE Therapy of Advanced Pancreatic Neuroendocrine Tumors Heavily Pretreated with Chemotherapy: Analysis of Outcome, Safety, and Their Determinants.

OBJECTIVE: To retrospectively analyze toxicity, progression-free survival (PFS), overall survival (OS), and their determinants in patients with advanced pancreatic neuroendocrine tumors (PanNETs), previously pretreated with chemothe-r-apy, undergoing peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE. METHODS: A total of 102 patients with advanced PanNETs, previously pretreated with one (67%) or several (33%) lines of chemotherapy, were included, of whom 90% had progressive disease and the majority (74.5%) had grade 2 tumors. 177Lu-DOTATATE, 7.4 GBq per cycle, was administered with 6- to 8-week intervals in 88% of patients utilizing a dosimetry-guided protocol until an absorbed dose of 23 Gy to the kidneys was reached. RESULTS: A mean dose of 32 ± 10.9 GBq per patient was administered in 1-10 cycles starting a median of 36 months after PanNET diagnosis. The median follow-up was 34 months, the median PFS was 24 months, and the median OS was 42 months from start of PRRT. Independent risk factors for both progression and death were liver tumor burden >50%, more than one line of previous chemotherapy, and elevated alkaline phosphatase. Resection of the primary tumor was linked to longer survival. Bone marrow toxicity grade 3-4 occurred in 10.8%. One patient (1.0%) developed acute myeloid leukemia. Bone marrow toxicity was unrelated to type and length of previous chemotherapy, amount of administered activity, and absorbed dose to the bone marrow. CONCLUSION: 177Lu-DOTATATE therapy was feasible, highly effective, and safe in patients with advanced PanNETs heavily pretreated with chemotherapy. More than one line of chemotherapy was a therapy-related independent risk factor for shorter PFS and OS.

Kidney dosimetry in 777 patients during 177Lu-DOTATATE therapy: aspects on extrapolations and measurement time points.

PURPOSE: Fractionated 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. METHODS: In 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. RESULTS: The 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. CONCLUSION: When 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.

Tumor Contrast-Enhancement for Monitoring of PRRT 177Lu-DOTATATE in Pancreatic Neuroendocrine Tumor Patients.

Background: Therapy monitoring of cancer treatment by contrast-enhanced CT (CECT), applying response evaluation criteria in solid tumors criteria version 1. 1 (RECIST 1.1) is less suitable for neuroendocrine tumors (NETs) which, when responding, tend to show stabilization rather than shrinkage. New methods are needed to further classify patients in order to identify non-responders at an early stage and avoid unnecessary adverse effects and costs. Changes in arterial tumor attenuation and contrast-enhancement could be used to identify the effect of therapy, perhaps even in early stages of treatment. Methods: Patients with metastatic pancreatic NETs (PNETs) receiving peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE underwent CECT at baseline, mid-treatment (PRRT cycles 3-5) and at follow-up, 3 months after the last PRRT cycle. At baseline CECT, the liver metastasis with the highest arterial attenuation was identified in each patient. The fold changes in arterial tumor attenuation (Hounsfield Units, HU), contrast-enhancement (HU), and transversal tumor area (cm2) between CECT at baseline, mid-treatment and follow-up were calculated. Correlation of the tumor metrics to outcome parameters such as progression-free survival (PFS) and time to best response was performed. Results: Fifty-two patients were included (27 men, 25 women), median age 60 years (range 29-80), median Ki-67 8% (range 1-30). Six patients had grade 1 PNETs, forty had grade 2 and four had grade 3 tumors. As an internal control, it was first tested and established that the tumor contrast-enhancement was not merely related to that of the abdominal aorta. The mean ± SD arterial attenuation of the liver metastases was similar at baseline, 217 ± 62 HU and at mid-treatment, 238 ± 80 HU and then decreased to 198 ± 62 HU at follow-up, compared to baseline (p = 0.024, n = 52) and mid-treatment (p = 0.0004, n = 43). The transversal tumor area decreased 25% between baseline and follow-up (p = 0.013, n = 52). Tumor contrast-enhancement increased slightly from baseline to mid-treatment and these fold changes correlated with PFS (R 2 = 0.33, p = 0.0002, n = 37) and with time to best response (R 2 = 0.34, p < 0.0001, n = 37). Conclusions: Early changes in contrast-enhancement and arterial attenuation in PNET liver metastases may for CECT monitoring of PRRT yield complementary information to evaluation by RECIST 1.1.

In Vivo Instability of 177Lu-DOTATATE During Peptide Receptor Radionuclide Therapy.

Peptide receptor radiotherapy using 177Lu-labeled somatostatin ligand analogs is a well-established treatment for neuroendocrine tumors, with 177Lu-DOTATATE having acquired marketing authorization in Europe and the United States. The investigation of the pharmacokinetics of these radiopharmaceuticals in vivo in humans is crucial for personalized treatment management and understanding of treatment effects. Such an investigation requires input data on the in vivo stability of the radiopharmaceuticals in blood and plasma. The work presented here is devoted to the investigation of the in vivo stability of 177Lu-DOTATATE in humans affected by neuroendocrine tumors. Methods: Blood samples of 6 patients undergoing 177Lu-DOTATATE were taken at 0.5, 4, 24, and 96 h after injection. Analysis of metabolic stability was performed using high-performance liquid chromatography. Results: A fast metabolism of the radiopharmaceutical was observed, with the fraction of intact 177Lu-DOTATATE in plasma decreasing rapidly to 23% ± 5% (mean ± SD) at 24 h and 1.7% ±0. 9% at 96 h after injection. Conclusion: The in vivo stability of 177Lu-DOTATATE is much lower than previously assumed, with the major part of radioactivity in plasma consisting of 177Lu-labeled metabolites already at 24 h after injection.

Favorable Outcome in Patients with Pheochromocytoma and Paraganglioma Treated with 177Lu-DOTATATE.

Peptide receptor radiotherapy (PRRT) with 177Lu-DOTATATE has emerged as a promising therapy for neuroendocrine tumors (NETs). This retrospective cohort study aimed to assess the outcome of PRRT for 22 patients with histopathologically confirmed pheochromocytoma (PCC) and paraganglioma (PGL), of which two were localized and 20 metastatic. Radiological response utilized response evaluation criteria in solid tumors 1.1 and toxicity was graded according to common terminology criteria for adverse events version 4. Median 4 (range 3-11) 7.4 GBq cycles of 177Lu-DOTATATE were administered as first-line therapy (n = 13) or because of progressive disease (n = 9). Partial response (PR) was achieved in two and stable disease (SD) in 20 patients. The median overall survival (OS) was 49.6 (range 8.2-139) months and median progression-free survival (PFS) was 21.6 (range 6.7-138) months. Scintigraphic response >50% was achieved in 9/19 (47%) patients. Biochemical response (>50% decrease) of chromogranin A was found in 6/15 (40%) patients and of catecholamines in 3/12 (25%) patients. Subgroup analysis showed Ki-67 <15% associated with longer OS (p = 0.013) and PFS (p = 0.005). PRRT as first-line therapy was associated with increased OS (p = 0.041). No hematological or kidney toxicity grade 3-4 was registered. 177Lu-DOTATATE therapy was associated with favorable outcome and low toxicity. High Ki-67 (≥15%) and PRRT received because of progression on previous therapy could constitute negative predictive factors for OS.

Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity.

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 177Lu-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 177Lu-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.

(99m)Tc-EDDA/HYNIC-octreotate - a new radiotracer for detection and staging of NET: a case of metastatic duodenal carcinoid.

Somatostatin receptor scintigraphy (SRS) has become a routine imaging method for the diagnostics of neuroendocrine tumours (NET). (99m)Tc-EDDA/HYNIC-octreotate (Polatom, Poland) is a new radiotracer with high affinity for SSTR2 and similar physiological biodistribution to (111)In-Octreoscan. We present a case of a 47-year-old man with disseminated duodenal carcinoid. The patient had been operated due to the tumour mass detected in pancreatic head area. Histopathology revealed carcinoid of the duodenal wall with local lymph node and liver metastases. The patient was qualified for chemotherapy stopped due to severe leucopenia. (99m)Tc EDDA/HYNIC-octreotate scintigraphy was performed for staging and to determine SSTR status of the tumour before planned 90Y-DOTATATE therapy. The multiple metastatic lesions were detected all over the body. The high quality images with high target/non target ratio were obtained. (99m)Tc-MDP scintigraphy confirmed multiple bone metastases. On the basis of SRS result the patient was qualified for 90Y-DOTA-TATE therapy. In conclusion, (99m)Tc EDDA/HYNIC-octreotate can be regarded as a promising tracer for staging and to determine SSTR status of NET.