Peptide Receptor Radionuclide Therapy versus Capecitabine/Temozolomide for the Treatment of Metastatic Pancreatic Neuroendocrine Tumors.

Background: Peptide Receptor Radionuclide Therapy (PRRT), a form of Radioligand Therapy (RLT), and Capecitabine/Temozolomide (CAPTEM) are cornerstones of systemic therapy for metastatic pancreatic neuroendocrine tumors (PNETs). Data regarding comparative efficacy are lacking. Herein, we compare the efficacy of PRRT vs. CAPTEM as second-line/beyond regimens and treatment sequencing. Methods: Clinicopathologic, radiographic, and genomic data were captured for metastatic PNETs seen in our multi-disciplinary NET clinic between 2013 and 2023. The primary outcome was progression-free survival (PFS) after progression on a previous line of systemic therapy. The secondary outcomes were objective response rate (ORR), time to response (TTR), and overall survival (OS). Results: Fifty-nine cases were included. PFS was similar in the PRRT (n = 29) and CAPTEM (n = 30) groups (PRRT = 21.90 months vs. CAPTEM = 20.03 months; HR 0.99; p = 0.97). On subgroup analysis, PRRT had longer PFS in cases without extrahepatic metastases (26.47 months vs. 17.67 months; p = 0.03) and cases with a mutation in the MEN1, DAXX, and/or ATRX genes (28.43 months vs. 18.67 months; p = 0.03). PRRT had reduced PFS in patients with grade 3 disease (7.83 months vs. 16.33 months; p = 0.02). ORR did not vary significantly (34.78% vs. 40.91%; p = 0.67). CAPTEM responders showed shorter TTR (6.03 months vs. 11.15 months; p = 0.03). In patients who received both, OS did not vary based on the sequence (HR 1.20; p = 0.75). Conclusions: PFS, ORR, and OS are similar when using PRRT vs. CAPTEM as second-line-and-beyond therapy for patients with metastatic PNETs. However, patients with MEN1, DAXX, and/or ATRX mutations or without extrahepatic metastases might better benefit from PRRT and patients with grade 3 disease from CAPTEM. Candidates for surgical debulking or with tumor-induced symptoms may benefit from initial treatment with CAPTEM due to shorter TTR.

A randomized phase II trial of Captem or Folfiri as second-line therapy in neuroendocrine carcinomas.

BACKGROUND: Neuroendocrine Carcinomas (NECs) prognosis is poor.No standard second-line therapy is currently recognized after failure of platinum-based first-line treatment. FOLFIRI and CAPTEM regimens have shown promising activity in preliminary studies. We aimed to evaluate these regimens in metastatic NEC patients. METHODS: This is an open-label, multicenter, randomized non-comparative phase II trial to evaluate the activity and safety of FOLFIRI or CAPTEM in metastatic NEC patients. Primary endpoints were the 12 weeks-Disease Control Rate (12w-DCR) by investigator assessment per RECIST v1.1 and safety per CTCAE v5.0. Additional endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Patients' serum samples were subject to NGS miRNome profiling in comparison with healthy donors to reveal differentially expressed miRNAs as candidate circulating biomarkers. RESULTS: The study was halted for futility at interim analysis, as the minimum 12w-DCR threshold of 10 out of 25 patients required for the first step was not reached. From 06/03/2017 to 18/01/2021, 53 out of 112 patients were enrolled. Median follow-up was 22.6 months (range: 1.4-60.4). The 12w-DCR was 39.1 % in the FOLFIRI arm and 28.0 % in the CAPTEM arm. In the FOLFIRI subgroup the 12-months OS rate was 28.4 % (95 % CI: 12.7-46.5) while in the CAPTEM subgroup it was 32.4 % (95 % CI: 14.9-51.3). The most common G3-G4 side effects were neutropenia (n = 5, 18.5 %) and anemia (n = 2, 7.4 %) for FOLFIRI and G3-G4 thrombocytopenia (n = 2, 8.0 %), G4 nausea/vomiting (n = 1, 4.0 %) for CAPTEM. Three microRNAs emerged as NEC independent predictors. High expression values were found to be significantly associated with decreased PFS and OS. CONCLUSION: The safety profile of FOLFIRI and CAPTEM was manageable. FOLFIRI and CAPTEM chemotherapy showed comparable activity in the second-line setting after progression on etoposide/platinum. GOV IDENTIFIER: NCT03387592.

Systemic Therapy for Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PanNETs) account for approximately 2% of all pancreatic malignancies. Several systemic treatment options have been developed over the last four decades, ranging from cytotoxic chemotherapy and octreotide to newer targeted therapies like sunitinib, cabozantinib, and lenvatinib. Although surgery or liver-directed therapy remains cornerstone for management of metastatic PanNETs, however, they remain unfeasible in majority of cases. PanNETs behave differently than SI-NETs (small intestinal NET); the former is more aggressive and less responsive to somatostatin-based therapies. The optimal sequence of the systemic therapies for the advanced PanNETs depends mainly on the tumor burden, Ki-67 index, and the tempo of the disease. In the end, drawing from ENETS (European Neuroendocrine Tumor Society) and ESMO (European Society for Medical Oncology) guidelines, we propose a working algorithm for the management of advanced PanNETs, not amenable to surgery or liver-directed therapies.

Utility of clinical and MR imaging parameters for prediction and monitoring of response to capecitabine and temozolomide (CAPTEM) therapy in patients with liver metastases of neuroendocrine tumors.

BACKGROUND: This study explores the predictive and monitoring capabilities of clinical and multiparametric MR parameters in assessing capecitabine and temozolomide (CAPTEM) therapy response in patients with neuroendocrine tumors (NET). PATIENTS AND METHODS: This retrospective study (n = 44) assessed CAPTEM therapy response in neuroendocrine liver metastases (NELM) patients. Among 33 monitored patients, as a subgroup of the overall study cohort, pretherapeutic and follow-up MRI data (size, apparent diffusion coefficient [ADC] values, and signal intensities), along with clinical parameters (chromogranin A [CgA] and Ki-67%), were analyzed. Progression-free survival (PFS) served as the reference. Responders were defined as those with PFS ≥ 6 months. RESULTS: Most patients were male (75%) and had G2 tumors (76%) with a pancreatic origin (84%). Median PFS was 5.7 months; Overall Survival (OS) was 25 months. Non-responders (NR) had higher Ki-67 in primary tumors (16.5 vs. 10%, p = 0.01) and increased hepatic burden (20% vs. 5%, p = 0.007). NR showed elevated CgA post-treatment, while responders (R) exhibited a mild decrease. ADC changes differed significantly between groups, with NR having decreased ADCmin (-23%) and liver-adjusted ADCmean/ADCmean liver (-16%), compared to R's increases of ADCmin (50%) and ADCmean/ADCmean liver (30%). Receiver operating characteristic (ROC) analysis identified the highest area under the curve (AUC) (0.76) for a single parameter for ∆ ADC mean/liver ADCmean, with a cut-off of < 6.9 (76% sensitivity, 75% specificity). Combining ∆ Size NELM and ∆ ADCmin achieved the best balance (88% sensitivity, 60% specificity) outperforming ∆ Size NELM alone (69% sensitivity, 65% specificity). Kaplan-Meier analysis indicated significantly longer PFS for ∆ ADCmean/ADCmean liver < 6.9 (p = 0.024) and ∆ Size NELM > 0% + ∆ ADCmin < -2.9% (p = 0.021). CONCLUSIONS: Survival analysis emphasizes the need for adapted response criteria, involving combined evaluation of CgA, ADC values, and tumor size for monitoring CAPTEM response in hepatic metastasized NETs.

Metronomic Temozolomide (mTMZ) and Bevacizumab-The Safe and Effective Frontier for Treating Metastatic Neuroendocrine Tumors (NETs): A Single-Center Experience.

Addressing the persistent challenges in treating metastatic neuroendocrine tumors (NETs) demands ongoing refinement and innovation in therapeutic strategies. This study investigates the potential advantages of combining metronomic temozolomide (mTMZ) with bevacizumab for patients diagnosed with metastatic NETs, particularly focusing on those with a Ki-67 index under 55%. Data from 30 patients were analyzed, using key performance indicators such as progression-free survival (PFS), overall survival (OS), and response rates to therapy, to gauge the treatment's efficacy. The results were encouraging: the median PFS recorded was 16.3 months, and the OS was 25.9 months. The disease control rate (DCR) reached an impressive 86.7%, and the objective response rate (ORR) stood at 63.3%. The treatment regimen was well-tolerated, with no reported instances of grade 4 toxicities. Such a safety profile indicates that this regimen may be particularly advantageous for older, fragile patients who might struggle with conventional dosage levels. These initial findings suggest that the mTMZ and bevacizumab combination could potentially rival the conventional temozolomide-capecitabine therapy in managing metastatic NETs. We aimed to meticulously assess the efficacy of the mTMZ and bevacizumab combination in treating metastatic NETs. Given the initial promising results, a more conclusive understanding of its efficacy will require further research through larger, multicenter prospective clinical trials.

Efficacy of Capecitabine and Temozolomide Regimen in Neuroendocrine Tumors: Data From the Turkish Oncology Group.

INTRODUCTION: This study aims to report the efficacy and safety of capecitabine plus temozolomide (CAPTEM) across different lines of treatment in patients with metastatic neuroendocrine tumors (NETs). METHODS: We conducted a multicenter retrospective study analyzing the data of 308 patients with metastatic NETs treated with CAPTEM between 2010 and 2022 in 34 different hospitals across various regions of Turkey. RESULTS: The median follow-up time was 41.0 months (range: 1.7-212.1), and the median age was 53 years (range: 22-79). Our results across the entire patient cohort showed a median progression-free survival (PFS) of 10.6 months and a median overall survival (OS) of 60.4 months. First-line CAPTEM treatment appeared more effective, with a median PFS of 16.1 months and a median OS of 105.8 months (median PFS 16.1, 7.9, and 9.6 months in first-, second- and ≥third-line respectively, P = .01; with median OS values of 105.8, 47.2, and 24.1 months, respectively, P = .003) In terms of ORR, the first-line treatment again performed better, resulting in an ORR of 54.7% compared to 33.3% and 30.0% in the second and third or higher lines, respectively (P < .001). Grade 3-4 side effects occurred only in 22.5% of the patients, leading to a discontinuation rate of 9.5%. Despite the differences in outcomes based on treatment line, we did not observe a significant difference in terms of side effects between the first and subsequent lines of treatment. CONCLUSIONS AND RELEVANCE: The substantial superior outcomes in patients receiving first-line CAPTEM treatment highlight its potential as an effective treatment strategy for patients with metastatic NET.

A case of frequent hypoglycemic attacks successfully controlled with capecitabine plus temozolomide and 177Lu-DOTATATE peptide receptor radionuclide therapy in a patient with recurrent pancreatic insulinoma.

A 59-year-old woman with metastatic pancreatic insulinoma, having undergone several treatment regimens including sunitinib, everolimus, lanreotide and streptozocin plus 5-fluorouracil, was admitted to our hospital because of frequent hypoglycemic attacks. These were refractory to medical treatment using diazoxide and required frequent daily intravenous glucose infusions. She was started on capecitabine and temozolomide (CAPTEM), followed by initiation of 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT). The frequency of hypoglycemic attacks decreased after treatment began and she was discharged on day 58 post-admission, without requiring daily glucose infusions. CAPTEM and PRRT were continued without any major adverse events. Computed tomography revealed shrinkage of primary and metastatic lesions, an anti-tumor effect that continued 8 months after treatment was initiated. Hypoglycemic attacks caused by insulinomas are often refractory to conventional therapy; however, combination treatment using CAPTEM and PRRT has demonstrated a positive and significant response, successfully restoring glycemic control.

Targeted Genomic Profiling and Chemotherapy Outcomes in Grade 3 Gastro-Entero-Pancreatic Neuroendocrine Tumors (G3 GEP-NET).

BACKGROUND: Grade 3 gastro-entero-pancreatic neuroendocrine tumors (G3 GEP-NET) are poorly characterized in terms of molecular features and response to treatments. METHODS: Patients with G3 GEP-NET were included if they received capecitabine and temozolomide (CAPTEM) or oxaliplatin with either 5-fluorouracile (FOLFOX) or capecitabine (XELOX) as first-line treatment (chemotherapy cohort). G3 NET which successfully undergone next-generation sequencing (NGS) were included in the NGS cohort. RESULTS: In total, 49 patients were included in the chemotherapy cohort: 15 received CAPTEM and 34 received FOLFOX/XELOX. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were 42.9%, 9.0 months, and 33.6 months, respectively. Calculating a Ki67 cutoff using ROC curve analysis, tumors with Ki67 ≥ 40% had lower ORR (51.2% vs. 0%; p = 0.007) and shorter PFS (10.6 months vs. 4.4 months; p < 0.001) and OS (49.4 months vs. 10.0 months; p = 0.023). In patients who received FOLFOX/XELOX as a first-line treatment, ORR, PFS, and OS were 38.2%, 7.9 months, and 30.0 months, respectively. In the NGS cohort (N = 13), the most mutated genes were DAXX/ATRX (N = 5, 38%), MEN1 (N = 4, 31%), TP53 (N = 4, 31%), AKT1 (N = 2, 15%), and PIK3CA (N = 1, 8%). CONCLUSIONS: FOLFOX/XELOX chemotherapy is active as the first-line treatment of patients with G3 GEP-NET. The mutational landscape of G3 NET is more similar to well-differentiated NETs than NECs.

Capecitabine and Temozolomide (CAPTEM) in Advanced Neuroendocrine Neoplasms (NENs): A Systematic Review and Pooled Analysis.

Background: Retrospective studies and single center experiences suggest a role of capecitabine combined with temozolomide (CAPTEM) in neuroendocrine tumors (NENs). Methods: We performed a systematic review to assess the efficacy and safety of CAPTEM in patients affected with NENs, with the aim to better clarify the role of this regimen in the therapeutic algorithm of NENs. Results: A total of 42 articles and 1818 patients were included in our review. The overall disease control rate was 77% (range 43.5%-100%). The median progression free survival ranged from 4 to 38.5 months, while the median overall survival ranged from 8 to 103 months. Safety analysis showed an occurrence of G3-G4 toxicities in 16.4% of the entire population. The most common toxicities were hematological (27.2%), gastrointestinal (8.3%,) and cutaneous (3.2%). Conclusion: This systematic review demonstrated that CAPTEM was an effective and relatively safe treatment for patients with advanced well-moderate differentiated NENs of gastroenteropancreatic, lung and unknown origin.

Efficacy of Capecitabine and Temozolomide in Small Bowel (Midgut) Neuroendocrine Tumors.

The capecitabine/temozolomide regimen has significant activity in pancreatic NETs; however, data are limited in NETs of the small bowel (midgut). A retrospective study of all patients with metastatic midgut NETs seen at Moffitt Cancer Center between January 2008 and June 2019 treated with CAPTEM was conducted. 32 patients with proven or suspected well-differentiated primary small bowel NETs (excluding duodenum) were identified. 6 patients were found to have a radiographic response (19%), 5 of whom had high-grade disease. Only one patient among 23 with low/intermediate-grade disease responded (4%), whereas the response rate for patients with high-grade disease was 56%. Among patients with low/intermediate-grade disease, 44% discontinued due to poor tolerability. The CAPTEM regimen appears to have an activity in patients with high-grade small bowel NETs and is largely inactive in patients with low/intermediate-grade tumors.

Efficacy of temozolomide combined with capecitabine (CAPTEM) on refractory prolactinomas as assessed using an ex vivo 3D spheroid assay.

PURPOSE: Refractory prolactinomas resistant to dopamine agonists (DAs) pose a clinical challenge. Temozolomide (TMZ) is a recommended treatment option, but its effects are difficult to predict, and the alternatives are limited. Recent reports suggested that TMZ combined with capecitabine (CAPTEM) can be effective for the treatment of aggressive pituitary tumors. This study sought to evaluate the effect of TMZ in an ex vivo three-dimensional (3D) spheroid culture assay and determine if this assay could be used to predict the therapeutic effect of CAPTEM in actual refractory prolactinomas. METHODS: Surgically resected tumor tissues from two patients with refractory prolactinoma were cultured as 3D spheroids. The effects of TMZ were assessed based on its suppression of cell viability and reduction of prolactin (PRL) levels. RESULTS: In Case 1, the 3D culture assay showed no effect of TMZ on cell viability or PRL suppression. Clinically, TMZ treatment did not reduce PRL levels (8870→8274 ng/mL) and the tumor progression. However, CAPTEM partially reduced PRL levels (9070→4046 ng/mL) and suppressed the tumor growth. In Case 2, TMZ in the 3D culture assay showed a 50% reduction of cell viability and 40% reduction of PRL levels. Clinically, CAPTEM was highly effective, with a considerable reduction in PRL level (17,500→210 ng/mL), and MRI showed almost no residual tumor. CONCLUSIONS: This is the first report to describe the effects of CAPTEM treatment on refractory prolactinomas. The ex vivo 3D spheroid culture assay reliably predicted TMZ sensitivity and informed the selection between TMZ or CAPTEM treatment for refractory prolactinomas.

Neuroendocrine Neoplasm of the Breast Presenting as a Liver Metastasis: A Rare Diagnostic Challenge.

We present a case of a 58-year-old female who presented initially to an outside institution with abdominal pain and was diagnosed on liver biopsy with a well-differentiated neuroendocrine tumor of an unknown primary source. She was referred to our academic institution for a second opinion after disease progression on the initial chemotherapy regimen. Through additional evaluation, diagnostics, and multi-disciplinary tumor board discussion she was diagnosed with metastases from a well-differentiated neuroendocrine neoplasm of the breast (NENB). Consequently, her treatment plan was modified leading to significant clinical and radiological improvement.

Multimodal Non-Surgical Treatments of Aggressive Pituitary Tumors.

Up to 35% of aggressive pituitary tumors recur and significantly affect mortality and quality of life. Management can be challenging and often requires multimodal treatment. Current treatment options, including surgery, conventional medical therapies such as dopamine agonists, somatostatin receptor agonists and radiotherapy, often fail to inhibit pituitary tumor growth. Recently, anti-tumor effects of chemotherapeutic drugs such as Temozolomide, Capecitabine, and Everolimus, as well as peptide receptor radionuclide therapy on aggressive pituitary tumors have been increasingly investigated and yield mixed, although sometimes promising, outcomes. The purpose of this review is to provide thorough information on non-surgical medical therapies and their efficacies and used protocols for aggressive pituitary adenomas from pre-clinical level to clinical use.

Treatment Outcomes of Well-Differentiated High-Grade Neuroendocrine Tumors.

INTRODUCTION: Recent classification of neuroendocrine neoplasms has defined well-differentiated high-grade neuroendocrine tumors (NET G3) as a distinct entity from poorly differentiated neuroendocrine carcinoma. The optimal treatment for NET G3 has not been well-described. This study aimed to evaluate metastatic NET G3 response to different treatment regimens. MATERIALS AND METHODS: This was a retrospective study of patients with NET G3 within the Mayo Clinic database. Patients' demographics along with treatment characteristics, responses, and survival were assessed. Primary endpoints were progression-free survival (PFS) and overall survival. Secondary endpoints were objective response rate (ORR) and disease control rate (DCR). RESULTS: Treatment data was available in 30 patients with median age of 59.5 years at diagnosis. The primary tumor was mostly pancreatic (73.3%). Ki-67 index was ≥55% in 26.7% of cases. Treatments included capecitabine + temozolomide (CAPTEM) (n = 20), lutetium 177 DOTATATE (PRRT; n = 10), Platinum-etoposide (EP; n = 8), FOLFOX (n = 7), and everolimus (n = 2). CAPTEM exhibited ORR 35%, DCR 65%, and median PFS 9.4 months (95% confidence interval, 2.96-16.07). Both EP and FOLFOX showed similar radiographic response rates with ORR 25.0% and 28.6%; however, median PFS durations were quite distinct at 2.94 and 13.04 months, respectively. PRRT had ORR of 20%, DCR of 70%, and median PFS of 9.13 months. CONCLUSION: Among patients with NET G3, CAPTEM was the most commonly used treatment with clinically meaningful efficacy and disease control. FOLFOX or PRRT are other potentially active treatment options. EP has some activity in NET G3, but responses appear to be short-lived. Prospective studies evaluating different treatments effects in patients with NET G3 are needed to determine an optimal treatment strategy. IMPLICATIONS FOR PRACTICE: High-grade well-differentiated neuroendocrine tumors (NET G3) are considered a different entity from low-grade NET and neuroendocrine carcinoma in terms of prognosis and management. The oral combination of capecitabine and temozolomide is considered a good option in the management of metastatic NET G3 and may be preferred. FOLFOX is another systemic option with reasonable efficacy. Similar to other well-differentiated neuroendocrine tumors, peptide receptor radionuclide therapy seems to have some efficacy in these tumors.

Randomised phase II trial of CAPTEM or FOLFIRI as SEcond-line therapy in NEuroendocrine CArcinomas and exploratory analysis of predictive role of PET/CT imaging and biological markers (SENECA trial): a study protocol.

INTRODUCTION: Patients with metastatic or locally advanced, non-resectable, grade 3 poorly differentiated gastroenteropancreatic (GEP) and lung neuroendocrine carcinomas (NECs) are usually treated with in first-line platinum compounds. There is no standard second-line treatment on progression. Accurate biomarkers are needed to facilitate diagnosis and prognostic assessment of patients with NEC. METHODS AND ANALYSIS: The SEcond-line therapy in NEuroendocrine CArcinomas (SENECA) study is a randomised, non-comparative, multicentre phase II trial designed to evaluate the efficacy and safety of folinic acid, 5-fluorouracil and irinotecan (FOLFIRI) or capecitabine plus temozolomide (CAPTEM) regimens after failure of first-line chemotherapy in patients with lung NEC and GEP-NEC. Secondary aims are to correlate the serum miRNA profile and primary mutational status of MEN1, DAXX, ATRX and RB-1 with prognosis and outcome and to investigate the prognostic and predictive role of the Ki-67 score and 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) or 68Ga-PET/CT. The main eligibility criteria are age ≥18 years; metastatic or locally advanced, non-resectable, grade 3 lung or GEP-NECs; progression to first-line platinum-based chemotherapy. A Bryant and Day design taking into account treatment activity and toxicity was used to estimate the sample size. All analyses will be performed separately for each treatment group in the intention-to-treat population. A total of 112 patients (56/arm) will be randomly assigned (1:1) to receive FOLFIRI every 14 days or CAPTEM every 28 days until disease progression or unacceptable toxicity or for a maximum of 6 months. Patients undergo testing for specific biomarkers in primary tumour tissue and for miRNA in blood samples. MiRNA profiling will be performed in the first 20 patients who agree to participate in the biological substudy. ETHICS AND DISSEMINATION: The SENECA trial, supported by Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), was authorised by the locals Ethics Committee and the Italian Medicines Agency (AIFA). Results will be widely disseminated via peer-reviewed manuscripts, conference presentations and reports to relevant authorities.The study is currently open in Italy. TRAIL REGISTRATION NUMBER: NCT03387592; Pre-results. EudraCT-2016-000767-17. PROTOCOL VERSION: Clinical Study Protocol Version 1, 7 November 2016.

Medical Management of Gastroenteropancreatic Neuroendocrine Tumors.

The increased incidence and prevalence of neuroendocrine tumors (NETs) over the past few decades has been accompanied by an improvement in overall survival. There are differences in the management of small bowel NETs versus pNETs. The management of all patients with NETs must be individualized based on patient characteristics as well tumor-related factors. This article reviews the role of somatostatin analogues, historical results with chemotherapy in gastroenteropancreatic NETs (GEPNETs), and more recent evidence for the use of cytotoxic chemotherapy in GEPNETs. The article also discusses molecular targeted therapies approved for use in GEPNETs and some ongoing clinical trials.