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Current understanding and approach to well differentiated lung neuroendocrine tumors: an update on classification and management.

ABSTRACT: Neuroendocrine tumors (NETs) are rare neoplasms that can arise from any tissue. They are classified based on embryonic gut derivative (i.e. foregut, midgut and hindgut) with midgut tumors being the most common (e.g. gastrointestinal NET). The second most common category of NETs is that which arises from the lung. In fact, 25% of primary lung cancers are NETs, including small cell lung cancer (SCLC), which comprises 20% of all lung cancers. The remaining 5% are large cell neuroendocrine cancer (LCNEC, 3%), typical carcinoids (TCs, 1.8%), and atypical carcinoids (ACs, 0.2%). The less common TCs/ACs are well differentiated lung NETs. Their incidence has been increasing in more recent years and although these tumors are slow growing, advanced disease is associated with poor survival. There have been advances in classification of lung NETs that have allowed for more appropriate management upfront. They are cured by surgical resection when disease is limited. However, advanced and metastatic disease requires medical therapy that is ever changing and expanding. In this review, the aim is to summarize the current understanding and classification of well differentiated lung NETs (i.e. TCs and ACs), and focus on recent updates in medical management of advanced disease, along with a brief discussion on potential future discoveries.

SUBMITTER: Hilal T

PROVIDER: S-EPMC5349423 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Current understanding and approach to well differentiated lung neuroendocrine tumors: an update on classification and management.

Hilal Talal T

Therapeutic advances in medical oncology 20161117 3

Neuroendocrine tumors (NETs) are rare neoplasms that can arise from any tissue. They are classified based on embryonic gut derivative (i.e. foregut, midgut and hindgut) with midgut tumors being the most common (e.g. gastrointestinal NET). The second most common category of NETs is that which arises from the lung. In fact, 25% of primary lung cancers are NETs, including small cell lung cancer (SCLC), which comprises 20% of all lung cancers. The remaining 5% are large cell neuroendocrine cancer (L ...[more]

PMID: 28344664

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Project description:IntroductionRecent 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 methodsThis 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).ResultsTreatment 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.ConclusionAmong 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 practiceHigh-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.

Project description:Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) represent the most common subtype of NETs. The incidence of all NETs, and specifically GEP NETs, has risen exponentially over the last three decades. Only within the past several years have these tumors been appropriately classified, allowing for meaningful drug development. Broadly, some of the most exciting drug classes being developed for patients with well-differentiated GEP NETs include newer types of peptide receptor radionuclide therapy (PRRT) or combinations which increase the potency of lutetium-177 (177Lu)-Dotatate, novel multi-target receptor tyrosine kinase inhibitors (RTKIs) and immunotherapy modalities, beyond checkpoint inhibitors, which seek to unleash the immune system against NETs. Specifically looking at newer types of PRRT, somatostatin receptor antagonists and alpha-emitter radionuclides each have demonstrated the ability to elicit greater DNA damage than 177Lu-Dotatate in preclinical models. Early clinical experiences with each of these agents suggest they may be more cytotoxic than 177Lu-Dotatate. Other approaches seeking to build upon the DNA damage created by 177Lu-Dotatate include combinations of PRRT with radiosensitizers such as heat shock protein 90 inhibitors, hedgehog inhibitors, chemotherapy combinations, and triapine. Many of these combinations have just begun to be tested clinically. With regards to novel RTKIs, some of the ones which have demonstrated potent cytoreductive potential include cabozantinib and lenvatinib. Other RTKIs which are further along the clinical development spectrum and have demonstrated benefit in randomized trials include surufatinib and pazopanib. And though single-agent immune checkpoint inhibitors have not demonstrated significant anti-tumor activity in patients with GEP NETs, outside of certain biomarker selected subsets, somatostatin receptor-directed chimeric antigen receptor (CAR) T cells and vaccines such as SurVaxM, which targets survivin, represent two means through which NET-directed immunity may be modulated. The potential of these agents, if clinically realized, will likely improve outcomes for patients with well-differentiated GEP NETs.

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Current understanding and approach to well differentiated lung neuroendocrine tumors: an update on classification and management.

Publications

Current understanding and approach to well differentiated lung neuroendocrine tumors: an update on classification and management.

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