The relationship between tumour dosimetry, response, and overall survival in patients with unresectable Neuroendocrine Neoplasms (NEN) treated with 177Lu DOTATATE (LuTate).

Peptide Receptor Radionuclide Therapy (PRRT) delivers targeted radiation to Somatostatin Receptor (SSR) expressing Neuroendocrine Neoplasms (NEN). We sought to assess the predictive and prognostic implications of tumour dosimetry with respect to response by 68 Ga DOTATATE (GaTate) PET/CT molecular imaging tumour volume of SSR (MITVSSR) change and RECIST 1.1, and overall survival (OS). METHODS: Patients with gastro-entero-pancreatic (GEP) NEN who received LuTate followed by quantitative SPECT/CT (Q-SPECT/CT) the next day (Jul 2010 to Jan 2019) were retrospectively reviewed. Single time-point (STP) lesional dosimetry was performed for each cycle using population-based pharmacokinetic modelling. MITVSSR and RECIST 1.1 were measured at 3-months post PRRT. RESULTS: Median of 4 PRRT cycles were administered to 90 patients (range 2-5 cycles; mean 27.4 GBq cumulative activity; mean 7.6 GBq per cycle). 68% received at least one cycle with radiosensitising chemotherapy (RSC). RECIST 1.1 partial response was 24%, with 70% stable and 7% progressive disease. Cycle 1 radiation dose in measurable lesions was associated with local response (odds ratio 1.5 per 50 Gy [95% CI: 1.1-2.0], p = 0.002) when adjusted by tumour grade and RSC. Median change in MITVSSR was -63% (interquartile range -84 to -29), with no correlation with radiation dose to the most avid lesion on univariable or multivariant analyses (5.6 per 10 Gy [95% CI: -1.6, 12.8], p = 0.133). OS at 5-years was 68% (95% CI: 56-78%). Neither baseline MITVSSR (hazard ratio 1.1 [95% CI: 1.0, 1.2], p = 0.128) nor change in baseline MITVSSR (hazard ratio 1.0 [95% CI: 1.0, 1.1], p = 0.223) were associated with OS when adjusted by tumour grade and RSC but RSC was (95% CI: 0.2, 0.8, p = 0.012). CONCLUSION: Radiation dose to tumour during PRRT was predictive of radiologic response but not survival. Survival outcomes may relate to other biological factors. There was no evidence that MITVSSR change was associated with OS, but a larger study is needed.

Australasian Consensus Statement on the Identification, Prevention, and Management of Hormonal Crises in Patients with Neuroendocrine Neoplasms Undergoing Peptide Receptor Radionuclide Therapy.

Hormonal crises are a rare but increasingly recognized phenomenon following peptide receptor radionuclide therapy (PRRT) in patients with neuroendocrine neoplasms (NENs). Due to the paucity of published studies, approaches to the identification, prevention, and management of risk factors are inconsistent between different institutions. This consensus statement aimed to provide guidance for NEN patients undergoing PRRT. Our statement has been created on the basis of clinical demand and concerns regarding the precipitation of hormonal crises. A formal literature review was conducted to identify available studies. A total of 19 Australian and New Zealand experts in the fields of medical oncology, nuclear medicine, anaesthetics, and endocrinology collaborated on this consensus statement. The main focus is on carcinoid crises. Other hormonal crises seen in patients with functional pancreatic NENs are addressed briefly. These recommendations are relevant to PRRT centres internationally and should be tailored to local experience and available resources.

Estimation of kidney doses from [177Lu]Lu-DOTA-TATE PRRT using single time point post-treatment SPECT/CT.

BACKGROUND: Dosimetry after [177Lu]Lu-DOTA-TATE therapy can be demanding for both patients and the clinical service due to the need for imaging at several time points. In this work we compare three methods of single time point (STP) kidney dosimetry after [177Lu]Lu-DOTA-TATE therapy with a multiple time point (MTP) dosimetry method. METHOD: Method 1 (MTP): Kidney doses were calculated from 31 patients including 107 therapy cycles. Post-therapy SPECT images were acquired on day 0, 4 and 7 along with a CT scan on day 4. A mono-exponential fit was used to calculate kidney doses using cycle specific data. Method 2 (Consistent effective half-life): The effective half-life [Formula: see text] calculated in cycle 1 was assumed consistent for subsequent cycles of therapy and the activity scaled using a single day 3-5 SPECT/CT. Methods 3 and 4 (Hänscheid and Madsen approximations): The Hänscheid approximation and Madsen approximation were both evaluated using a single SPECT/CT acquired on day 0, 4 and 7. All STP methods were compared to the MTP method for accuracy. RESULTS: Using the MTP method, mean right and left kidney doses were calculated to be 2.9 ± 1.1 Gy and 2.8 ± 0.9 Gy respectively and the population [Formula: see text] was 56 ± 13 h. For the consistent [Formula: see text], Hänscheid and Madsen methods, the percentage of results within ± 20% of MTP method were 96% (n = 70), 95% (n = 80) and 94% (n = 80) respectively. CONCLUSION: All three single time point methods had > 94% of results within ± 20% of the MTP method, however the consistent [Formula: see text] method resulted in the highest alignment with the MTP method and is the only method which allows for calculation of the patient-specific [Formula: see text]. If only a single scan can be performed, day 4 is optimal for kidney dosimetry where the Hänscheid or Madsen approximation can be implemented with good accuracy.

Case Report: Hypoglycemia Due to Metastatic Insulinoma in Insulin-Dependent Type 2 Diabetes Successfully Treated With 177 Lu-DOTATATE.

We describe a 96-year-old man with insulin-dependent type 2 diabetes mellitus who, despite insulin cessation, presented with recurrent hypoglycemia associated with confirmed inappropriate endogenous hyperinsulinemia. 68Ga-DOTATATE-PET/CT scans demonstrated increased uptake in the pancreatic tail with multiple large intensely active liver metastases. Liver biopsy confirmed the diagnosis of well-differentiated metastatic neuroendocrine tumor. He was unsuitable for surgical resection and long-acting somatostatin analog therapy was ineffective. Subsequent management with four cycles of Lutate [177-Lutetium-DOTA0-Tyr3-octreotate (177Lu-DOTATATE)] resulted in resolution of hypoglycemia and ongoing clinical, biochemical, and radiological response 6 years after. This case is unique due to not only the paradoxical entity of insulinoma in insulin-dependent diabetes but also the positive sustained outcome after 177Lu-DOTATATE, given that unresectable metastatic insulinoma carries a poor prognosis. We review published cases of metastatic insulinoma in patients with diabetes mellitus as well as the literature to-date investigating efficacy and safety of Lutate therapy in metastatic insulinoma.

Chemotherapy-Induced Upregulation of Somatostatin Receptor-2 Increases the Uptake and Efficacy of 177Lu-DOTA-Octreotate in Neuroendocrine Tumor Cells.

The peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-octreotate (LuTate) is recommended for different types of neuroendocrine tumors (NETs) which overexpress somatostatin receptors (SSTR). A combination with chemotherapy improves objective response to LuTate in NET patients and here we characterized chemotherapy-induced upregulation of SSTR2 receptors as a cause for this improved response to LuTate. The NET cell lines with low (BON-1) or relatively high (NCI-H727) SSTR2-expression levels, and non-NET cancer and normal cells were treated with chemotherapeutic drugs and assessed for upregulation of SSTR2. We report that an exposure to low or high doses of drugs, such as temozolomide for 24 h or 5 day results in upregulation of SSTR2 between 3-7 days, increased LuTate uptake and decreased rate of cell proliferation. This effect is at the level of SSTR2-mRNA and is more pronounced in low SSTR2 expressing BON-1 than in high SSTR2 expressing NCI-H727 or non-NET cancer or normal cells. Thus, a properly timed pre-treatment with low-dose chemotherapy could not only improve therapeutic efficacy of LuTate in NET patients who are presently eligible for PRRT, but also allow PRRT to be administered to patients with low SSTR-expressing NETs, who would otherwise not respond to this modality because of insufficient radiation delivery.

A Comparison of 2D and 3D Kidney Absorbed Dose Measures in Patients Receiving 177Lu-DOTATATE.

OBJECTIVES: To investigate and compare quantitative accuracy of kidney absorbed dose measures made from both 2D and 3D imaging in patients receiving 177Lu-DOTATATE (Lutate) for treatment of neuroendocrine tumours (NETs). METHODS: Patients receiving Lutate therapy underwent both whole body planar imaging and SPECT/CT imaging over the kidneys at time points 0.5, 4, 24, and 96-120 hours after injection. Planar data were corrected for attenuation using transmission data, and were converted to units of absolute activity via two methods, using either a calibration standard in the field of view or relative to pre-voiding image total counts. Hand drawn regions of interest were used to generate time activity curves and kidney absorbed dose estimates in OLINDA-EXM. Fully quantitative SPECT data were generated using CT-derived corrections for both scatter and attenuation, before correction for dead time and application of a camera specific sensitivity factor to convert data to units of absolute activity. Volumes of interest were defined for kidney using the co-registered x-ray CT, before time activity curves and absorbed dose measures were generated in OLINDA-EXM, both with and without corrections made to the model for patient specific kidney volumes. Quantitative SPECT data were also used to derive dose maps through dose kernel convolution (DKC), which was treated as the gold standard. RESULTS: A total of 50 studies were analysed, corresponding to various cycles of treatment from 21 patients. Planar absorbed dose estimates were consistently higher than SPECT derived estimates by, on average, a factor of 3. CONCLUSION: Quantitative SPECT is considered the gold standard approach for organ specific dosimetry however often relies on in house software. As such planar methods for estimating absorbed dose are much more widely available, and in particular, are often the only source of reference in previously published data. For the case of Lutate dosimetry, planar measures may lead to a three-fold increase in measures of kidney absorbed dose.

First Results and Experience with PRRT in South Africa.

Neuroendocrine tumors (NETs) are a diverse group of tumors that often present late due to nonspecific symptoms. These tumors frequently express somatostatin receptors (SSRs), which allows for positron emission tomography/computed tomography (PET/CT) imaging with Ga-68-DOTATATE. In eligible patients, this may then be followed by peptide receptor radionuclide therapy (PRRT). Here, we report our initial results and experience with PRRT in a developing country, as one of the first groups to provide this therapy in South Africa. Eligible patients with confirmed inoperable NETs were recruited prospectively and treated with Lu-177-DOTATATE. Baseline imaging was performed with either single-photon emission CT- or PET-based SSR analogs, whereas follow-up was performed with 68Ga-DOTATATE PET/CT 6 months post treatment completion. Interim treatment response evaluation was based on post therapy imaging of Lu-177-DOTATATE. A total of 48 patients with a mean age of 58 years were treated with PRRT, of whom 22 (46%) demonstrated stable disease, 20 (42%) demonstrated a partial response, and 6 (12%) demonstrated progressive disease. The median progression-free survival (PFS) was 20 months with an interquartile range (IQR)25%-75% of 4.5-30 months. The median freedom from progression duration was 32 months with an IQR25%-75% of 25-40 months, and the median overall survival was 10 months with an (IQR)25%-75% of 5-24 months. Our subgroup analysis demonstrated an inverse association between metabolic tumor volume with PFS, which requires further validation. In conclusion, PRRT with Lu-177-DOTATATE resulted in a median PFS of 20 months in patients with inoperable NETs in the absence of significant side effects.

Feasibility and accuracy of single time point imaging for renal dosimetry following 177Lu-DOTATATE ('Lutate') therapy.

BACKGROUND: This study aims to assess both feasibility and accuracy of renal dosimetry imaging protocols in patients receiving Lutate therapy for neuroendocrine tumours (NETs), when data acquisition over multiple days is not possible on all cycles. METHOD: Patients who had received a full 4 cycles of Lutate therapy with complete imaging at each cycle were included. Imaging consisted of quantitative SPECT/CT of the kidneys at 4, 24 and 96-120 h post injection. Renal absorbed dose was calculated for each data set, and in addition, five alternative methods were explored for comparison. Method 1: a patient average clearance time (t1/2 average) derived from the first half of contributing patient data was used to estimate absorbed dose for subsequent patients based on 4 h imaging alone; method 2: t1/2 average was applied to subsequent patients on 24 h imaging alone; method 3: a patient-specific clearance rate (t1/2 patient) was determined from complete image data of cycle 1 and applied subsequently to remaining cycles using 4 h image data alone; method 4: t1/2 patient was applied to 24 h imaging alone in subsequent cycles; method 5: the 120 h data was estimated on subsequent cycles based on the cycle 1 fraction of injected activity (%IA) at 24 and 120 h. RESULTS: Twenty treatments from 18 patients, resulting in 80 cycles of therapy, were analysed. The measured average renal absorbed dose per cycle of treatment was 0.38 ± 0.19 Gy/GBq when derived from full imaging data. The use of t1/2 average applied to a single time point led to large deviations of dose estimates from true values (on average 59% and 30%, when using 4 h data and 24 h data, respectively). The use of complete image data on cycle 1 and the derivation of t1/2 patient led to improved dose estimates, with an average deviation from true values of 13% and 2% when using 4 h data only and 24 h data only, respectively. The use of a 120 h %IA derived from cycle 1 led to an average deviation from true dose estimates of 14%. CONCLUSION: In instances where demands on both patients and facilities make multiple time point data acquisition impractical, renal dosimetry is best derived through complete imaging at cycle 1 only followed by a single 24 h imaging time point on subsequent cycles, assuming no significant changes in renal function during the time course of therapy.

Safety and efficacy of everolimus in gastrointestinal and pancreatic neuroendocrine tumors after (177)Lu-octreotate.

Although (177)Lu-octreotate is an effective treatment for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), some patients will fail or develop disease progression necessitating further treatment. We examined whether the safety and efficacy of everolimus after prior treatment with (177)Lu-octreotate is different from the published safety profile of everolimus in GEP-NETs. In this multicenter study, 24 GEP-NET patients were included. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Tumor response was measured according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. Major clinical adverse events (grade 3 or 4) during treatment with everolimus were hyperglycemia (20.8%), fatigue (8.3%), thrombocytopenia (8.3%), and elevated alanine transaminase levels (8.3%). By radiological review, there were four partial responses (16.7%), five patients (62.5%) with stable disease, and three patients (12.5%) with progressive disease. For two patients (8.3%), no data on tumor response were available. Median progression-free survival (PFS) was 13.1 months (95% CI, 11.5-21.2). Median PFS of the current study was longer when compared with the RADIANT-3 trial (13.1 vs 11.4 months) and shorter when compared with the RADIANT-1 trial (13.1 vs 16.7 months). In conclusion, the safety profile of everolimus is not influenced by previous treatment with peptide receptor radiotherapy.