Neuroendocrine tumors (NETs) are a rare, heterogeneous group of malignancies that arise from neuroendocrine cells throughout the body, with the lungs and GI tract being the most common sites of ...origin. Despite increasing incidence, awareness of lung NETs remains low among thoracic specialists who are often involved in the assessment and early treatment of these patients. Successful treatment requires accurate and timely diagnosis; however, classification can be challenging, particularly for well-differentiated and intermediate-differentiated lung NET types (typical carcinoids TC and atypical carcinoids AC). Diagnosis and management of lung NETs are further complicated by the nonspecificity of symptoms, variable natural history, and lack of high-level clinical evidence; a multidisciplinary approach is required, which has been shown to improve prognosis. Currently, surgery remains the only curative option for TC/AC. Inconsistencies between guideline recommendations for systemic therapies, especially for chemotherapy, result in a lack of consensus on a standardized treatment for unresectable disease. Recent data from the Phase III RAD001 in Advanced Neuroendocrine Tumors, Fourth Trial (RADIANT-4), which contained a large population of patients with advanced, well-differentiated, nonfunctional lung NETs in addition to those with GI NETs, found a reduced risk of disease progression and death with everolimus compared with placebo, leading to US approval of everolimus in these patient populations. This study is the first high-level therapeutic evidence in patients with TC/AC, and everolimus is currently the only agent approved for treatment of TC/AC. Increased awareness, prompt diagnosis, and additional adequately powered controlled clinical trials of patients with well-differentiated and intermediate-differentiated lung NETs are needed to further improve evidence-based care.
Highlights ► Dysregulation of the PI3K/Akt/mTOR pathway can occur at multiple nodes in pNETs, providing several potential drug targets. ► PI3K pathway inhibitors target pNETs by direct inhibition of ...individual pathway nodes, or indirectly by inhibiting HSP90. ► Combination of PI3K and mTOR inhibitors, or agents with dual activity, can overcome limitations of mTOR inhibitors alone. ► Akt inhibitors target pNET cells, and MK-2206 has provided responses in pNET patients, with combination trials ongoing. ► Clinical studies are underway evaluating dual node inhibitors in pNET, including novel agents such as NVP-BEZ235.
As compared with placebo, extended-release lanreotide (120 mg every 28 days) was associated with delayed disease progression in patients with nonfunctional, slowly progressing neuroendocrine tumors. ...Progression-free survival at 24 months was 65% with lanreotide and 33% with placebo.
Neuroendocrine tumors are rare neoplasms,
1
,
2
with an annual incidence of 5 cases per 100,000 people in the United States.
1
More than 50% of cases involve tumors originating in the gastrointestinal system or pancreas, and patients commonly have distant metastases at diagnosis.
1
Since many of these patients have inoperable disease, medical therapy is often initiated to control disease progression. Treatment may also be required to relieve symptoms arising from the overproduction of amines or peptide hormones in functioning tumors.
Few medical treatments for advanced neuroendocrine tumors have been approved on the basis of their antiproliferative effects (i.e., efficacy in inhibiting . . .
Neuroendocrine tumors (NET) of the lung represent approximately 25% of all primary lung tumors and can be classified as low grade (typical carcinoids), intermediate grade (atypical carcinoids), or ...high grade (large cell neuroendocrine carcinoma or small cell lung carcinoma). Low‐ and intermediate‐grade lung NET are increasingly recognized as biologically distinct from high‐grade lung NET based on clinical behavior and underlying molecular abnormalities. This review summarizes current knowledge and challenges in the diagnosis and management of low‐ and intermediate‐grade lung NET. Accurate histopathologic classification of lung NET is critical to determining appropriate treatment options but can be challenging even for experts. For low‐ and intermediate‐grade lung NET, surgery remains the mainstay of treatment for localized disease. Although no standard systemic therapy has been established for the treatment of advanced, unresectable disease, a number of promising treatment options are emerging, including somatostatin analogs, temozolomide‐based chemotherapy, targeted therapy with mammalian target of rapamycin or vascular endothelial growth factor inhibitors, and peptide receptor radionuclide therapy. Given the difficulty in accurately diagnosing these tumors, and the paucity of data supporting establishment of standard systemic therapy options, management of patients within the setting of a multidisciplinary team, including specialists with expertise in NET, is recommended. Ongoing and future clinical trials hopefully will provide stronger evidence to support treatment recommendations for low‐ and intermediate‐grade lung NET.
Implications for Practice:
Treatment of neuroendocrine tumors (NET), particularly those of lung origin, continues to evolve. This review seeks to educate oncologists on the most up‐to‐date options and supporting data regarding management of two rare lung neoplasms, typical and atypical carcinoid tumors. Although surgical resection has been the mainstay of treatment, several systemic options have been studied in the treatment of NET of various origins that may potentially play a role in treating typical carcinoid tumors and atypical carcinoid tumors.
This review summarizes current knowledge and challenges in the diagnosis and management of low‐ and intermediate‐grade lung neuroendocrine tumors. Treatment guidelines recommend consideration of systemic therapies for patients with unresectable, advanced bronchopulmonary disease. Additional data from randomized trials in lung neuroendocrine tumors are needed to support establishment of standard treatment regimens.
Summary Background Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown antitumour activity in patients with advanced pancreatic neuroendocrine tumours. We aimed to ...assess the combination of everolimus plus octreotide long-acting repeatable (LAR) in patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid). Methods We did a randomised, double-blind, placebo-controlled, phase 3 study comparing 10 mg per day oral everolimus with placebo, both in conjunction with 30 mg intramuscular octreotide LAR every 28 days. Randomisation was by interactive voice response systems. Participants were aged 18 years or older, with low-grade or intermediate-grade advanced (unresectable locally advanced or distant metastatic) neuroendocrine tumours, and disease progression established by radiological assessment within the past 12 months. Our primary endpoint was progression-free survival. Adjusted for two interim analyses, the prespecified boundary at final analysis was p≤0·0246. This study is registered at ClinicalTrials.gov , number NCT00412061. Findings 429 individuals were randomly assigned to study groups; 357 participants discontinued study treatment and one was lost to follow-up. Median progression-free survival by central review was 16·4 (95% CI 13·7–21·2) months in the everolimus plus octreotide LAR group and 11·3 (8·4–14·6) months in the placebo plus octreotide LAR group (hazard ratio 0·77, 95% CI 0·59–1·00; one-sided log-rank test p=0·026). Drug-related adverse events (everolimus plus octreotide LAR vs placebo plus octreotide LAR) were mostly grade 1 or 2, and adverse events of all grades included stomatitis (62% vs 14%), rash (37% vs 12%), fatigue (31% vs 23%), and diarrhoea (27% vs 16%). Interpretation Everolimus plus octreotide LAR, compared with placebo plus octreotide LAR, improved progression-free survival in patients with advanced neuroendocrine tumours associated with carcinoid syndrome. Funding Novartis Pharmaceuticals.
Summary Background Effective systemic therapies for patients with advanced, progressive neuroendocrine tumours of the lung or gastrointestinal tract are scarce. We aimed to assess the efficacy and ...safety of everolimus compared with placebo in this patient population. Methods In the randomised, double-blind, placebo-controlled, phase 3 RADIANT-4 trial, adult patients (aged ≥18 years) with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomly assigned in a 2:1 ratio by an interactive voice response system to receive everolimus 10 mg per day orally or identical placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and previous somatostatin analogue treatment. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival assessed by central radiology review, analysed by intention to treat. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov , number NCT01524783. Findings Between April 3, 2012, and Aug 23, 2013, a total of 302 patients were enrolled, of whom 205 were allocated to everolimus 10 mg per day and 97 to placebo. Median progression-free survival was 11·0 months (95% CI 9·2–13·3) in the everolimus group and 3·9 months (3·6–7·4) in the placebo group. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (hazard ratio HR 0·48 95% CI 0·35–0·67, p<0·00001). Although not statistically significant, the results of the first pre-planned interim overall survival analysis indicated that everolimus might be associated with a reduction in the risk of death (HR 0·64 95% CI 0·40–1·05, one-sided p=0·037, whereas the boundary for statistical significance was 0·0002). Grade 3 or 4 drug-related adverse events were infrequent and included stomatitis (in 18 9% of 202 patients in the everolimus group vs 0 of 98 in the placebo group), diarrhoea (15 7% vs 2 2%), infections (14 7% vs 0), anaemia (8 4% vs 1 1%), fatigue (7 3% vs 1 1%), and hyperglycaemia (7 3% vs 0). Interpretation Treatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours. The safety findings were consistent with the known side-effect profile of everolimus. Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract. Funding Novartis Pharmaceuticals Corporation.
In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We ...report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki-67 ≤10%) non-functioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n=101) or placebo (n=103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n=41; placebo, n=47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment-related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection bias by assuming that patients with SD on lanreotide in the core study and not entering the OLE (n=13) had PD 24 weeks after last core assessment, found median PFS remaining consistent: 30.8 months (95% CI: 30.0, 31.3). Median time to further PD after placebo-to-lanreotide switch (n=32) was 14.0 months (10.1; not reached). This OLE study suggests long-term treatment with lanreotide Autogel 120 mg maintained favourable safety/tolerability. CLARINET OLE data also provide new evidence of lanreotide anti-tumour benefits in indolent and progressive pancreatic/intestinal NETs.
Carcinoid syndrome symptoms significantly reduce quality of life in patients with neuroendocrine tumors. Evidence supporting the use of somatostatin analogues in carcinoid syndrome symptom control ...dates back 30 years. The introduction of new treatment options for carcinoid syndrome, such as telotristat ethyl in 2017, highlights the need for a review of high-level evidence of new and established systemic treatments.
To examine the efficacy and safety of systemic treatment options for patients with carcinoid syndrome.
A systematic review of English language articles was conducted using PubMed, EMBASE, and the Cochrane Controlled Trials Register using the search terms carcinoid syndrome, clinical trial, clinical study, and prospective study. Additional studies were identified by searching abstracts from oncology or neuroendocrine tumor congresses during the previous year. Prospective, interventional, phase II or III clinical trials or pivotal trials leading to drug approval were included. Studies were required to have >85% of patients with carcinoid syndrome; secondary publications were excluded.
The search identified 233 unique records, of which 12 trials met the criteria for inclusion. Interventions assessed in these trials included short-acting and long-acting octreotide, lanreotide prolonged-release and autogel/depot, short-acting and long-acting pasireotide, telotristat ethyl, everolimus, and peptide receptor radionuclide therapy. Somatostatin analogues provided substantial symptom relief for patients with carcinoid syndrome. For refractory symptoms, an increased dose of somatostatin analogue or addition of telotristat ethyl were valuable options. Interventions were generally well tolerated, with few serious treatment-related adverse events.
By critically evaluating high-level evidence in a rigorous manner, this review highlights the general lack of consensus regarding what defines symptom control in studies of carcinoid syndrome and the need for standardized treatment guidelines for this disease. More prospective trials of treatments for carcinoid syndrome are warranted to assist oncologists with optimizing treatment selection and sequencing in this patient population.
Purpose Treatment options for neuroendocrine tumors (NETs) remain limited. This trial assessed the progression-free survival (PFS) of bevacizumab or interferon alfa-2b (IFN-α-2b) added to octreotide ...among patients with advanced NETs. Patients and Methods Southwest Oncology Group (SWOG) S0518, a phase III study conducted in a US cooperative group system, enrolled patients with advanced grades 1 and 2 NETs with progressive disease or other poor prognostic features. Patients were randomly assigned to treatment with octreotide LAR 20 mg every 21 days with either bevacizumab 15 mg/kg every 21 days or 5 million units of IFN-α-2b three times per week. The primary end point was centrally assessed PFS. This trial is registered with ClinicalTrials.gov as NCT00569127. Results A total of 427 patients was enrolled, of whom 214 were allocated to bevacizumab and 213 to IFN-α-2b. The median PFS by central review was 16.6 months (95% CI, 12.9 to 19.6 months) in the bevacizumab arm and was 15.4 months (95% CI, 9.6 to 18.6 months) in the IFN arm (hazard ratio HR, 0.93; 95% CI, 0.73 to 1.18; P = .55). By site review, the median PFS times were 15.4 months (95% CI, 12.6 to 17.2 months) for bevacizumab and 10.6 months (95% CI, 8.5 to 14.4 months) for interferon (HR, 0.90; 95% CI, 0.72 to 1.12; P = .33). Time to treatment failure was longer with bevacizumab than with IFN (HR, 0.72; 95% CI, 0.58 to 0.89; P = .003). Confirmed radiologic response rates were 12% (95% CI, 8% to 18%) for bevacizumab and 4% (95% CI, 2% to 8%) for IFN. Common adverse events with bevacizumab and octreotide included hypertension (32%), proteinuria (9%), and fatigue (7%); with IFN and octreotide, they included fatigue (27%), neutropenia (12%), and nausea (6%). Conclusion No significant differences in PFS were observed between the bevacizumab and IFN arms, which suggests that these agents have similar antitumor activity among patients with advanced NETs.
A randomized study involving 410 patients with advanced pancreatic neuroendocrine tumors showed that everolimus, as compared with placebo, more than doubled the median progression-free survival (11 ...months vs. 4.6 months). Most of the adverse events were grade 1 or 2 in severity.
The incidence and prevalence of pancreatic neuroendocrine tumors are increasing
1
–
3
; these tumors represent approximately 1.3% of all cases of pancreatic cancer in incidence and 10% of cases in prevalence.
1
–
3
Pancreatic neuroendocrine tumors are frequently diagnosed at a late stage, with approximately 65% of patients presenting with unresectable or metastatic disease; as a result, these patients have a poor prognosis. The median survival time for patients with distant metastatic disease is 24 months,
2
and limited treatment options are available for this population.
Streptozocin is the only approved therapy for pancreatic neuroendocrine tumors in the United States; however, the . . .
PDF
