Undergoing Peptide Receptor Radionuclide Therapy Research Articles

Systemic Cancer Hallmarks as Novel Markers Associated with Progression-Free Survival in Gastroenteropancreatic Neuroendocrine Tumor Patients Undergoing Peptide Receptor Radionuclide Therapy

Introduction: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of tumors often detected at the metastatic stage. The aim of this study was to profile the peripheral blood transcriptome through RNA-Seq and investigate the association of the systemic cancer hallmarks with progression-free survival, in peptide receptor radionuclide therapy (PRRT)-treated GEP-NET patients. Methods: The cohorts were discovery cohort [PRRT-naïve well-differentiated GEP-NETs, n = 59; age- and sex-matched healthy individuals, n = 38], and independent evaluation cohort [GEP-NETs, n = 66]. Peripheral blood transcriptomes were profiled through RNA sequencing and cancer hallmarks were identified via Gene Set Enrichment Analysis (GSEA). Activities of cancer hallmarks in each sample were calculated using Gene Set Variation Analysis. Differentially expressed genes were identified with DESeq2. Progression-free survival was used as a primary endpoint and prognostic association was evaluated using univariate and multivariate Cox proportional hazard (COXPH) analyses. Results: RNA-Seq captured global changes in the peripheral blood transcriptome of GEP-NET patients. Peripheral blood transcriptome of NET patients showed differential enrichment of 30 systemic cancer hallmarks viz., TNF-α signaling via NF-κB, IL2/STAT5 signaling, TNF-α response, TNF-γ response, IL6/JAK/STAT signaling, TGF-β signaling, heme metabolism, etc. In the univariate analyses, two cancer hallmarks were prognostically significant (p < 0.05) in GEP-NETs. Heme metabolism and IL2/STAT5 signaling were statistically significant in the discovery cohort (n = 58) and independent evaluation cohort (n = 66). In multivariate COXPH analyses, heme metabolism and IL2/STAT5 signaling were independently associated with PFS in GEP-NET patients undergoing PRRT. Conclusions: This study provides comprehensive coverage of the peripheral blood transcriptome of GEP-NET patients via RNA-Seq and identifies systemic cancer hallmarks as independent prognostic factors in NETs.

Prognostic value of interim [68Ga]Ga-DOTA-TOC PET/CT in patients with neuroendocrine tumour who underwent peptide receptor radionuclide therapy.

This study evaluated the prognostic value of basal and interim [68Ga]Ga-DOTA-TOC PET/CT in patients with locally advanced or metastatic neuroendocrine tumour (NET) who received peptide receptor radionuclide therapy (PRRT). Patients with NET who received PRRT with [177Lu]Lu-DOTA-TATE at our institution were retrospectively reviewed. Among them, patients who underwent both basal and interim (after two cycles of PRRT) [68Ga]Ga-DOTA-TOC PET/CT were included. Alongside clinicopathologic parameters, PET parameters of maximum standardised uptake value (SUVmax), tumour-to-liver ratio (TLR), whole tumour volume (WTV) and total receptor expression (TRE: WTV multiplied by mean standardised uptake value) were obtained from basal and interim [68Ga]Ga-DOTA-TOC PET/CT, and their proportional changes (∆) were assessed for associations with progression-free survival (PFS) using Kaplan-Meier analysis, log-rank tests, and a Cox proportional-hazards regression model. Twenty-four patients were finally included (10 men and 14 women, median age of 56.5 years, age range 32-74 years). Among them, 16 patients (66.7%) experienced disease progression. In univariate analysis, high ∆WTV (≥ -10%, hazard ratio [HR] = 3.053 [1.003-9.289], p = 0.049) and high ∆TRE (≥ -21%, HR = 3.567 [1.144-11.122], p = 0.028) were significantly associated with shorter PFS. In multivariate analyses adjusted for WHO grade, high ∆WTV (HR = 3.345 [1.055-10.601], p = 0.043) and high ∆TRE (HR = 3.894 [1.194-12.695], p = 0.024) were significant predictors of shorter PFS. The study demonstrates that basal and interim [68Ga]Ga-DOTA-TOC PET/CT scans, through proportional changes in WTV and TRE, effectively predict PFS in neuroendocrine tumour patients receiving PRRT. Question Peptide receptor radionuclide therapy is utilised for patients with somatostatin receptor-positive well-differentiated neuroendocrine tumours; however, prognostic predictors are not well established. Findings Progression-free survival was significantly associated with the proportional change in whole tumour volume and total receptor expression between basal and interim [68Ga]Ga-DOTA-TOC PET/CT. Clinical relevance Interim [68Ga]Ga-DOTA-TOC PET/CT can serve as a valuable imaging method to predict prognosis of peptide receptor radionuclide therapy.

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.

Plasma Markers for Therapy Response Monitoring in Patients with Neuroendocrine Tumors Undergoing Peptide Receptor Radionuclide Therapy.

Pretherapeutic chromogranin A, alkaline phosphatase (ALP), or De Ritis ratio (aspartate aminotransferase/alanine aminotransferase) are prognostic factors in patients with metastatic neuroendocrine tumors (NET) undergoing peptide receptor radionuclide therapy (PRRT). However, their value for intratherapeutic monitoring remains unclear. We evaluated if changes in plasma markers during PRRT can help identify patients with unfavorable outcomes. A monocentric retrospective analysis of 141 patients with NET undergoing PRRT with [177Lu]Lu-DOTATOC was conducted. Changes in laboratory parameters were calculated by dividing the values determined immediately before each cycle of PRRT by the pretherapeutic value. Patients with low vs. high PFS were compared with the Wilcoxon rank-sum test. Progression, relapse, or death after PRRT was observed in 103/141 patients. Patients with low PFS showed a significant relative ALP increase before the third (p = 0.014) and fourth (p = 0.039) cycles of PRRT. Kaplan-Meier analysis revealed a median PFS of 24.3 months (95% CI, 20.7-27.8 months) in patients with decreasing ALP values (Δ > 10%) during treatment, 12.5 months (95% CI, 9.2-15.8 months) in patients with increasing ALP values (Δ > 10%), and 17.7 months (95% CI, 13.6-21.8 months) with stable ALP values (Δ ± 10%). Based on these exploratory data, a rise in plasma ALP might indicate disease progression and should be interpreted cautiously during therapy.

Evaluation of Hepatotoxicity from Peptide Receptor Radionuclide Therapy in Patients with Gastroenteropancreatic Neuroendocrine Tumors and a Very High Liver Tumor Burden.

The aim of the current study was to describe the risk of hepatotoxicity for patients with gastroenteropancreatic neuroendocrine tumors undergoing peptide receptor radionuclide therapy (PRRT) with a very high liver tumor burden, defined as tumor involving more than 75% of the liver. Methods: We conducted a retrospective analysis of 371 patients who received at least 1 cycle of 177Lu-DOTATATE at Mayo Clinic for advanced gastroenteropancreatic neuroendocrine tumors. We identified 15 total patients with more than 75% liver involvement on 68Ga-DOTATATE PET/CT and with either a contrast-enhanced abdominal MRI or dual-phase abdominal CT examination. Results: Of the 15 patients with more than 75% liver involvement, 1 experienced hepatotoxicity (i.e., worsening liver enzymes or bilirubin) as defined by the Common Terminology Criteria for Adverse Events, version 5.0. No patients had grade 3-5 hepatotoxicity (i.e., clinical signs of liver failure). Conclusion: When considering the risk of liver injury from PRRT due to burden of disease, our data suggest that PRRT may be a safe option in patients with more than 75% liver involvement. Future efforts should be made to determine the safety profile of PRRT in patients with varying degrees of liver involvement.

Somatostatin receptor-directed molecular imaging for therapeutic decision-making in patients with medullary thyroid carcinoma

BackgroundSomatostatin receptor (SSTR) positron emission tomography/computed tomography (PET/CT) is increasingly deployed in the diagnostic algorithm of patients affected with medullary thyroid carcinoma (MTC). We aimed to assess the role of SSTR-PET/CT for therapeutic decision making upon restaging.Methods23 pretreated MTC patients underwent SSTR-PET/CT and were discussed in our interdisciplinary tumor board. Treatment plans were initiated based on scan results. By comparing the therapeutic regimen before and after the scan, we assessed the impact of molecular imaging on therapy decision. SSTR-PET was also compared to CT portion of the SSTR-PET/CT (as part of hybrid imaging).ResultsSSTR-PET/CT was superior in 9/23 (39.1%) subjects when compared to conventional CT and equivalent in 14/23 (60.9%). Those findings were further corroborated on a lesion-based level with 27/73 (37%) metastases identified only by functional imaging (equivalent to CT in the remaining 46/73 (63%)). Investigating therapeutic decision making, no change in treatment was initiated after PET/CT in 7/23 (30.4%) patients (tyrosine kinase inhibitor (TKI), 4/7 (57.2%); surveillance, 3/7 (42.8%)). Imaging altered therapy in the remaining 16/23 (69.6%). Treatment prior to PET/CT included surgery in 6/16 (37.5%) cases, followed by TKI in 4/16 (25%), active surveillance in 4/16 (25%), and radiation therapy (RTx) in 2/16 (12.5%) subjects. After SSTR-PET/CT, the therapeutic regimen was changed as follows: In the surgery group, 4/6 (66.7%) patients underwent additional surgery, and 1/6 (16.7%) underwent surveillance and TKI, respectively. In the TKI group, 3/4 (75%) individuals received another TKI and the remaining subject (1/4, 25%) underwent peptide receptor radionuclide therapy. In the surveillance group, 3/4 (75%) underwent surgery (1/4, (25%), RTx). In the RTx group, one patient was switched to TKI and another individual was actively monitored (1/2, 50%, respectively). Moreover, in the 16 patients in whom treatment was changed by molecular imaging, control disease rate was achieved in 12/16 (75%) during follow-up.ConclusionsIn patients with MTC, SSTR-PET/CT was superior to CT alone and provided relevant support in therapeutic decision-making in more than two thirds of cases, with most patients being switched to surgical interventions or systemic treatment with TKI. As such, SSTR-PET/CT can guide the referring treating physician towards disease-directed treatment in various clinical scenarios.

Best Practices for the Coordinated Care of Patients With Neuroendocrine Tumors Undergoing Peptide Receptor Radionuclide Therapy.

Neuroendocrine tumors (NETs) are rare, diverse malignancies; approximately two thirds originate in the gastrointestinal tract and pancreas and are known as gastroenteropancreatic NET. Most cases are diagnosed in the advanced or metastatic setting and overexpress somatostatin receptors. Recommended first-line treatment is somatostatin analogs; however, disease progression is common. [177Lu]Lu-DOTA-TATE is a radiolabeled peptide receptor radionuclide therapy (PRRT) indicated for the treatment of adult patients with somatostatin receptor-positive foregut, midgut, and hindgut gastroenteropancreatic NETs and progression on first-line somatostatin analogs. Many primary oncology practices may lack the staff, expertise, and infrastructure to treat patients with PRRT and primary oncologists may therefore refer their patients to a NET specialist at a tertiary center for treatment. Given the amount of organization required, PRRT treatment may seem to be complex; however, this process will be managed by a care coordinator who acts as a consistent point of contact for primary physicians regarding the care of their patients and ensures blood tests and scans are scheduled. In this article, we share our opinions, procedures, workflow, best practice, and roles and responsibilities when caring for patients receiving [177Lu]Lu-DOTA-TATE and focus on the role of the primary oncologist before, during, and after PRRT treatment.

Familial SDHB gene mutation in disseminated non-hypoxia-related malignant paraganglioma treated with [90Y]Y/[177Lu]Lu- DOTATATE.

Familial paraganglioma may be related to mutations in succinate dehydrogenase (SDH) enzyme complex genes. Among patients with hereditary paraganglioma, SDH subunit B (SDHB) gene mutations are associated with the highest morbidity and mortality related to a higher malignancy rate. We report a family with the c.689G>A (p.Arg230His) mutation in the SDHB gene identified in two family members, a father and his daughter. While the 14-year-old daughter had no evidence of clinical disease, recurrent and later disseminated [131I]metaiodobenzylguanidine uptake-negative head and neck paraganglioma with multiple bone metastases developed in the father who underwent peptide receptor radionuclide therapy with [90Y]Y/[177Lu]Lu-dodecane tetraacetic acid octreotate (DOTATATE) at the time of the genetic diagnosis. This treatment was repeated 6 years later due to disease progression and the patient, who is currently 49 years old, remains alive and in good overall clinical condition at 8 years of follow-up after the original presentation at our unit. The growing armamentarium of imaging methods available for such patients may inform decision making regarding choice of the optimal treatment approach, potentially contributing to improved outcomes.

RADI-15. Radiotheranostic Approach in Brain Tumor

Abstract Purpose The aim of this study is feasibility and potential treatment of targeted radionuclide theranostic approach for patients with brain tumors. Methods For the period 2020–2021, 6 child and adult patients who had been diagnosed with brain tumors were treated using theranostic approach followed by refractory to conventional therapy. Two patients that were presented with HER-2 positive, ER and PR negative breast cancer and brain metastases as well as a history of several cycles of chemotherapy sessions and radiotherapy using gamma knife were treated with 177Lu-Trastuzumab (Herceptin). Three other patients with primary brain tumor underwent peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE. The last case was a patient with refractory primary cerebral lymphoma to standard therapy with confirmed CD20-positive B-cell lymphoma who underwent 177Lu-Rituximab. Results A two women with HER-2 positive breast cancer and brain metastasis underwent two cycles of 177Lu-trastuzumab. Post-therapy assessment showed some improvement. Next, a man with a high-grade glioma tumor in the left frontal lobe with history of debunking surgery in combination with chemoradiation received 177Lu-DOTATATE that resulted in a short-term stable situation. Another patient presented with a right cerebellopontine angle meningioma underwent PRRT with 177Lu-DOTATATE. She had a stable disease with some improvement in the clinical status. Also, a girl with an astrocytoma in suprasellar cistern underwent 2 cycles of 177Lu-DOTATATE. The complete response was designed. Finally, a patient with refractory primary cerebral lymphoma received 177Lu-Rituximab. Conclusion Nuclear oncology in the field of neuro-oncology (neuroradiotheranostics) has been toward a personalized approach, effective and safe therapy. These preliminary studies might demonstrate feasibility and therapeutic potential of theranostics in patients with primary, relapsed or metastasis brain tumors. Further studies preferentially well-designed multicenter international clinical trial is warranted.

Case Series of Metastatic VIPoma With Partial Response to Somatostatin Receptor Ligand and Review of Therapeutic Options

Background: Vasoactive intestinal polypeptide secreting islet cell tumors (VIPoma) are rare neuroendocrine tumors of pancreatic origin, characterized by secretory diarrhoea and electrolyte imbalances. Metastasis, commonly hepatic, frequently occur at diagnosis in up to 80% patients. Surgery of the primary tumour remains the gold standard management and in metastatic tumors, somatostatin receptor ligands (SRL) are the drugs of choice for symptom relief and disease control. Some patients will require other approaches to control symptoms, such as liver-targeted therapy, peptide receptor radionuclide therapy (PRRT) or chemotherapy. We describe a case series of metastatic VIPoma which partially-responded to SRL and review of other treatment modalities to achieve disease and symptom control. Case: We report 3 cases, ages 37 to 58 years, with metastatic VIPoma whom presented with secretory diarrhoea, hypokalaemia, achlorhydria and elevated serum VIP levels. CT and 68Gallium PET-CT imaging identified metastases in liver, bone, lungs, spleen and lymph nodes. One case underwent distal pancreatectomy and splenectomy at diagnosis and two cases were advanced and non-resectable. All received long-acting SRL initially and achieved partial control of the gastrointestinal symptoms. Two cases underwent Peptide Receptor Radionuclide Therapy (PRRT) and one case received cytotoxic chemotherapy. Two patients have progressive disease and one succumbed to advanced disease. For inoperable disease, PRRT is useful adjuvant therapy for symptom relief and may improve progression free survival (PFS). Cytotoxic chemotherapy is an option for patients with progressive or symptomatic unresectable tumor. Chemoembolization or liver-targeted therapy are used in liver metastasis for loco-regional control. Alfa-interferon and targeted therapies such as everolimus and sunitinib are other treatment options that can be considered. Conclusion: Metastatic VIPoma remains a challenging disease to manage, requiring multimodal treatment approaches. With timely diagnosis and advancing therapeutic options, more patients can achieve improved symptom and disease control as well as increased survival.

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

BackgroundMonitoring 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).MethodsIn 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.ResultsSixty-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).DiscussionTGR in PanNET patients decreases considerably during PRRT with 177Lu-DOTATATE. TGR may be useful as a biomarker to identify patients with the shortest PFS.

First-in-Humans Study of the SSTR Antagonist 177Lu-DOTA-LM3 for Peptide Receptor Radionuclide Therapy in Patients with Metastatic Neuroendocrine Neoplasms: Dosimetry, Safety, and Efficacy.

The objective of this study was to assess the safety, dosimetry, and efficacy of the 177Lu-labeled somatostatin receptor (SSTR) antagonist DOTA-p-Cl-Phe-cyclo(d-Cys-Tyr-d-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)d-Tyr-NH2 (177Lu-DOTA-LM3) in patients with metastatic neuroendocrine neoplasms (NENs). Methods: Fifty-one patients (aged 27-76 y; mean, 51.6 ± 13.9 y) with metastatic NENs underwent peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-LM3 between August 2017 and December 2019. The median administered activity per cycle was 6.1 ± 0.88 GBq (range, 2.8-7.4 GBq). 68Ga-NODAGA-LM3 PET/CT was used for patient selection and follow-up after 177Lu-DOTA-LM3 PRRT. Morphologic and molecular responses were evaluated in accordance with RECIST 1.1 and the criteria of the European Organisation for Research and Treatment of Cancer (EORTC). Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Dosimetry was performed on 11 patients and compared with the SSTR agonist 177Lu-DOTATOC in 247 patients undergoing PRRT on the same dosimetry protocol. Results: Higher uptake and a longer effective half-life were found for 177Lu-DOTA-LM3 than for the agonist 177Lu-DOTATOC in the whole body and in the kidneys, spleen, and metastases, resulting in higher mean absorbed organ and tumor doses. All patients tolerated therapy without any serious acute adverse effects. Mild nausea without vomiting was observed in 5 (9.8%) patients; no other symptoms were reported. The most severe delayed adverse event was Common Terminology Criteria (CTC)-3 thrombocytopenia in 3 (5.9%) patients. Neither CTC-4 thrombocytopenia nor CTC-3-4 anemia or leukopenia was observed after treatment. No significant decline in renal function was observed, nor was hepatotoxicity. According to RECIST 1.1, disease control could be reached in 40 patients (disease control rate, 85.1%) of the 47 patients monitored after 177Lu-DOTA-LM3 PRRT, with a partial response in 17 (36.2%) and stable disease in 23 (48.9%), whereas 7 patients (14.9%) had progressive disease, and by EORTC criteria, there was complete remission in 2 patients (4.3%), partial remission in 21 (44.7%), stable disease in 18 (38.3%), and progressive disease in 6 (12.8%). Conclusion: The antagonist PRRT with 177Lu-DOTA-LM3 could be administered without severe adverse effects and was well tolerated by most patients, with thrombocytopenia occurring in only a few. No other severe adverse effects were observed; in particular, there was no nephrotoxicity. The SSTR antagonist 177Lu-DOTA-LM3 appears to be promising for PRRT, provides a favorable biodistribution and higher tumor radiation doses than SSTR agonists, and was effective in treating advanced metastatic NENs, especially in patients with low or no SSTR agonist binding, even achieving complete remission in some patients.

The Prognostic Value of the De Ritis Ratio for Progression-Free Survival in Patients with NET Undergoing [177Lu]Lu-DOTATOC-PRRT: A Retrospective Analysis.

Simple SummaryPeptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NET) has shown variable response rates between 9% and 39%. Therefore, better criteria are needed that help doctors to identify patients who will show a favorable outcome to PRRT, and which patients may not. The so-called De Ritis ratio, which is calculated using two basic laboratory parameters of liver function, has shown that it can help to predict the patient outcome in various tumor types. This retrospective study included 125 patients with NET who were treated with PRRT. We demonstrated that a high De Ritis ratio and high levels of the tumor marker Chromogranin A (CgA) each improved the prediction of the progression-free survival after treatment. A consequence for clinical care might be that patients with both high De Ritis ratio and high CgA levels may benefit from intensified follow-up imaging after PRRT because they have a higher risk of early progression.Background: The De Ritis ratio (aspartate aminotransferase [AST]/alanine aminotransferase [ALT]) has demonstrated prognostic value in various cancer entities. We evaluated the prognostic capability of the De Ritis ratio in patients with metastatic neuroendocrine tumors (NET) undergoing peptide receptor radionuclide therapy (PRRT). Methods: Unicentric, retrospective analysis of 125 patients with NET undergoing PRRT with [177Lu]Lu-DOTATOC (female: 37%; median age: 66 years; G1+G2 NET: 95%). The prognostic value regarding progression-free survival (PFS) was analyzed with univariable and multivariable Cox regression. Prognostic accuracy was determined with Harrell’s C index and a likelihood ratio test. Results: Progression, relapse, or death after PRRT was observed in 102/125 patients. Median progression-free survival (PFS) was 15.8 months. Pancreatic or pulmonary origin, high De Ritis ratio, and high Chromogranin A (CgA) significantly predicted shorter PFS in univariable Cox. In multivariable Cox regression, only high De Ritis ratio >0.927 (HR: 1.7; p = 0.047) and high CgA >twice the upper normal limit (HR: 2.1; p = 0.005) remained independent predictors of shorter PFS. Adding the De Ritis ratio to the multivariable Cox model (age, Eastern Cooperative Oncology Group (ECOG) performance status, primary origin, CgA) significantly improved prognostic accuracy (p < 0.001). Conclusions: The De Ritis ratio is simple to obtain in clinical routine and can provide independent prognostic value for PFS in patients with NET undergoing PRRT.

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 chemothe­r­apy, 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.

Influence of Gender on Therapy and Outcome of Neuroendocrine Tumors of Gastroenteropancreatic Origin: A Single-Center Analysis

Introduction: Gender-specific treatment is gaining growing attention in various fields of medicine. In gastrointestinal cancer, influence of sex on outcome has been discussed, while this has not been the case in neuroendocrine tumors. Overall, the incidence of neuroendocrine neoplasms is rising, especially for appendiceal neuroendocrine neoplasms in women. Also, women seem to have a slight advantage in response to therapy, especially for liver metastases. Objectives: This single-center analysis aimed to investigate gender-specific differences in our cohort related to distribution, therapy, and outcome. Methods: Patients from the NET registry as well as the clinic database were evaluated retrospectively concerning overall survival and response to therapy with respect to gender. A subgroup analysis was carried out for patients with low grading and response to chemotherapy, as well as for patients with good and moderate grading receiving peptide receptor radionuclide therapy and for a group of patients with liver surgery. Results: No specific differences could be detected for overall survival or response to therapy between male and female patients. Mean survival was estimated with 242.2 months (±10.39 SD) altogether and 221.7 months (± 13.02 SD) for male patients and 253.5 months (±15.24 SD) for female patients from the NET registry from initial diagnosis. There was no significant difference between female and male patients (p = 0.136). For patients receiving chemotherapy, overall survival from initial diagnosis was calculated with 26 months (±2.59) and did not show any significant differences between female and male patients 24.8 months (±2.81 SD) vs. 27.8 months (±3.86 SD, p = 0.87). Patients undergoing peptide receptor radionuclide therapy showed a median progression-free survival of 26.9 months (±2.82 SD), with 16.9 (±5.595 SD) and 26.9 months (±3.019 SD) for male and female patients, respectively (p = 0.2). In the group of patients with liver surgery, female patients reached an estimated overall survival of 64.7 months (±4.16 SD), male patients 65.1 months (±2.79 SD, p = 0.562). Conclusion: Our cohort did not reveal significant differences in outcome and response to therapy with regards to gender.

Gamma Emitters in Pancreatic Endocrine Tumors Imaging in the PET Era: Is there a Clinical Space for 99mTc-peptides?

Pancreatic Neuroendocrine Tumors (PNETs) are rare neoplasms, sporadic or familial, even being part of a syndrome. Their diagnosis is based on symptoms, hormonal disorders or may be fortuitous. The role of Nuclear Medicine is important, mainly because of the possibility of a theranostic strategy. This approach is allowed by the availability of biochemical agents, which may be labeled with radionuclides suitable for diagnostic or therapeutic purposes, showing almost identical pharmacokinetics. The major role for radiopharmaceuticals is connected with radiolabeled Somatostatin Analogues (SSA), since somatostatin receptors are highly expressed on some of the neoplastic cell types. Nowadays, in the category of radiolabeled SSA, although 111In-pentetreotide, firstly commercially proposed, is still used, the best choice for diagnosis is related to the so called DOTAPET radiotracers labeled with 68-Gallium (Ga), such as 68Ga-DOTATATE, 68Ga-DOTANOC, and 68Ga-DOTATOC. More recently, labeling with 64-Copper (Cu) (64Cu-DOTATATE) has also been proposed. In this review, we discuss the clinical interest of a SAA (Tektrotyd©) radiolabeled with 99mTc, a gamma emitter with better characteristics, with respect to 111Indium, radiolabeling Octreoscan ©. By comparing both pharmacokinetics and pharmacodynamics of Octreoscan©, Tektrotyd© and PET DOTA-peptides, on the basis of literature data and of our own experience, we tried to highlight these topics to stimulate further studies, individuating actual clinical indications for all of these radiotracers. In our opinion, Tektrotyd© could already find its applicative dimension in the daily practice of NETs, either pancreatic or not, at least in centers without a PET/CT or a 68Ga generator. Because of wider availability, a lower cost, and a longer decay, compared with respect to peptides labeled with 68Ga, it could be also proposed, in a theranostic context, for a dosimetry evaluation of patients undergoing Peptide Receptor Radionuclide Therapy (PRRT), and for non-oncologic indications of radiolabelled SSA. In this direction, and for a more rigorous cost/effective evaluation, more precisely individuating its clinical role, further studies are needed.

Correction to: Pre-therapy Somatostatin Receptor-Based Heterogeneity Predicts Overall Survival in Pancreatic Neuroendocrine Tumor Patients Undergoing Peptide Receptor Radionuclide Therapy.

The article "Pre-therapy Somatostatin Receptor-Based Heterogeneity Predicts Overall Survival in Pancreatic Neuroendocrine Tumor Patients Undergoing Peptide Receptor Radionuclide Therapy," was originally published electronically on the publisher's internet portal without open access.

Efficacy of Peptide Receptor Radionuclide Therapy in a United States-Based Cohort of Metastatic Neuroendocrine Tumor Patients: Single-Institution Retrospective Analysis.

The aim of this study was to analyze in a retrospective cohort study the outcomes of a United States-based group of metastatic neuroendocrine tumor (NET) patients who underwent peptide receptor radionuclide therapy (PRRT). Twenty-eight patients from a single US NET Center were treated with PRRT. Toxicities were assessed using Common Terminology Criteria for Adverse Events version 4.03. Progression was determined by the Response Evaluation Criteria in Solid Tumors version 1.1. Univariate and multivariate Cox regression was performed to identify potential predictors of progression-free survival (PFS) and overall survival (OS). The median age at NET diagnosis was 56 years, 50% of the patients were male, 46% of NET primaries were located in the pancreas, 71% of tumors were nonfunctional, 25% were World Health Organization (WHO) grade III, and 20% had at least a 25% hepatic tumor burden. Anemia (36%) was the most common post-PRRT toxicity, followed by leukopenia (31%), nephrotoxicity (27%), and thrombocytopenia (24%). Median PFS was 18 months, and median OS was 38 months. Having a WHO grade III NET and receiving systemic chemotherapy prior to PRRT were found to be to independent predictors of shorter PFS and OS. Peptide receptor radionuclide therapy is an effective therapy in a US population. Progression-free survival and OS were better in WHO grade I/II NETs and when PRRT was sequenced prior to systemic chemotherapy.

Aggressive Pituitary Adenomas: The Dark Side of the Moon

Although pituitary adenomas are considered benign lesions, a small group may show clinically aggressive behavior, sometimes independently from the classic markers of aggressiveness, including the Ki67 labeling index or p53 expression. We selected 7 patients harboring a pituitary tumor with clinical features of aggressiveness. Patients underwent a full preoperative and postoperative endocrinologic and neuroradiologic workup. Two were nonfunctioning, 2 prolactin-secreting, 2 adrenocorticotrophic hormone-secreting, and 1 a growth hormone-secreting adenoma. The 7 patients underwent a total of 17 surgical procedures. At the first surgical procedure, gross total removal was achieved in none of the patients, whereas subtotal removal (>90% of tumor removed) was achieved in 4/7 cases and partial removal (<90% of tumor removed) in 3/7 cases. At first operation, 4/7 patients showed a Ki67 index ≤3% and 2/7 >3%; this information was not available for 1 patient. Postoperatively, all patients underwent radiation therapy. Three patients received chemotherapy with temozolomide. Three patients underwent peptide receptor radionuclide therapy. To date, 1 patient has died of tumor progression, and 2 patients are in a poor general condition. The remaining 4 patients are in a fair/good condition, without any major complaints. The mean follow-up is 43.42 months. Aggressive pituitary adenomas represent a specific and still underestimated entity, often diagnosed late. Clinical and neuroradiologic rapid progression is often the only marker of aggressiveness. Surgical debulking remains the first therapeutic option. Multidisciplinary management is mandatory to offer these patients targeted therapeutic options.

Correlation between dose rate and physical factors of patients undergoing peptide receptor radionuclide therapy with (Lu-177)-DOTATATE

In peptide receptor radionuclide therapy (PRRNT) for the treatment of neuroendocrine tumors with (Lu-177)-DOTATATE, large variations in dose rate at 1 m from the patient's body surface administered with same amount of Lu-177 activity are observed. The aim of this prospective study was to explain the cause of the variations and see if there is correlation between the dose rate per unit activity at 1 m distance from patient's body surface in PRRNT with (Lu-177)-DOTATATE and physical factors such as height, weight, age, body surface area (BSA), body mass index (BMI), height/weight (H/W) ratio, and BSA/BMI ratio. From this study, it is observed that dose rate per unit activity at 1 m distance from patient's body surface is significantly correlated with BMI, H/W ratio, and weight of the patients. Male and female patient's data were also separately analyzed, and there was no statistically significant difference observed in these groups of patients. As BMI or weight of the patient is increases, dose rate per unit activity at 1 m distance from patient's body surface decreases and as H/W ratio increases dose rate per unit activity at 1 m distance from patient's body surface also increases. Moderate correlation was seen with BSA and BSA/BMI ratio of the patients. No correlation was seen with age and height of the patients. From this study, H/W ratio can be considered as a good parameter for correlating the dose rate and activity retained in the patient's body. H/W ratio of patient affects the external dose measurement at 1 m from body surface immediately post-Lu-177 labeled PRRNT therapy. Thus, the study is important in formulating the regulatory criterion for discharge of patients after the treatment.