[177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high­dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study.

BACKGROUND: There are currently no standard first-line treatment options for patients with higher grade 2-3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) treatment. METHODS: NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous 177Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (177Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with ClinicalTrials.gov, NCT03972488, and is active and not recruiting. FINDINGS: Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the 177Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7-13·8) in the control group and 22·8 months (19·4-not estimated) in the 177Lu-Dotatate group (stratified hazard ratio 0·276 [0·182-0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the 177Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period. INTERPRETATION: First-line 177Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177Lu-Dotatate should be considered a new standard of care in first-line therapy in this population. FUNDING: Advanced Accelerator Applications, a Novartis Company.

177 Lu-DOTATATE PRRT Safety and Organ-at-Risk Dosimetry in Patients With Gastroenteropancreatic Neuroendocrine Tumors : Data From the Prospective Phase 2 LUMEN Study.

PURPOSE: The aim of this study was to assess the association among toxicity, dosimetry of organs-at-risk, and disease progression in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with 177 Lu-DOTATATE. PATIENTS AND METHODS: Thirty-seven patients with GEP-NETs underwent 177 Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in a single-arm, prospective, phase 2 study, where patients were followed up with blood tests, isotopic glomerular filtration rate (iGFR), and imaging examinations (CT/MRI and PET) every 6 months until disease progression. Adverse events (AEs) graded per CTCAEv4.03 and occurring during treatment were collected and followed up until resolution. Dosimetry, including biologically effective doses (BEDs) to kidneys, BED to bone marrow, and absorbed dose (AD) to spleen, was performed after each PRRT cycle. Statistical analyses explored associations among dosimetry, toxicity, and patient progression free-survival. RESULTS: The most common AEs were anemia and lymphopenia (65%), followed by thrombocytopenia and fatigue (each 51%), alopecia (46%), and nausea (41%). The most common grade ≥3 AE was lymphopenia (43%). There was no grade ≥3 nephrotoxicity. The median iGFR % decrease was 11% ( P < 0.001), at a median follow-up of 23 months. iGFR %decrease and renal BED did not correlate (Spearman ρ = -0.09). Similarly, no significant association was found between bone marrow BED or spleen AD and the grades of hematological toxicities. We observed no association between progression free-survival and either the decline of renal function or the occurrence of hematological toxicities during PRRT. CONCLUSIONS: This study confirms the safety profile of 177 Lu-DOTATATE PRRT in patients with GEP-NETs irrespective of the dosimetry of organs at risk. Kidney, bone marrow, and spleen dosimetry measures were not associated with renal or hematological toxicity.

Absorbed Dose-Response Relationship in Patients with Gastroenteropancreatic Neuroendocrine Tumors Treated with [177Lu]Lu-DOTATATE: One Step Closer to Personalized Medicine.

[177Lu]Lu-DOTATATE has been approved for progressive and inoperable gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that overexpress somatostatin receptors. The absorbed doses by limiting organs and tumors can be quantified by serial postinfusion scintigraphy measurements of the γ-emissions from 177Lu. The objective of this work was to explore how postinfusion [177Lu]Lu-DOTATATE dosimetry could influence clinical management by predicting treatment efficacy (tumor shrinkage and survival) and toxicity. Methods: Patients with GEP-NETs treated with [177Lu]Lu-DOTATATE between 2016 and 2022 and who underwent dosimetry were included. Absorbed doses were calculated for healthy organs (liver, kidneys, bone marrow, and spleen) and tumors using PLANET Dose and the local energy deposition method based on serial posttreatment SPECT/CT. Up to 5 lesions per site were selected and measured on images collected at baseline and 3 mo after treatment end (measurement masked to the somatostatin receptor imaging uptake). For toxicity assessment, laboratory parameters were regularly monitored. Clinical data, including time to death or progression, were collected from the patients' health records. Correlations between absorbed doses by organs and toxicity and between absorbed doses by lesions and tumor volume variation were studied using regression models. Results: In total, 35 dosimetric studies were performed in patients with mostly grade 2 (77%) tumors and metastases in liver (89%), lymph nodes (77%), and bone (34%), and 146 lesions were analyzed: 1-9 lesions per patient, mostly liver metastases (65%) and lymph nodes (25%). The median total absorbed dose by tumors was 94.4 Gy. The absorbed doses by tumors significantly decreased between cycles. The absorbed dose by tumors was significantly associated with tumor volume variation (P < 0.001) 3 mo after treatment end, and it was a significant prognostic factor for survival. Toxicity analysis showed a correlation between the decrease of hematologic parameters such as lymphocytes or platelet concentrations and the absorbed doses by the spleen or bone marrow. The mean absorbed dose by the kidneys was not correlated with nephrotoxicity during the studied period. Conclusion: In patients treated with [177Lu]Lu-DOTATATE for GEP-NETs, tumor and healthy organ dosimetry can predict survival and toxicities, thus influencing clinical management.

Outcome on Mesenteric Mass Response of Small-Intestinal Neuroendocrine Tumors Treated by 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy: The MesenLuth Study, a National Study from the French Group of Endocrine Tumors and Endocan-RENATEN Network.

A mesenteric mass (MM), characterized by fibrotic reaction, is present in most small-intestinal neuroendocrine tumors (SI-NETs). 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) has shown its efficacy in patients with progressive SI-NETs. However, because of specific tissue characteristics of desmoplastic MMs, we hypothesize that these lesions may be refractory to 177Lu-DOTATATE PRRT. Methods: From the national French Groupe d'étude des Tumeurs Endocrines database, we identified patients with an advanced SI-NET and a MM (≥2 cm with a retractile aspect) of a SI-NET treated by at least 1 course of 177Lu-DOTATATE PRRT. The primary endpoint was a MM objective response rate (ORR) of less than 5%. Secondary endpoints were metabolic response, MM-related safety, and clinical response, as well as MM progression-free survival (PFS) and non-MM PFS. Results: In total, 52 patients were included. The MM ORR was 4% (n = 2), and the non-MM ORR was 8% (n = 4). No patient had a MM metabolic response, and the non-MM metabolic response rate was 12% (n = 6). Among the 26 patients with baseline MM-related symptoms, 46% had a clinical response. Four patients presented with gastrointestinal complications during PRRT. The median MM-related PFS was not reached, and the non-MM PFS was 50.3 mo (95% CI, 38.2-61.7 mo). Conclusion: This study confirms that 177Lu-DOTATATE PRRT does not lead to morphologic response on MMs (ORR < 5%). However, it allows MM stability, with few MM-related side effects, and has a relevant impact on MM-related symptoms.

Neuroendocrine Tumors and Peptide Receptor Radionuclide Therapy: When Is the Right Time?

Since its approval in 2018 by the US Food and Drug Administration, peptide receptor radionuclide therapy (PRRT) has become a mainstay in the treatment of neuroendocrine tumors. Lutetium-177-DOTATATE, the only approved agent, is indicated for the treatment of gastroenteropancreatic-neuroendocrine tumors. Although patient selection appears straightforward with somatostatin receptor-positron emission tomography, there is considerable complexity when deciding which patients to treat and when to start PRRT. Herein, we review the many factors that affect patient selection, focusing on the optimal patients to treat. Although significant effort has been expended to determine which patients benefit the most from PRRT, a validated predictive biomarker remains elusive. Although PRRT has been used for more than 2 decades in Europe and standards of care exist for safe treatment, there remain numerous questions regarding when PRRT should be used relative to other treatments. It is important to remember that multidisciplinary discussions are essential. Currently, there are a number of ongoing studies looking to assess the efficacy of PRRT compared with other treatment options and to optimize treatment through combination therapy, different dosing strategies, or use of different radionuclides and radioligands.

Peptide receptor radionuclide therapy implementation and results in a predominantly gastrointestinal neuroendocrine tumor population: A two-year experience in a nonuniversity setting.

ABSTRACT: Neuroendocrine tumors (NETs) are rare, but the incidence and prevalence of NETs are increasing in the United States. While surgery is the preferred treatment for NETs, it is not a viable option for metastatic disease. Lutathera (177Lu-DOTATATE) is approved by the United States Food and Drug Administration and the European Medicines Agency for the treatment of gastroenteropancreatic (GEP)-NETs in adults. There is limited information on GEP-NET treatment responses to Lutathera.Our institution launched a peptide receptor radionuclide therapy (PRRT) service line using Lutathera with involvement from a multidisciplinary team and complete collaboration between hospital administration and clinical providers. A prospective registry study was also established in order to collect patient demographics and clinical data regarding the treatment of GEP primary NETs with Lutathera.Between August 2018 and July 2020, 35 GEP-NET patients were treated with Lutathera, of which 65.71% received 4 complete cycles and 25.71% received 3 cycles; 5.71% and 2.86% received 2 and 1 cycles of PRRT, respectively. Most adverse events during the course of our study were low grade using the common terminology criteria for adverse events system. Of the patients who completed all 4 cycles: 22% showed partial response to Lutathera, 44% showed stable disease, and 13% showed disease progression based on a qualitative assessment of positron emission tomography/computed tomography imaging.From our experience, Lutathera was well tolerated in patients with GEP-NET. Additional studies are needed to examine long-term clinical and patient-reported outcomes associated with GEP-NET treatment as well as financial considerations for hospitals embarking on a PRRT program.

Cell-Free DNA and Clinical Characteristics in Patients with Small Intestinal or Pancreatic Neuroendocrine Tumors.

INTRODUCTION: Neuroendocrine tumors (NETs) are rare and characterized by a heterogeneous clinical course and an unmet need for better prognostic markers. Plasma cell-free DNA (cfDNA) has prognostic value in other malignancies but is not previously investigated in NETs. We studied cfDNA levels in patients with mainly low-grade small intestinal NET -(siNET) or pancreatic NET (pNET) and evaluated the prognostic potential of cfDNA. MATERIALS AND METHODS: We included 70 NET patients, siNET (n = 50) and pNET (n = 20). Plasma cfDNA levels were determined by droplet digital PCR for the beta-2-microglobulin gene every 6 months during a period of 3 years, including in a subgroup of 19 patients during peptide receptor radionuclide therapy (PRRT) therapy. RESULTS: cfDNA levels were higher in both siNET and pNET compared to a previously established healthy cohort (p < 0.0001). -cfDNA levels did not predict overall survival (crude hazard ratio [HR] 0.95 [0.57-1.58], p = 0.837, adjusted for smoking status HR 0.77 [0.51-1.17], p = 0.22). The impact of cfDNA level on progression-free survival showed different trends in siNET and pNET. There was no effect of PRRT treatment on cfDNA levels and no difference in cfDNA levels between patients with and without progressive disease after PRRT (ANOVA p = 0.66). cfDNA levels were significantly higher in never-smokers and previous smokers than in current smokers (p = 0.029). DISCUSSION/CONCLUSION: cfDNA levels are higher in NET patients than in healthy controls; however, there was no association with prognosis, and cfDNA levels were unaffected by PRRT. Our observations suggest that cfDNA levels are not associated with the disease course in low-grade NET in contrast to other malignancies.

177Lu-DOTATATE Plus Radiosensitizing Capecitabine Versus Octreotide Long-Acting Release as First-Line Systemic Therapy in Advanced Grade 1 or 2 Gastroenteropancreatic Neuroendocrine Tumors: A Single-Institution Experience.

PURPOSE: To compare the efficacy and safety of 177Lu-DOTATATE plus radiosensitizing capecitabine and octreotide long-acting release (LAR) as first-line systemic therapy in advanced well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). MATERIALS AND METHODS: Data of consecutive patients of advanced inoperable or metastatic grade 1 or 2 GEP-NETs treated with first-line 177Lu-DOTATATE plus radiosensitizing capecitabine or octreotide LAR from September 2012 to December 2019 were collected and analyzed for response, toxicity, and survival outcomes. RESULTS: Seventy-six patients (median age: 53 years; range 14-81 years) with treatment-naïve advanced grade 1 or 2 GEP-NETs were included. Thirty-six patients received a median cumulative dose of 27.3 GBq of 177Lu-DOTATATE intravenously at 8-12 weeks' intervals along with 1,250 mg/m2 oral capecitabine on days 0-14 of each cycle of 177Lu-DOTATATE, whereas 40 patients were administered 30 mg octreotide LAR intramuscularly every 4 weeks. Using response evaluation criteria in solid tumor 1.1, the objective response rate was 38% in the 177Lu-DOTATATE arm compared with 15% in the octreotide LAR arm (P = .025), whereas the disease control rates were 88% and 67% in 177Lu-DOTATATE and octreotide LAR arms, respectively (P = .035). The median durations of progression-free survival in the 177Lu-DOTATATE and octreotide LAR arms were 54 months and 16 months, respectively (P = .017), whereas the median overall survival was not reached and not significantly different across both the arms. Of the treatment-related adverse events, no major difference was observed in the occurrence of grade 3 or 4 toxicities between the two treatment arms. CONCLUSION: First-line systemic 177Lu-DOTATATE plus radiosensitizing capecitabine achieved better radiologic response and longer progression-free survival compared with octreotide LAR in patients with advanced grade 1 or 2 GEP-NETs. Future randomized controlled trials are, however, required to determine the best treatment sequence for the treatment-naïve patients with advanced GEP-NETs.

PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors.

Patients with advanced-stage gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have a poor overall prognosis despite chemotherapy and radiotherapy (e.g., peptide receptor radionuclide therapy (PRRT)). Better treatment options are needed to improve disease regression and patient survival. The purpose of this study was to examine a new treatment strategy by combining PI3K/mTOR dual inhibition and radiotherapy. First, we assessed the efficacy of two PI3K/mTOR dual inhibitors, PF-04691502 and PKI-402, to inhibit pAkt and increase apoptosis in NET cell lines (BON and QGP-1) and patient-derived tumor spheroids as single agents or combined with radiotherapy (XRT). Treatment with PF-04691502 decreased pAkt (Ser473) expression for up to 72 h compared with the control; in contrast, decreased pAkt expression was noted for less than 24 h with PKI-402. Simultaneous treatment with PF-04691502 and XRT did not induce apoptosis in NET cells; however, the addition of PF-04691502 48 h after XRT significantly increased apoptosis compared to PF-04691502 or XRT treatment alone. Our results demonstrate that schedule-dependent administration of a PI3K/mTOR inhibitor, combined with XRT, can enhance cytotoxicity by promoting the radiosensitivity of NET cells. Moreover, our findings suggest that radiotherapy, in combination with timed PI3K/mTOR inhibition, may be a promising therapeutic regimen for patients with GEP-NET.

Strategies Towards Improving Clinical Outcomes of Peptide Receptor Radionuclide Therapy.

PURPOSE OF REVIEW: Peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3] octreotate is an effective and safe second- or third-line treatment option for patients with low-grade advanced gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN). In this review, we will focus on possible extensions of the current use of PRRT and on new approaches which could further improve its treatment efficacy and safety. RECENT FINDINGS: Promising results were published regarding PRRT in other NENs, including lung NENs or high-grade NENs, and applying PRRT as neoadjuvant or salvage therapy. Furthermore, a diversity of strategic approaches, including dosimetry, somatostatin receptor antagonists, somatostatin receptor upregulation, radiosensitization, different radionuclides, albumin binding, alternative renal protection, and liver-directed therapy in combination with PRRT, have the potential to improve the outcome of PRRT. Also, novel biomarkers are presented that could predict response to PRRT. Multiple preclinical and early clinical studies have shown encouraging potential to advance the clinical outcome of PRRT in NEN patients. However, at this moment, most of these strategies have not yet reached the clinical setting of randomized phase III trials.

The State of Peptide Receptor Radionuclide Therapy and Its Sequencing among Current Therapeutic Options for Gastroenteropancreatic Neuroendocrine Tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are the most common form of neuroendocrine neoplasia, but there is no current consensus for the sequencing of approved therapies, particularly with respect to peptide receptor radionuclide therapy (PRRT). This comprehensive review evaluates the data supporting approved therapies for GEP-NETs and recommendations for therapeutic sequencing with a focus on how PRRT currently fits within sequencing algorithms. The current recommendations for PRRT sequencing restrict its use to metastatic, inoperable, progressive midgut NETs; however, this may change with emerging data to suggest that PRRT might be beneficial as neoadjuvant therapy for inoperable tumors, is more tolerable than other treatment modalities following first-line standard dose somatostatin analogs, and can be used as salvage therapy after disease relapse following prior successful cycles of PRRT. PRRT has also been shown to reduce tumor burden, improve quality of life, and prolong the time to disease progression in a broad spectrum of patients with GEP-NETs. As the various potential benefits of PRRT in GEP-NET therapy continues to expand, it is necessary to review and critically evaluate our treatment algorithms for GEP-NETs.

Desmoplastic mesenteric lesions do not respond radiographically to peptide receptor radionuclide therapy.

177 Lu-Dotatate treatment is indicated for progressive, well-differentiated, small bowel neuroendocrine tumours) NETs. These tumours often metastasise to mesenteric lymph nodes and produce a desmoplastic reaction, consisting of tumour cells interspersed with fibrotic tissue. We hypothesised that, in patients treated with 177 Lu-Dotatate, mesenteric tumours would remain stable even as liver tumour size changes were observed. We retrospectively reviewed the records of all patients treated with 177 Lu-Dotatate between April 2018 and December 2019. Among patients with desmoplastic mesenteric tumours and liver metastases, we evaluated changes in tumour size of mesenteric and liver lesions based on pre- and post-treatment anatomic scans. As a result of the infrequency of objective radiographic response, any reported changes in tumour size were considered significant. Twenty-one patients met the inclusion criteria: nine had evidence of shrinkage of liver lesion(s), one had mild progression of liver lesions, seven had stable hepatic disease and four had a mixed hepatic response. Two of the patients with hepatic tumour shrinkage met the criteria for a partial response via RECIST 1.1 (https://recist.eortc.org). Desmoplastic mesenteric lesions remained unchanged in size, regardless of the changes detected in liver lesions. In conclusion, 177 Lu-Dotatate does not impact desmoplastic mesenteric tumours which are typically associated with midgut NETs. Patients whose disease is predominantly confined to desmoplastic mesenteric lesions are unlikely to respond radiographically to peptide receptor radionuclide therapy. Moreover, the inclusion of desmoplastic mesenteric lesions as target lesions in RECIST measurements tends to increase rates of disease stability vs response or progression.

Lutetium oxodotreotide (177Lu-Dotatate) for the treatment of unresectable or metastatic progressive gastroenteropancreatic neuroendocrine tumors: a cost-effectiveness analysis for Scotland.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent a heterogenous group of tumors. Findings from the phase III NETTER-1 trial showed that treatment of unresectable/metastatic progressive gastrointestinal (GI) NETs with 177Lu-Dotatate resulted in a significant improvement in progression-free survival (PFS) and overall survival (OS) compared with best supportive care (BSC) with high dose octreotide long-acting repeatable (LAR) 60 mg. A health economic analysis was performed using input data from clinical studies and data derived from an indirect comparison to determine the cost-effectiveness of 177Lu-Dotatate in the treatment of GI-NETs and pancreatic NETs (P-NETs) in Scotland. METHODS: Cost-effectiveness analysis was performed from the payer perspective using a three-state partitioned survival model. In the base case 177Lu-Dotatate was compared with BSC in gastrointestinal (GI)-NETs using clinical data from the NETTER-1 trial. A secondary analysis comparing 177Lu-Dotatate with BSC, everolimus or sunitinib in patients with P-NETs was also performed using hazard ratios inferred from indirect comparisons. The base case analysis was performed over a 20-year time horizon with an annual discount rate of 3.5% for both costs and clinical outcomes. RESULTS: For unresectable/metastatic progressive GI-NETs treatment with 177Lu-Dotatate led to a gain in quality-adjusted life expectancy of 1.33 quality-adjusted life years (QALYs) compared with BSC due to extended PFS and OS. Mean total lifetime costs were GBP 35,701 higher with 177Lu-Dotatate, leading to an incremental cost-effectiveness ratio (ICER) of GBP 26,830 per QALY gained. In analyses in patients with P-NETs 177Lu-Dotatate was associated with ICERs below GBP 30,000 per QALY gained in comparisons with BSC, sunitinib and everolimus. CONCLUSIONS: Cost-effectiveness analyses demonstrated that, in Scotland, from the payer perspective, 177Lu-Dotatate at the set acquisition cost is a cost-effective treatment option for patients with unresectable or metastatic progressive GI-NETs or P-NETs.

Response rates in metastatic neuroendocrine tumors receiving peptide receptor radionuclide therapy and implications for future treatment strategies.

BACKGROUND: Peptide receptor radionuclide therapy is a targeted therapy used to treat unresectable somatostatin receptor-positive neuroendocrine tumors. The objective of this study was to evaluate response rates among neuroendocrine tumors of different primaries and identify factors relevant to future treatment strategies. METHODS: We retrospectively reviewed patients who received peptide receptor radionuclide therapy for neuroendocrine tumors from 2018 to 2019 at our institution. Patients were assessed with computed tomography/magnetic resonance imaging and 68Ga-DOTATATE-positron emission tomography before and after 2 or 4 cycles of peptide receptor radionuclide therapy. Tumor response was evaluated by RECIST 1.1. Statistics included multinomial logistic regression models and Fisher exact test. RESULTS: Twenty-seven patients underwent 92 cycles of peptide receptor radionuclide therapy: pancreas (n = 11), small bowel (n = 7), and other (n = 9) neuroendocrine tumors. Overall, 30% (8 of 27) had partial response, 59% (16 of 27) stable disease, and 11% (3 of 27) progressed. Pancreatic neuroendocrine tumors responded differently from small bowel neuroendocrine tumors regardless of cycle number (P = .01). The majority of pancreatic neuroendocrine tumors (6 of 11) had partial response to peptide receptor radionuclide therapy, while all small bowel neuroendocrine tumors had stable disease. Pancreatic neuroendocrine tumors stable after 2 cycles were more likely to respond to additional cycles versus other neuroendocrine tumors (probability: 60% vs 11%). CONCLUSION: Patients with unresectable advanced or metastatic pancreatic neuroendocrine tumors may benefit from a full course of peptide receptor radionuclide therapy, whereas other neuroendocrine tumors appear less likely to respond. Large prospective studies are needed to confirm these findings.

How We Do It: A Multidisciplinary Approach to 177Lu DOTATATE Peptide Receptor Radionuclide Therapy.

Lutetium 177 (177Lu) DOTA-0-Tyr3-Octreotate (DOTATATE) peptide receptor radionuclide therapy (PRRT) is an effective treatment for advanced gastroenteropancreatic neuroendocrine tumors. This review presents a clinical practice workflow that has been successful since 177Lu DOTATATE PRRT was approved by the U.S. Food and Drug Administration. The workflow relies heavily on the input of a multidisciplinary team and involves a nuclear medicine consultation service, tumor board, and specific preparations in advance of therapy and day-of-therapy procedures. A systematic checklist designed to ensure appropriate selection of treatment candidates and identification of any concerns to address to safely administer PRRT is provided. All patients were evaluated with gallium 68 DOTATATE PET/CT, and in cases of high-grade tumors, they were also evaluated with fluorine 18 fluorodeoxyglucose PET/CT, with imaging findings reviewed as part of the systematic checklist before PRRT. Adverse effects are discussed and imaging follow-up regimens are reviewed, including alternative diagnostic contrast materials. Approaches to multiple challenging patient scenarios are illustrated through case examples. Finally, alternative theranostic radionuclides and treatment strategies are discussed.

Clinical Assessment of 177Lu-DOTATATE Quantification by Comparison of SUV-Based Parameters Measured on Both Post-PRRT SPECT/CT and 68Ga-DOTATOC PET/CT in Patients With Neuroendocrine Tumors: A Feasibility Study.

PATIENTS AND METHODS: Patients with WD-GEP-NET who benefited from a pretherapeutic 68Ga-DOTATOC PET/CT and a 177Lu-DOTATATE SPECT/CT after the cycle 1 of peptide receptor radionuclide therapy were prospectively included. SPECT/CT acquisitions were performed on a system calibrated with a conversion factor of 9.48 counts/MBq per second and were reconstructed with an iterative algorithm allowing quantification using the SPECTRA Quant software (MIM Software, Cleveland, OH). For each patient, different SUV parameters were recorded on both PET/CT (Ga parameters) and SPECT/CT (Lu parameters) for comparison: physiological uptakes (liver/spleen), tumor uptake (1-10/patient; SUVmax, SUVmean, SUVpeak, MTV), tumor-to-liver and tumor-to-spleen ratios according to liver/spleen SUVmax and SUVmean (TLRmax, TLRmean, TSRmax, and TSRmean, respectively). RESULTS: Ten patients (8 female; 2 male) aged from 50 to 83 years presenting with a metastatic progressive WD-GEP-NET (7 small intestine, 2 pancreas, 1 rectum) were included. Median values of lesional Lu-SUV were significantly lower than the corresponding Ga-SUV (P < 0.001), whereas median values of lesional Lu-MTV, Lu-TLR, and Lu-TSR were significantly higher than the corresponding Ga-MTV, Ga-TLR, and Ga-TSR (P < 0.02). Pearson correlation coefficients were strong for both SUV and MTV parameters (0.779-0.845), weak for TLR parameters (0.365-0.394), and moderate-to-strong for TSR parameters (0.676-0.750). CONCLUSIONS: Our results suggest the feasibility of 177Lu-DOTATATE SPECT/CT quantification in clinical practice and show a strong correlation of several SUV-based parameters with the corresponding in 68Ga-DOTATOC PET/CT.

[Radiation-oncology horizon 2030: From microbiota to plasma laser]. / Oncologie-radiothérapie horizon 2030 : du microbiote au laser plasma.

Advances in physical, technological and biological fields have made radiation oncology a discipline in continual evolution. New current research areas could be implemented in the clinic in the near future. In this review in the form of several interviews, various promising themes for our specialty are described such as the gut microbiota, tumor organoids (or avatar), artificial intelligence, connected therapies, nanotechnologies and plasma laser. The individual prediction of the best therapeutic index combined with the integration of new technologies will ideally allow highly personalized treatment of patients receiving radiation therapy.

Could the skewness and kurtosis texture parameters of lesions obtained from pretreatment Ga-68 DOTA-TATE PET/CT images predict receptor radionuclide therapy response in patients with gastroenteropancreatic neuroendocrine tumors?

PURPOSE: In our study, tumor heterogeneity was evaluated using the parameters skewness and kurtosis on pretreatment Ga-68 DOTA-TATE PET/CT to assess therapy responses of lesions in patients with gastroenteropancreatic neuroendocrine tumors (GEP NETs) treated with peptide receptor radionuclide therapy (PRRT). METHOD: We retrospectively studied the texture analysis with relatively simple first-order parameters skewness and kurtosis on pretreatment Ga-68 DOTA-TATE PET/CT from 22 patients (eight females, 14 males; with a mean age: 54 ± 11 years) with GEP NETs who were treated with 2-6 therapy cycles of Lu-177 DOTA-TATE. A total of 326 lesions of 22 patients were evaluated in terms of treatment response by Ga-68 DOTA-TATE PET/CT examination performed before and after treatment. Receiver-operating characteristic (ROC) curves were generated to assess skewness and kurtosis to discriminate between responder and nonresponder lesions. RESULT: A total of 326 lesions of 22 patients were evaluated and 137 lesions responded partially or completely to the treatment, 189 lesions did not respond to treatment, remained stable or progressed. The skewness and kurtosis values of the lesions which did not respond to the PRRT were significantly higher than those with response to PRRT treatment (P < 0.001 and P = 0.004, respectively). However, ROC curves provided a moderate area under the curve value for skewness and a relatively low value for kurtosis (0.619 and 0.518, respectively). CONCLUSION: Texture analysis using skewness and kurtosis of the lesions on pretreatment Ga-68 DOTA-TATE PET/CT was able to predict their responsiveness to PRRT.