PURPOSESomatostatin 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 METHODSWe 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).RESULTSWe 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.CONCLUSIONThe 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.
Neuroendocrine tumors (NETs) are a heterogeneous family of neoplasms of increasing incidence and high prevalence due to their relatively indolent nature. Their wide anatomic distribution and their characteristic ability to secrete hormonally active substances pose unique challenges for clinical management. They are also characterized by the common expression of somatostatin receptors, a target that has been extremely useful for diagnosis and treatment (i.e., somatostatin analogues (SSAs) and peptide-receptor radionuclide therapy (PRRT)). Chemotherapy is of limited use for NETs of non-pancreatic origin, and the only approved targeted agents for advanced progressive NETs are sunitinib for those of pancreatic origin, and everolimus for lung, gastrointestinal and pancreatic primaries. Despite recent therapeutic achievements, thus, systemic treatment options remain limited. In this review we will discuss the state-of-the-art targeted therapies in the field of NETs, and also future perspectives of novel therapeutic drugs or strategies in clinical development, including recently presented results from randomized trials of yet unapproved antiangiogenic agents (i.e., pazopanib, surufatinib and axitinib), PRRT including both approved radiopharmaceuticals (177Lu-Oxodotreotide) and others in development (177Lu-Edotreotide, 177Lu-Satoreotide Tetraxetan), immunotherapy and other innovative targeted strategies (antibody-drug conjugates, bites,…) that shall soon improve the landscape of personalized treatment options in NET patients.
Poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are aggressive neoplasms of challenging clinical management. A small proportion of patients with early-stage disease may achieve long-term survival, but the majority of patients present with rapidly lethal metastatic disease. Current standard of care still follows the treatment paradigm of small-cell lung cancer (SCLC), a far more common G3 NEN, although emerging molecular and clinical data increasingly question this approach. In this manuscript we will briefly summarize epidemiology and prognosis of GEP NECs to emphasize the very low incidence, aggressive nature and orphan status of this tumor entity. We will also discuss the current pathological classification and its limitations, as well as recent data on their differential biological background as compared to SCLC, and its potential implications for patients care. Then, we will review the standard of care of systemic therapy, basically focused on platinum-based cytotoxic chemotherapy, including some recent randomized trials providing evidence regarding efficacy of irinotecan vs etoposide platinum-doublets. Finally, we will present a comprehensive overview of novel therapeutic strategies in current clinical development, including recently reported data on immunotherapy, tumor-agnostic therapies (microsatellite instability, high tumor mutational burden, NTRK and RET gene fusions, BRAF or KRAS inhibitors) and additional treatment strategies targeting other tumor vulnerabilities (i.e. Notch pathway, novel targets for radioligand therapy), and provide some insights regarding unmet needs and future perspectives to improve patient’s care and prognosis.
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