Peptide Receptor Radionuclide Therapy Research Articles

Retrospective evaluation of the predictive value of tumour burden at baseline [68 Ga]Ga-DOTA-TOC or -TATE PET/CT and tumour dosimetry in GEP-NET patients treated with PRRT

PurposeThere is a lack of validated imaging biomarkers for prediction of response to peptide receptor radionuclide therapy (PRRT). The primary objective was to evaluate if tumour burden at baseline PET/CT could predict treatment outcomes to PRRT with [177Lu]Lu-DOTA-TATE. Secondary objectives were to evaluate if there was a correlation between tumour burden and mean tumour absorbed dose (AD) during first cycle, and if mean tumour AD or the relative change of tumour burden at first follow-up PET/CT could predict progression free survival (PFS) or overall survival (OS).MethodsPatients with gastroenteropancreatic neuroendocrine tumour (GEP-NET) treated with [177Lu]Lu-DOTA-TATE PRRT were retrospectively included. Tumour burden was quantified from [68 Ga]Ga-DOTA-TOC/TATE PET/CT-images at baseline and first follow-up and expressed as; whole-body somatostatin receptor expressing tumour volume (SRETVwb), total lesion somatostatin receptor expression (TLSREwb), largest tumour lesion diameter and highest SUVmax. The relative change of tumour burden was evaluated in three categories. Mean tumour AD was estimated from the first cycle of PRRT. PFS was defined as time from start of PRRT to radiological or clinical progression. OS was evaluated as time to death. Kaplan Meier survival curves and log-rank test were used to compare PFS and OS between different groups.ResultsThirty-one patients had a baseline PET/CT < 6 months before treatment and 25 had a follow-up examination. Median tumour burden was 132 ml (IQR 61–302) at baseline and 71 ml (IQR 36–278) at follow-up. Twenty-two patients had disease progression (median time to progression 17.2 months) and 9 patients had no disease progression (median follow-up 28.7 months). SRETVwb dichotomized by the median at baseline was not associated with longer PFS (p = 0.861) or OS (p = 0.937). Neither TLSREwb, largest tumour lesion or SUVmax showed significant predictive value. There was a moderately strong correlation, however, between SUVmax and mean tumour AD r = 0.705, p < 0.001, but no significant correlation between SRETVwb nor TLSREwb and mean tumour AD. An increase of SRETVwb, TLSREwb or largest tumour lesion at first follow-up PET/CT was significantly correlated with shorter PFS/OS.ConclusionTumour burden at baseline showed no predictive value of PFS/OS after PRRT in this small retrospective study. An increase of tumour burden was predictive of worse outcome.

MEN1/DAXX/ATRX mutations enhance progression-free survival in gastroenteropancreatic neuroendocrine tumors treated with peptide receptor radionuclide therapy.

Pre-clinical data suggest that mutations in the MEN1, DAXX, and/or ATRX genes may potentially increase radiation efficacy in cancer cells. Herein, we explore the association between response to peptide receptor radionuclide therapy (PRRT) and those mutations in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We analyzed tissue-based next generation sequencing (NGS) assay results and clinicopathologic data from 28 patients with GEP-NETs treated with PRRT. Findings were correlated with progression-free survival (PFS) and objective response rate (ORR). Patients with mutations in MEN1, DAXX, and/or ATRX (n = 13) had a longer median PFS (26.47 vs 12.13 months; P = 0.014) than wild-type (n = 15) patients when adjusted for surgery prior to PRRT, tumor grade, and presence of TP53 mutation. Alterations in MEN1 along with a concurrent mutation in either DAXX or ATRX (n = 6) trended toward longer PFS compared to patients without concurrent mutations (31.53 vs 17.97 months; P = 0.09). ORR was higher in patients with a mutation in MEN1, DAXX, or ATRX (41.67% vs 15.38%). In pancreatic NET patients, these target mutations also showed a longer PFS (28.43 vs 9.83 months; P = 0.04). TP53 alterations showed a shorter PFS than wild-type cases (11.17 vs 20.47 months; P = 0.009). Mutations in MEN1/DAXX/ATRX are associated with improved PFS in patients with GEP-NETs receiving PRRT and might be used as a biomarker for treatment response.

Peptide Receptor Radionuclide Therapy or Everolimus in Metastatic Neuroendocrine Tumors: The SeqEveRIV Study, a National Study from the French Group of Endocrine Tumors and Endocan-RENATEN Network.

Everolimus and peptide receptor radionuclide therapy (PRRT, 177Lu-DOTATATE) are 2 treatments recommended in guidelines for gastroenteropancreatic metastatic neuroendocrine tumors. However, the best treatment sequence remains unknown. Methods: We designed a retrospective multicenter study that included patients from the national prospective database of the Groupe d'Étude des Tumeurs Endocrines who had been treated using everolimus and PRRT between April 2004 and October 2022. The primary aim was to compare the 2 treatments (everolimus and PRRT) in terms of efficacy and safety, and the secondary aim was to evaluate the sequences (PRRT followed by everolimus or everolimus followed by PRRT) based on overall progression-free survival (PFS) (PFS during first treatment + PFS during second treatment) in patients with metastatic neuroendocrine tumors. Results: Both treatments were used for 84 patients. The objective response rate and median PFS were 5 (6.0%) and 16.1 mo (95% CI, 11.5-20.7 mo), respectively, under everolimus and 19 (22.6%) and 24.5 mo (95% CI, 17.7-31.3 mo), respectively, for PRRT. The safety profile was also better for PRRT. Median overall PFS was 43.2 mo (95% CI, 33.7-52.7 mo) for the everolimus-PRRT sequence and 30.6 mo (95% CI, 17.8-43.4 mo) for the PRRT-everolimus sequence (hazard ratio, 0.69; 95% CI, 0.39-1.24; P = 0.22). Conclusion: PRRT was more effective and less toxic than everolimus. Overall PFS was similar between the 2 sequences, suggesting case-by-case discussion if the patient is eligible for both treatments, but PRRT should be used first when an objective response is needed or in frail populations.

Spleen Volume Reduction Is a Reliable and Independent Biomarker for Long-Term Risk of Leukopenia Development in Peptide Receptor Radionuclide Therapy.

177Lu-DOTATATE therapy is an effective treatment for advanced neuroendocrine tumors, despite its dose-limiting hematotoxicity. Herein, the significance of off-target splenic irradiation is unknown. Our study aims to identify predictive markers of peptide receptor radionuclide therapy-induced leukopenia. Methods: We retrospectively analyzed blood counts and imaging data of 88 patients with histologically confirmed, unresectable metastatic neuroendocrine tumors who received 177Lu-DOTATATE treatment at our institution from February 2009 to July 2021. Inclusion criterium was a tumor uptake equivalent to or greater than that in the liver on baseline receptor imaging. We excluded patients with less than 24 mo of follow-up and those patients who received fewer than 4 treatment cycles, additional therapies, or blood transfusions during follow-up. Results: Our study revealed absolute and relative white blood cell counts and relative spleen volume reduction as independent predictors of radiation-induced leukopenia at 24 mo. However, a 30% decline in spleen volume 12 mo after treatment most accurately predicted patients proceeding to leukopenia at 24 mo (receiver operating characteristic area under the curve of 0.91, sensitivity of 0.93, and specificity of 0.90), outperforming all other parameters by far. Conclusion: Automated splenic volume assessments demonstrated superior predictive capabilities for the development of leukopenia in patients undergoing 177Lu-DOTATATE treatment compared with conventional laboratory parameters. The reduction in spleen size proves to be a valuable, routinely available, and quantitative imaging-based biomarker for predicting radiation-induced leukopenia. This suggests potential clinical applications for risk assessment and management.

Metabolic Tumor Volume on 18-Fluorodeoxyglucose Positron Emission Tomography as a Prognostic Marker of Survival in Patients With Locally Advanced or Metastatic Neuroendocrine Neoplasms Treated With 177Lutetium-DOTA-Octreotate Peptide Receptor Radionuclide Therapy.

We investigated metabolic tumor volume (MTV) and total lesion glycolysis (TLG) on pre-treatment FDG-PET as prognostic markers for survival in patients with metastatic neuroendocrine neoplasms (NENs) receiving peptide receptor radionuclide therapy (PRRT). A retrospective review of patients with metastatic NENs receiving PRRT was undertaken. Pre-treatment FDG-PET images were analyzed and variables collected included MTV and TLG (dichotomized by median into high vs low). Main Outcomes were overall survival (OS) and progression-free survival (PFS) by MTV and TLG (high vs low). One hundred five patients were included. Median age was 64 years (50% male). Main primary NEN sites were small bowel (43.8%) and pancreas (40.0%). Median MTV was 3.8 mL and median TLG was 19.9. Dichotomization formed identical cohorts regardless of whether MTV or TLG were used. Median OS was 72 months; OS did not differ based on MTV/TLG high versus low (47.4 months vs not reached; hazard ratio, 0.43; 95% confidence interval [CI], 0.18-1.04; P = 0.0594). Median PFS was 30.4 months; PFS differed based on MTV/TLG high versus low (21.6 months vs 45.7 months; hazard ratio, 0.35; 95% CI, 0.19-0.64; P = 0.007). Low MTV/TLG on pre-treatment FDG-PET was associated with longer PFS in metastatic NEN patients receiving PRRT.

Improvement of Laboratory Hepatic Parameters After Treatment With 177 Lu-DOTATATE : Cohort in an Oncology Reference Center.

Well-differentiated neuroendocrine neoplasms (NETs) overexpress the somatostatin receptor, which is the target for the peptide receptor radionuclide therapy (PRRT). NETs have a slow growth rate and can metastasize to liver, bone, and lungs. In NETs patients, liver metastasis is an important prognostic marker because liver failure is one of the most common causes of death in this population. In this regard, we aimed to describe the changes in laboratorial parameters in patients submitted to PRRT with 177 Lu-DOTATATE, focusing on hepatic parameters. One hundred ten patients treated with 1 to 4 cycles of 7.4 GBq (200 mCi) of 177 Lu-DOTATATE from January 2011 to December 2021 were analyzed in this retrospective observational single-center study. Patients were submitted to blood tests before and after each cycle of PRRT. Laboratory measurements were collected to assess liver function, cholestasis, kidney, and bone marrow function. In the general population (n = 110), ALP ( P = 0.013) and GGT ( P < 0.001) showed a statistically significant reduction. Patients with high liver disease volume showed a statistically significant reduction in ALT ( P = 0.016), whereas patients with low liver disease volume showed a statistically significant reduction in GGT ( P = 0.013). All parameters for bone marrow function showed a statistically significant decrease in all population subsets. Patients treated with 177 Lu-DOTATATE showed a significant improvement in liver function and cholestasis parameters, and a consistent decrease in bone marrow function, even in the presence of advanced liver disease.

Preclinical evaluation of [225Ac]Ac-crown-TATE – An alpha-emitting radiopharmaceutical for neuroendocrine tumors

BackgroundTargeted alpha therapy (TAT) of somatostatin receptor-2 (SSTR2) positive neuroendocrine tumors (NETs) involving Ac-225 ([225Ac]Ac-DOTA-TATE) has previously demonstrated improved therapeutic efficacy over conventional beta particle-emitting peptide receptor radionuclide therapy agents. DOTA-TATE requires harsh radiolabeling conditions for chelation of [225Ac]Ac3+, which can limit the achievable molar activities and thus therapeutic efficacy of such TAT treatments. Macropa-TATE was recently highlighted as a potential alternative to DOTA-TATE, owing to the mild radiolabeling conditions and high affinity toward [225Ac]Ac3+; however, elevated liver and kidney uptake were noted as a major limitation and a suitable imaging radionuclide is yet to be reported, which will be required for patient dosimetry studies and assessment of therapeutic benefit. Previously, [155Tb]Tb-crown-TATE has shown highly effective imaging of NETs in preclinical SPECT/CT studies, with high tumor uptake and low non-target accumulation; these favourable properties and the versatile coordination behavior of the crown chelator may therefore show promise for combination with Ac-225 for TAT. MethodsCrown-TATE was labeled with Ac-225, and radiochemical yield was analyzed as the function of crown-TATE concentration. LogD7.4 was measured as the indication of hydrophilicity. Free [225Ac]Ac3+ release from [225Ac]Ac-crown-TATE in human serum was studied. Biodistribution studies of [225Ac]Ac-crown-TATE in mice bearing AR42J tumors was evaluated at 1, 4, 24, 48, and 120 h, and the absorbed dose to major organs calculated. Therapy-monitoring studies with AR42J tumor bearing mice were undertaken using 30 kBq and 55 kBq doses of [225Ac]Ac-crown-TATE and compared to controls treated with PBS or crown-TATE. Results[225Ac]Ac-crown-TATE was successfully prepared with high molar activity (640 kBq/nmol), and characterized as a moderately hydrophilic radioligand (LogD7.4 = −1.355 ± 0.135). No release of bound Ac-225 was observed over 9 days in human serum. Biodistribution studies of [225Ac]Ac-crown-TATE showed good initial tumor uptake (11.1 ± 1.7% IA/g at 4 h) which was sustained up to 120 h p.i. (6.92 ± 2.03% IA/g). Dosimetry calculations showed the highest absorbed dose was delivered to the tumors. Therapy monitoring studies demonstrated significant (log-rank test, P < 0.005) improved survival in both treatment groups compared to controls. ConclusionsThis preclinical study demonstrated the therapeutic efficacy of [225Ac]Ac-crown-TATE for treatment of NETs, and highlights the potential of using crown chelator for stable chelation of Ac-225 under mild conditions.

Safety and Efficacy of Peptide Receptor Radionuclide Therapy (PRRT) Following Bland Embolization for Metastatic Neuroendocrine Tumors.

Rationale: Evaluating the long-term safety and efficacy of peptide receptor radionuclide therapy (PRRT) in patients with metastatic neuroendocrine tumors (mNETs) who have undergone prior bland hepatic transarterial embolization (TAE). Methods: Retrospective review of mNET patients who received PRRT with 177Lu-DOTATATE between 4/2018 and 02/2022 with and without prior TAE. The most recent clinical, imaging, and laboratory findings, including hepatic Common Terminology Criteria for Adverse Events v5.0, were compared to pre-PRRT. Results: 171 patients (95 M, 76 F, median age = 66) with mNET of different primary sites (9 foregut, 100 midgut, 9 hindgut, 44 pancreas, 9 unknown) received at least 1 cycle of PRRT with at least 6 months of follow-up, 110 of whom were embolization-naïve and 61 who had prior TAE. The median follow up was 22 months (range: 6-43). Patients with prior TAE had higher liver tumor burden on average than patients without prior TAE; however, the difference was not statistically significant (p = 0.06). There was no significant difference in the rates of G3 or G4 hepatotoxicity (p = 0.548 and p = 0.999, respectively) in patients who underwent prior TAE and those who were TAE-naïve. The hepatic progression-free survival was 22.9 months in TAE-naïve patients and 25.7, 20.2, and 12.8 months in patients with 1, 2, and 3 prior TAE treatments, respectively. Conclusion: Peptide receptor radionuclide therapy following transarterial bland embolization for mNET is safe and effective.

Aggressive Metastatic Insulinoma in a Patient of Diabetes Mellitus with Documentation on Dual-Tracer PET-CT ([68Ga]Ga-DOTATATE and [18F]FDG): Clinical Benefits with Combined Chemo-PRRT Approach

AbstractInsulinoma is a relatively uncommon pancreatic neuroendocrine tumor, with approximately 10% of the cases being malignant. Diabetes mellitus (DM) with concurrent insulinoma is very rare and the diagnosis of such condition is easily missed as it can be misconstrued as improved glycemic control. Therefore, persistent hypoglycemic symptoms even after stopping antidiabetic medications may be considered for insulinoma. Herein, we present a patient with DM and pancreatic insulinoma with extensive hepatic and skeletal metastases on dual-tracer positron emission tomography/computed tomography (PET/CT) ([68Ga]Ga-DOTATATE and [18F]fluorodeoxyglucose). Given the extensive disease, the patient was treated with a combination of peptide receptor radionuclide therapy (PRRT) and chemotherapy (capecitabine and temozolomide). During therapy, patient showed early clinical and imaging response for insulinoma leading to unmasking of poor glycemic control necessitating requirement of insulin administration for DM. The patient did not experience any life-threatening hypoglycemia during the chemo-PRRT treatment and showed an improvement in quality of life. Unfortunately, the disease progressed at the 4th cycle, 10 months after the initiation of PRRT. We conclude that combined chemo-PRRT may be considered an effective treatment option for patients with metastatic insulinoma and DM owing to its favorable imaging response and effective symptom control.

Novel Detection of Pleomorphic Adenomas via Analysis of 68Ga-DOTATOC PET/CT Imaging.

Currently, the diagnosis of salivary gland tumors using imaging techniques is unreliable. In this monocentric retrospective study, we examined patients who received a 68Ga-DOTATOC PET/CT and subsequently underwent a salivary gland tumor resection between 1 January 2010 and 31 December 2021. PET/CT image assessment was compared with somatostatin receptor (SSTR) expression and histology. Thirteen patients (five pleomorphic adenoma (PA) and eight other parotid lesions (OPL)) received a 68Ga-DOTATOC PET/CT. Imaging displayed strong focal tracer uptake in all PA except for one with strong tumor to background discrimination. PA revealed higher SUVmax, SUVmean, liver and blood pool quotients than those of Warthin tumors (WT) and of OPL. In comparison to the contralateral parotid, SUVmax (p = 0.02), SUVmean (p = 0.02), liver quotient (p = 0.03) and blood pool quotient (p = 0.03) were all significantly higher. In contrast, WT and OPL showed in relation to the contralateral parotid no significant differences of SUVmax (WT p = 0.79; OPL p = 0.11), SUVmean (WT p = 1.0; OPL p = 0.08), liver quotient (WT p = 0.5; OPL p = 0.08) and blood pool quotient (WT p = 0.8; OPL p = 0.19). Two PA and one granuloma were not available for examination. In the immunohistochemal analysis, all PA demonstrated the highest intensity of SSTR2 expression (grade 3). Furthermore, PA had a high percentage of cells expressing SSTR2 (20%, 80% and 55%). A strong tracer uptake in PA was shown in 68Ga-DOTATOC PET/CT. This may allow physicians to utilize radioligated somatostatin analogue PET CT/MR imaging to accurately diagnose PA. Additionally, it may be possible in the future to treat the PA with a noninvasive peptide receptor radionuclide therapy or with somatostatin analogues.

Surgery for pancreatic neuroendocrine tumors during the COVID-19 pandemic: a retrospective cohort from a high-volume center

During the COVID-19 pandemic, pancreatic surgery for pancreatic neuroendocrine tumors (PNETs) with surgical indications was postponed or canceled. Patients with PNET patients who underwent pancreatic surgery during the COVID-19 restriction period (3 years) were compared with a similar cohort of patients who underwent surgery in the previous 3 years. Data on patients’ characteristics, waiting time, and surgical and pathology outcomes were evaluated. During the study period, 370 patients received surgery for PNETs, 205 (55%) during the first period, and 165 (45%) during the pandemic. A lengthening of the waiting list (182 [IQR 100–357] vs. 60 [40–88] days, p < 0.001) and increased use of anti-tumor medical treatments (any therapy, peptide receptor radionuclide therapy, and somatostatin analogs; all p < 0.001) was found. During the pandemic, surgery occurred after a median of 381 days [IQR 200–610] from diagnosis (vs. 103 [IQR 52–192] of the pre-COVID-19 period, p < 0.001). No statistically significant differences in tumor size and grading distribution were found between the two periods (both p > 0.05), yet only a modest increase of the median Ki67 values in cases operated during the pandemic (4% vs. 3%, p = 0.03). Lastly, these latter patients experienced less major postoperative complications (13% vs. 24%, p = 0.007). During COVID-19, the surgical waiting list of PNET patients was drastically extended, and bridge therapies were preferred. This did not result in more advanced cases at final pathology. PRRT and SSA are valid alternative therapies for PNETs when surgery is not feasible.

Update in the management of gastroenteropancreatic neuroendocrine tumors.

Neuroendocrine neoplasms are a diverse group of neoplasms that can occur in various areas throughout the body. Well-differentiated neuroendocrine tumors (NETs) most often arise in the gastrointestinal tract, termed gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Although GEP-NETs are still uncommon, their incidence and prevalence have been steadily increasing over the past decades. The primary treatment for GEP-NETs is surgery, which offers the best chance for a cure. However, because GEP-NETs are often slow-growing and do not cause symptoms until they have spread widely, curative surgery is not always an option. Significant advances have been made in systemic and locoregional treatment options in recent years, including peptide-receptor radionuclide therapy with α and β emitters, somatostatin analogs, chemotherapy, and targeted molecular therapies.

Investigating the Radiobiological Response to Peptide Receptor Radionuclide Therapy Using Patient-Derived Meningioma Spheroids.

Peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTA-TATE has recently been evaluated for the treatment of meningioma patients. However, current knowledge of the underlying radiation biology is limited, in part due to the lack of appropriate in vitro models. Here, we demonstrate proof-of-concept of a meningioma patient-derived 3D culture model to assess the short-term response to radiation therapies such as PRRT and external beam radiotherapy (EBRT). We established short-term cultures (1 week) for 16 meningiomas with high efficiency and yield. In general, meningioma spheroids retained characteristics of the parental tumor during the initial days of culturing. For a subset of tumors, clear changes towards a more aggressive phenotype were visible over time, indicating that the culture method induced dedifferentiation of meningioma cells. To assess PRRT efficacy, we demonstrated specific uptake of 177Lu-DOTA-TATE via somatostatin receptor subtype 2 (SSTR2), which was highly overexpressed in the majority of tumor samples. PRRT induced DNA damage which was detectable for an extended timeframe as compared to EBRT. Interestingly, levels of DNA damage in spheroids after PRRT correlated with SSTR2-expression levels of parental tumors. Our patient-derived meningioma culture model can be used to assess the short-term response to PRRT and EBRT in radiobiological studies. Further improvement of this model should pave the way towards the development of a relevant culture model for assessment of the long-term response to radiation and, potentially, individual patient responses to PRRT and EBRT.

Unplanned Emergency Department or Inpatient Acute Care Within 1 Week After Administration of Peptide Receptor Radionuclide Therapy: Frequency of Occurrence and Standard Operating Procedures for Radioprotection in These Situations

Peptide receptor radionuclide therapy (PRRT) is a rapidly developing treatment modality. These treatments are indicated for patients who are either heavily pretreated and/or may have neurohormonal active disease, increasing the risk of acute adverse effects and the need for unplanned acute care. The goals of this report were to characterize the frequency of unplanned acute care utilization after PRRT infusion and detail a comprehensive standard operating procedure (SOP) for radioprotection during unplanned post-PRRT acute care. The records of patients treated with PRRT were reviewed. The event of interest was emergency department (ED) utilization and/or inpatient admission within 7 days of PRRT infusion. A multidisciplinary group developed a radioprotection SOP for all phases of unplanned acute care including the clinical infusion space and emergency medical services transport to the ED, within the ED, and on the inpatient floor. A total of 232 patients received 814 infusions of PRRT, with 134 (58%) receiving Lutathera and 98 (42%) receiving Pluvicto. Nineteen patients received unplanned acute care at an ED within 7 days of PRRT infusion (8% of patients, 2% of infusions), of which 10 received Lutathera (8% of patients, 2% of infusions). Two patients (2% of patients, 0.5% of infusions) experienced carcinoid crises within 24 hours of Lutathera infusion. The median and average intervals between infusion and ED visit were 0.5 days and 1.3 days, respectively. Nine patients received Pluvicto (9% of patients, 3% of infusions). The median and average intervals between infusion and ED visit were 4 and 4.7 days, respectively. Emergency room utilization and/or inpatient admission after PRRT administration are relatively infrequent events, but not unexpected. Centers that administer PRRT should have a comprehensive SOP in place to effectively care for radioactive patient emergencies while maximizing medical staff protection.

Gastroenteropancreatic neuroendocrine neoplasms-Surgery in amultimodal concept

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are mainly found in the small intestine and pancreas. The course of the disease in patients is highly variable and depends on the degree of differentiation (G1-G3) of the neoplasm. The potential for metastasis formation of GEP-NEN is high even with good differentiation (G1). Lymph node metastases and, in many cases, liver metastases are also often found. Less common are bone metastases or peritoneal carcinomas. The treatment of these GEP-NENs is surgical, whenever possible. If an R0resection with removal of all lymph node and liver metastases is successful, the prognosis of the patients is excellent. Patients with diffuse liver or bone metastases can no longer be cured by surgery alone. The long-term survival of these patients is nowadays possible due to the availability of drugs (e.g., somatostatin analogues, tyrosine kinase inhibitors), peptide receptor radionuclide therapy (PRRT) and liver-directed procedures, with agood quality of life.

Long-Term Follow-Up Data of Tumor-Induced Osteomalacia Managed with Surgery and/or Radiofrequency Ablation from a Single Center.

Data on radiofrequency ablation (RFA) in tumor-induced osteomalacia (TIO) are restricted to case reports (~ 11 patients) and long-term follow-up data are further scarce. We describe our experience on managing TIO from a tertiary care center in India. Retrospective study of patients with localized TIO was performed and clinical, biochemical, treatment and follow-up details were retrieved. Normalization of serum phosphorus in absence of phosphate supplementation was defined as remission. Of 33 patients (23 males), 24 patients underwent surgery as first-line treatment, and early remission, delayed remission (> 1month for phosphorus normalization) and persistence were observed 12, 3, and 9 patients at a median follow-up of 5 (4-9) years. The gender, age, tumor size, location of tumors and FGF23 levels were not statistically different in patients who were in remission after surgery versus those with persistent disease. Second/third line treatment included conventional medical treatment and/or repeat surgery (n = 3), radiotherapy (n = 3), peptide receptor radionuclide therapy (n = 1), RFA (n = 1). Two patients had transient worsening (weeks) of weakness post-surgery. 10 patients underwent RFA (first-line n = 9); at the last follow-up 5 (4-10) years, 7 are in remission. Two of three persistent disease patients had large tumors (5.6 and 3.6cm). There were no RFA-related complications except local ulcer in one. Although persistent disease was present in a few patients in both arms, there was no recurrence in either RFA or surgical cohort. RFA provide durable response similar to surgery, persistence requires multi-modality treatment.

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

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. 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. 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. 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.

Factors Predicting Prognosis in Metastatic Grade 1 Gastro-entero-pancreatic Neuroendocrine Tumors

IntroductionThe incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NET) has steadily increased. These tumors are considered relatively indolent even when metastatic. What determines survival outcomes in such situations is understudied.Materials and MethodsRetrospective analysis of a prospectively maintained NET clinic database, to include patients of metastatic grade 1 GEP-NET, from January 2018 to December 2021, to assess factors affecting progression-free survival (PFS).ResultsOf the 589 patients of GEP-NET treated during the study period, 100 were grade 1, with radiological evidence of distant metastasis. The median age was 50 years, with 67% being men. Of these, 15 patients were observed, while 85 patients received treatment in the form of surgery (n = 32), peptide receptor radionuclide therapy (n = 50), octreotide LAR (n = 22), and/or chemotherapy (n = 4), either as a single modality or multi-modality treatment. The median (PFS) was 54.5 months. The estimated 3-year PFS and 3-year overall survival rates were 72.3% (SE 0.048) and 93.4% (SE 0.026), respectively. On Cox regression, a high liver tumor burden was the only independent predictor of PFS (OR 3.443, p = 0.014). The 5-year OS of patients with concomitant extra-hepatic disease was significantly lower than that of patients with liver-limited disease (70.7% vs. 100%, p = 0.017).ConclusionA higher burden of liver disease is associated with shorter PFS in patients with metastatic grade I GEP-NETs. The OS is significantly lower in patients with associated extrahepatic involvement. These parameters may justify a more aggressive treatment approach in metastatic grade 1 GEP-NETs.

Immunohistochemical Profiling of SSTR2 and HIF-2α with the Tumor Microenvironment in Pheochromocytoma and Paraganglioma.

Metastatic pheochromocytomas and paragangliomas (PPGLs) are rare endocrine malignancies with limited effective treatment options. The association between the tumor microenvironment (TME) with somatostatin receptor 2 (SSTR2) and hypoxia-induced factor-2α (HIF-2α) in PPGLs, critical for optimizing combination therapeutic strategies with immunotherapy, remains largely unexplored. To evaluate the association of SSTR2 and HIF-2α immunoreactivity with the TME in patients with PPGLs, we analyzed the expression of SSTR2A, HIF-2α, and TME components, including tumor-infiltrating lymphocytes (CD4 and CD8), tumor-associated macrophages (CD68 and CD163), and PD-L1, using immunohistochemistry in patients with PPGLs. The primary outcome was to determine the association of the immune profiles with SSTR2A and HIF-2α expression. Among 45 patients with PPGLs, SSTR2A and HIF2α were positively expressed in 21 (46.7%) and 14 (31.1%) patients, respectively. The median PD-L1 immunohistochemical score (IHS) was 2.0 (interquartile range: 0-30.0). Positive correlations were observed between CD4, CD8, CD68, and CD163 levels. A negative correlation was found between the CD163/CD68 ratio (an indicator of M2 polarization) and SSTR2A expression (r = -0.385, p = 0.006). HIF-2α expression showed a positive correlation with PD-L1 IHS (r = 0.348, p = 0.013). The co-expression of PD-L1 (HIS > 10) and HIF-2α was found in seven patients (15.6%). No associations were observed between SDHB staining results and the CD163/CD68 ratio, PD-L1, or SSTR2A expression. Our data suggest the potential of combination therapy with immunotherapy and peptide receptor radionuclide therapy or HIF-2α inhibitors as a treatment option in selected PPGL populations.

Clonal Hematopoiesis in Patients With Neuroendocrine Tumor Treated With Lutetium-177 and the Risk of Thrombocytopenia: A Prospective Study.

Thrombocytopenia is a relatively common dose-limiting toxicity during peptide receptor radionuclide therapy (PRRT) in patients with NET. Although uncommon, some patients develop persistent cytopenia and eventually therapy-related myeloid neoplasm (t-MN), which has a dismal prognosis. As the indications for PRRT are expanding, it is important to investigate factors that may predict cytopenias during/after PRRT. We prospectively evaluated the prevalence of clonal hematopoiesis (CH) and cytopenia in patients with NET undergoing PRRT. Patients with metastatic NET with plan to receive four cycles of lutetium-177 were enrolled. CH was evaluated before PRRT using a panel of 220 genes with a targeted depth of ≥1,000×. Patients were followed during PRRT and every 3 months thereafter. Of 37 patients enrolled, the median age was 68 years and 51.4% were male. Previous treatment exposures included alkylating agents in 30%, platinum agents in 8%, and external radiation in 13%. CH was detected in 35.1% using a variant allele frequency (VAF) cutoff of ≥2% and 45.9% with a VAF of ≥1%. The most common mutations were in age-related genes (DNMT3A, TET2). CH was not associated with anemia or neutropenia; however, it was associated with lower platelet count at baseline and more time spent in a thrombocytopenic state during/after PRRT. Five patients had bone marrow biopsies (BMBs) because of sustained hematologic dysfunction post-PRRT, and of those, diagnoses included clonal cytopenia of undetermined significance (CCUS) in three and idiopathic cytopenia of undetermined significance (ICUS) in two. CH is present in 35.1% of patients with NET and is associated with thrombocytopenia risk during PRRT. Future studies with long-term follow-up will delineate whether CH might be a predictor for higher risk of t-MN after PRRT.