Prediction of Progression-Free Survival in Patients With Advanced, Well-Differentiated, Neuroendocrine Tumors Being Treated With a Somatostatin Analog: The GETNE-TRASGU Study

PURPOSE Somatostatin analogs (SSAs) are recommended for the first-line treatment of most patients with well-differentiated, gastroenteropancreatic (GEP) neuroendocrine tumors; however, benefit from treatment is heterogeneous. The aim of the current study was to develop and validate a progression-free survival (PFS) prediction model in SSA-treated patients. PATIENTS AND METHODS We extracted data from the Spanish Group of Neuroendocrine and Endocrine Tumors Registry (R-GETNE). Patient eligibility criteria included GEP primary, Ki-67 of 20% or less, and first-line SSA monotherapy for advanced disease. An accelerated failure time model was developed to predict PFS, which was represented as a nomogram and an online calculator. The nomogram was externally validated in an independent series of consecutive eligible patients (The Christie NHS Foundation Trust, Manchester, United Kingdom). RESULTS We recruited 535 patients (R-GETNE, n = 438; Manchester, n = 97). Median PFS and overall survival in the derivation cohort were 28.7 (95% CI, 23.8 to 31.1) and 85.9 months (95% CI, 71.5 to 96.7 months), respectively. Nine covariates significantly associated with PFS were primary tumor location, Ki-67 percentage, neutrophil-to-lymphocyte ratio, alkaline phosphatase, extent of liver involvement, presence of bone and peritoneal metastases, documented progression status, and the presence of symptoms when initiating SSA. The GETNE-TRASGU (Treated With Analog of Somatostatin in Gastroenteropancreatic and Unknown Primary NETs) model demonstrated suitable calibration, as well as fair discrimination ability with a C-index value of 0.714 (95% CI, 0.680 to 0.747) and 0.732 (95% CI, 0.658 to 0.806) in the derivation and validation series, respectively. CONCLUSION The GETNE-TRASGU evidence-based prognostic tool stratifies patients with GEP neuroendocrine tumors receiving SSA treatment according to their estimated PFS. This nomogram may be useful when stratifying patients with neuroendocrine tumors in future trials. Furthermore, it could be a valuable tool for making treatment decisions in daily clinical practice.

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Outcome of Patients With Metastatic Lung Neuroendocrine Tumors Submitted to First Line Monotherapy With Somatostatin Analogs

Frontiers in Endocrinology ◽

10.3389/fendo.2021.669484 ◽

2021 ◽

Vol 12 ◽

Author(s):

Elisa Lenotti ◽

Andrea Alberti ◽

Francesca Spada ◽

Vito Amoroso ◽

Patrick Maisonneuve ◽

...

Keyword(s):

Overall Survival ◽

Neuroendocrine Tumors ◽

Somatostatin Analogs ◽

Case Series ◽

Progression Free Survival ◽

First Line ◽

Ki 67 ◽

Typical Carcinoid ◽

Free Survival ◽

Metastatic Lung

ObjectiveAntiproliferative activity of somatostatin analogs (SSAs) has been demonstrated in digestive neuroendocrine tumors (NETs), but few data have been published in patients with pulmonary NETs. We therefore conducted a retrospective study to provide additional data on the outcome of patients with metastatic lung NETs submitted to front line SSAs.Research Design and MethodsPatients with metastatic lung NET treated with first line SSA-monotherapy (octreotide or lanreotide) in two different reference Institutions were reviewed. Outcome measures were progression-free survival (PFS) overall survival (OS), overall response rate and safety. We also explored prognostic factors associated with PFS.MethodsThe outcome of consecutive patients (pts) with metastatic lung NETs, who underwent first-line treatment with SSAs, recruited from 2014 on 2019 in two Italian reference Institutions, was retrospectively evaluated.ResultsThirty-one patients entered the study: 14 (45.2%) with typical and 17 (54.8%) atypical carcinoid. Six patients (19.4%) had a carcinoid syndrome. 60.0% of patients had Ki-67 ≤ 10%. Two (6.5%) patients obtained a partial response, 24 (77.4%) disease stabilization while 5 (16.1%) had progressive disease. Median progression free survival (PFS) was 28.6 months, median overall survival (OS) was not attained. Ki-67 ≤ 10%, typical carcinoid histotype and non-functioning disease, were associated with a non-significant PFS prolongation. PFS in patients with atypical carcinoids and in those with Ki-67 >10% was greater than 19 months.ConclusionsThe long PFS and OS obtained in this case series suggest that SSAs could be effective as first line approach in the management of patients with progressive, metastatic pulmonary NET.

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Ki-67 proliferative index predicts progression-free survival of patients with well-differentiated ileal neuroendocrine tumors

Human Pathology ◽

10.1016/j.humpath.2011.06.011 ◽

2012 ◽

Vol 43 (4) ◽

pp. 489-495 ◽

Cited By ~ 49

Author(s):

Deepti Dhall ◽

Richard Mertens ◽

Catherine Bresee ◽

Rugvedita Parakh ◽

Hanlin L. Wang ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Progression Free Survival ◽

Proliferative Index ◽

Ki 67 ◽

Free Survival ◽

Well Differentiated

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Somatostatin analogs in association with peptide receptor radionucleotide therapy in advanced well-differentiated NETs

Future Oncology ◽

10.2217/fon-2019-0138 ◽

2019 ◽

Vol 15 (26) ◽

pp. 3015-3024

Author(s):

Natalie Prinzi ◽

Alessandra Raimondi ◽

Marco Maccauro ◽

Massimo Milione ◽

Enrico Garanzini ◽

...

Keyword(s):

Overall Survival ◽

Neuroendocrine Tumors ◽

Somatostatin Analogs ◽

Progression Free Survival ◽

Hazard Ratio ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Free Survival ◽

Peptide Receptor ◽

Treatment Beyond Progression ◽

Well Differentiated

Aim: Data from 69 well-differentiated gastroenteropancreatic neuroendocrine tumors treated with peptide receptor radionucleotide therapy + somatostatin analogs (SSAs) after SSA treatment failure were evaluated. Methods: We identified two groups: S1 – patients who kept the same SSA treatment beyond progression; S2 – patients who switched the SSA with another SSA after progression. Results: Median progression-free survival was 53 and 127 months in S1 and S2, respectively (p = 0.001; hazard ratio: 0.31; 95% CI: 0.15–0.63). Median overall survival was 69 versus 150 months in S1 and S2, respectively (p = 0.004; hazard ratio: 0.32; 95% CI: 0.14–0.71). Conclusion: In patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumors treated with peptide receptor radionucleotide therapy plus SSA after SSA failure, the ‘switch’ strategy of SSA after progression improve progression-free survival and overall survival.

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FAS and Subsequent Therapies in Pancreatic Neuroendocrine Tumors

Neuroendocrinology ◽

10.1159/000514339 ◽

2021 ◽

Author(s):

Jane E. Rogers ◽

Michael Lam ◽

Daniel M. Halperin ◽

Cecile G. Dagohoy ◽

James C. Yao ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Cox Regression ◽

Progression Free Survival ◽

Pancreatic Neuroendocrine Tumors ◽

Free Survival ◽

Prior Therapy ◽

Well Differentiated ◽

Grade 3 ◽

Line Of Therapy

We evaluated outcomes of treatment with 5-fluorouracil (5-FU), doxorubicin, and streptozocin (FAS) in well-differentiated pancreatic neuroendocrine tumors (PanNETs) and its impact on subsequent therapy (everolimus or temozolomide). Advanced PanNET patients treated at our center from 1992 to 2013 were retrospectively reviewed. Patients received bolus 5-FU (400 mg/m2), streptozocin (400 mg/m2) (both IV, days 1-5) and doxorubicin (40 mg/m2 IV, day 1) every 28 days. Overall response rate (ORR) was assessed using RECIST version 1.1. Of 243 eligible patients, 220 were evaluable for ORR, progression-free survival (PFS), and toxicity. Most (90%) had metastatic, nonfunctional PanNETs; 14% had prior therapy. ORR to FAS was 41% (95% confidence interval [CI]: 36-48%). Median follow-up was 61 months. Median PFS was 20 (95% CI: 15-23) months; median overall survival (OS) was 63 (95% CI: 60-71) months. Cox regression analyses suggested improvement with first-line vs subsequent lines of FAS therapy. Main adverse events ≥ grade 3 were neutropenia (10%) and nausea/vomiting (5.5%). Dose reductions were required in 32% of patients. Post-FAS everolimus (n=108; 68% second line) had a median PFS of 10 (95% CI: 8-14) months. Post-FAS temozolomide (n=60; 53% > fourth line) had an ORR of 13% and median PFS of 5.2 (95% CI: 4-12) months. In this largest reported cohort of PanNETs treated with chemotherapy, FAS demonstrated activity without significant safety concerns. FAS did not appear to affect subsequent PFS with everolimus; this sequence is being evaluated prospectively. Responses were noted with subsequent temozolomide-based regimens although PFS was possibly limited by line of therapy.

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

JCO Global Oncology ◽

10.1200/go.21.00103 ◽

2021 ◽

pp. 1167-1175

Author(s):

Swayamjeet Satapathy ◽

Bhagwant R. Mittal ◽

Ashwani Sood ◽

Apurva Sood ◽

Rakesh Kapoor ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Systemic Therapy ◽

Objective Response ◽

Progression Free Survival ◽

First Line ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Free Survival ◽

Octreotide Lar ◽

Treatment Naïve ◽

Long Acting

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

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Treatment of Liver Metastases in Patients with Neuroendocrine Tumors of Gastroesophageal and Pancreatic Origin

International Journal of Hepatology ◽

10.1155/2012/131659 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 9

Author(s):

Ping Gu ◽

Jennifer Wu ◽

Elliot Newman ◽

Franco Muggia

Keyword(s):

Liver Metastasis ◽

Neuroendocrine Tumors ◽

Somatostatin Analogs ◽

Hepatic Metastases ◽

Progression Free Survival ◽

Therapeutic Options ◽

Free Survival ◽

Octreotide Lar ◽

Pancreatic Net ◽

Pancreatic Origin

Well-to-moderately differentiated neuroendocrine tumors of gastroesophageal and pancreatic origin (GEP-NETs) with liver metastasis are a heterogeneous group of malignancies for which a range of therapeutic options have been employed. Surgical resection of hepatic metastases or hepatic artery embolization may be beneficial in patients with hepatic-predominant metastatic disease. Patients with “carcinoid” syndrome and syndromes associated with functional pancreatic NET (PNET) can be effectively treated with somatostatin analogs. On the other hand, the efficacy of systemic chemotherapy for these patients is limited. A placebo-controlled, double-blind, prospective, and randomized study showed that octreotide LAR improves progression-free survival in patients with advanced midgut functional “carcinoids.” In patients with advanced pancreatic NET, randomized, placebo-controlled studies have recently demonstrated that treatment with the tyrosine kinase inhibitor sunitinib or with mTOR inhibitor everolimus is associated with improved progression-free survival. Based on these studies, octreotide LAR, sunitinib, or everolimus are now considered as first-line therapeutic options in patients with advanced NET. Future studies will likely further define the role of these agents in patients with carcinoid liver metastasis and pancreatic NET liver metastasis.

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Anti-tumour activity of everolimus and sunitinib in neuroendocrine neoplasms

Endocrine Connections ◽

10.1530/ec-19-0134 ◽

2019 ◽

Vol 8 (6) ◽

pp. 641-653 ◽

Cited By ~ 2

Author(s):

Kosmas Daskalakis ◽

Marina Tsoli ◽

Anna Angelousi ◽

Evanthia Kassi ◽

Krystallenia I Alexandraki ◽

...

Keyword(s):

Progression Free Survival ◽

Clinicopathological Characteristics ◽

Neuroendocrine Neoplasms ◽

Second Line ◽

First Line ◽

Free Survival ◽

Predictors Of Response ◽

Well Differentiated ◽

Tumour Activity ◽

Additive Toxicity

Comparisons between everolimus and sunitinib regarding their efficacy and safety in neuroendocrine neoplasms (NENs) are scarce. We retrospectively analysed the clinicopathological characteristics and outcomes in 92 patients with well-differentiated (WD) NEN of different origin (57 pancreatic NENs (PanNENs)), treated with molecular targeted therapy (MTT) with everolimus or sunitinib, first- (73:19) or second-line (sequential; 12:22) for progressive disease. Disease control rates (DCR: partial response or stable disease) at first-line were higher in all patients treated with everolimus than sunitinib (64/73 vs 12/19, P = 0.012). In PanNENs, DCR at first-line everolimus was 36/42 versus 9/15 with sunitinib (P = 0.062). Progression-free survival (PFS) at first-line everolimus was longer than sunitinib (31 months (95% CI: 23.1–38.9) vs 9 months (95% CI: 0–18.5); log-rank P < 0.0001) in the whole cohort and the subset of PanNENs (log-rank P < 0.0001). Median PFS at second-line MTT was 12 months with everolimus (95% CI: 4.1–19.9) vs 13 months with sunitinib (95% CI: 9.3–16.7; log-rank P = 0.951). Treatment with sunitinib (HR: 3.47; 95% CI: 1.5–8.3; P value: 0.005), KI67 >20% (HR: 6.38; 95% CI: 1.3–31.3; P = 0.022) and prior chemotherapy (HR: 2.71; 95% CI: 1.2–6.3; P = 0.021) were negative predictors for PFS at first line in multivariable and also confirmed at multi-state modelling analyses. Side effect (SE) analysis indicated events of serious toxicities (Grades 3 and 4: n = 13/85 for everolimus and n = 4/41 for sunitinib). Discontinuation rate due to SEs was 20/85 for everolimus versus 4/41 for sunitinib (P = 0.065). No additive toxicity of second-line MTT was confirmed. Based on these findings, and until reliable predictors of response become available, everolimus may be preferable to sunitinib when initiating MTT in progressive NENs.

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Prevention and Management of Hormonal Crisis during Theragnosis with LU-DOTA-TATE in Neuroendocrine Tumors. A Systematic Review and Approach Proposal

Journal of Clinical Medicine ◽

10.3390/jcm9072203 ◽

2020 ◽

Vol 9 (7) ◽

pp. 2203 ◽

Cited By ~ 1

Author(s):

Maria Isabel del Olmo-García ◽

Maria Angustias Muros ◽

Martín López-de-la-Torre ◽

Marc Agudelo ◽

Pilar Bello ◽

...

Keyword(s):

Systematic Review ◽

Neuroendocrine Tumors ◽

Somatostatin Receptors ◽

Somatostatin Analogs ◽

Progression Free Survival ◽

Metabolic Complications ◽

Literature Searches ◽

Prisma Statement ◽

Well Differentiated ◽

Meta Analyses

Neuroendocrine tumors (NETs) frequently overexpress somatostatin receptors (SSTR) on their cell surface. The first-line pharmacological treatment for inoperable metastatic functioning well-differentiated NETs are somatostatin analogs. On second line, Lu-DOTA-TATE (177Lu-DOTA0 Tyr 3 octreotate) has shown stabilization of the disease and an increase in progression free survival, as well as effectiveness in controlling symptoms and increasing quality of life. The management of functional NETs before and during LU-DOTA-TATE treatment is specially challenging, as several complications such as severe carcinoid and catecholamine crisis have been described. The aim of this review is to establish practical guidance for the management and prevention of the most common hormonal crises during radionuclide treatment with Lu-DOTA-TATE: carcinoid syndrome (CS) and catecholamine hypersecretion, as well as to provide a brief commentary on other infrequent metabolic complications. To establish a practical approach, a systematic review was performed. This systematic review was developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and conducted using MEDLINE (accessed from PubMed), Google Scholar and ClinicalTrials.gov. Literature searches found 449 citations, and finally nine were considered for this systematic review.

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Outcomes of patients treated with capecitabine and temozolamide (CapTem) for advanced pancreatic neuroendocrine tumors (PNETs) and non-PNETs.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.343 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 343-343 ◽

Cited By ~ 4

Author(s):

Renata D'Alpino Peixoto ◽

Krista Noonan ◽

Hagen F. Kennecke ◽

Howard John Lim

Keyword(s):

Progression Free Survival ◽

Median Number ◽

First Line ◽

Primary Tumors ◽

Free Survival ◽

Entire Cohort ◽

First Line Therapy ◽

Poor Tolerance ◽

Well Differentiated ◽

Number Of Cycles

343 Background: Retrospective studies have demonstrated high response rates among patients with advanced PNETs treated with CapTem while responses are infrequently seen among non-PNETs. The objective of the study was to describe progression free survival (PFS) and overall survival (OS) among sequential NET patients treated with CapTem and to identify factors associated with response. Methods: Patients who initiated therapy with CapTem between 2009 and 2013 for advanced NETs and referred to one of 6 provincial cancer treatment centers were included. Patients received Cap 2000 mg/m2 day 1-14 and TMZ 200 mg/m2 on days 10-14 every 28 days. Their characteristics and outcomes were retrospectively analyzed. Results: In our cohort, 29 patients (16 male) with a median age of 59 (range 26 – 76) received palliative CapTem, 15 of them as first-line chemotherapy and 14 as subsequent lines. Primary tumors included pancreas (48.3%), small bowel (20.7%), lung (10.3%), unknown (10.3), rectum (6.9%) and appendix (3.4%). Median number of cycles was 3. For the entire cohort, median PFS and OS were 4.7 and 20.2 months, respectively. Although pancreatic NETs (PNETs) had shorter OS (18.8 months versus not reached, p=0.37), their PFS was longer than non-PNETs (4.9 versus 2.8 months, p=0.178). There was no difference in PFS between first or subsequent lines of therapy. Patients with Ki67 above 10% had a shorter PFS when compared to lower Ki67 (3.1 versus 5.5 months, p = 0.028). Three patients had to discontinue CapTem due to poor tolerance (2 intractable nauseas and 1 myocardial infarction). There were no treatment-related deaths. Conclusions: CapTem showed good activity among NETs, especially for PNETS, who derived the greatest benefit. Effectiveness was not exclusive to first-line therapy and seems better for well-differentiated tumors.

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A Renaissance in Therapeutic Options for Pancreatic Neuroendocrine Tumors

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2012.32.136 ◽

2012 ◽

pp. 271-274

Author(s):

Pamela L. Kunz

Keyword(s):

Neuroendocrine Tumors ◽

Advanced Disease ◽

Somatostatin Analogs ◽

Progression Free Survival ◽

Therapeutic Options ◽

Pancreatic Neuroendocrine Tumors ◽

Free Survival ◽

Future Studies ◽

Published Research

Overview: The field of pancreatic neuroendocrine tumors (NETs) has seen a remarkable renaissance in recent years with exponential increases in published research, clinical trials, and U.S. Food and Drug Administration (FDA)-approved treatments. Surgical resection remains the foundation for management of locoregional disease. However, for patients with advanced disease, novel therapeutic options have emerged. Two separate randomized placebo-controlled studies have shown prolonged progression-free survival (PFS) with everolimus or sunitinib. Future studies are designed to answer questions about the role of somatostatin analogs as antiproliferative agents, combinations of biologic therapies, and new cytotoxic chemotherapy backbones.

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