Future Directions in the Treatment of Neuroendocrine Tumors: Consensus Report of the National Cancer Institute Neuroendocrine Tumor Clinical Trials Planning Meeting

Abstract

Neuroendocrine tumors (NETs) arise from a variety of anatomic sites and share the capacity for production of hormones and vasoactive peptides. Because of their perceived rarity, NETs have not historically been a focus of rigorous clinical research. However, the diagnosed incidence of NETs has been increasing, and the estimated prevalence in the United States exceeds 100,000 individuals. The recent completion of several phase III studies, including those evaluating octreotide, sunitinib, and everolimus, has demonstrated that rigorous evaluation of novel agents in this disease is both feasible and can lead to practice-changing outcomes. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trials planning meeting to identify key unmet needs, develop appropriate study end points, standardize clinical trial inclusion criteria, and formulate priorities for future NET studies for the US cooperative group program. Emphasis was placed on the development of well-designed clinical trials with clearly defined efficacy criteria. Key recommendations include the evaluation of pancreatic NET separately from NETs of other sites and the exclusion of patients with poorly differentiated histologies from trials focused on low-grade histologies. Studies evaluating novel agents for the control of hormonal syndromes should avoid somatostatin analog washout periods when possible and should include quality-of-life end points. Because of the observed long survival after progression of many patients, progression-free survival is recommended as a feasible and relevant primary end point for both phase III studies and phase II studies where a delay in progression is expected in the absence of radiologic responses. J Clin

Role of targeted agents in neuroendocrine tumors: Results from a meta-analysis

“…Therefore, we may confirm the important role of targeted agents in treating the advanced NETs and in this setting, the completion of several randomized phase III studies has brought to the approval of 2 new sunitinib, and everolimus. 32 Because of the observed long survival after progression of many patients, PFS is recommended as a feasible and relevant primary end point for both phase III studies and phase II studies, 33 however we have been able to show a statistically significant improvement also in OS for patients with NETs treated with targeted therapies. In the subgroup analysis, we have reported a better PFS in patients with pancreatic NETs versus other site of NETs (HR D 0.49 and 0.71 respectively).…”

Diagnosis and therapy are walking together on radiopeptides’ avenue

“…Other molecules include angiogenesis inhibitors (such as bevacizumab) which may alone, or in combination with cytotoxic agents, have some significance. Rapamycin (everolimus), an oral inhibitor of the mammalian target of rapamycin (mTOR) signalling pathway alone, or in combination with cytotoxic treatment, might become of value for treatment in NETs [36].…”

Whither peptide receptor radionuclide therapy for neuroendocrine tumors: an Einsteinian view of the facts and myths

“…The surfeit reflects two issues: firstly the multifaceted challenges posed by NETs (heterogeneous, functional, and protean in their behavior [2]) and secondly the substantial limitations of each of the different therapeutic strategies [3,4]. This has led to a change in the "end point" of efficacy of a treatment thereby accommodating different visions of efficacy [5]. No longer is the overall survival (OS) of homo sapiens "with NET" a principal matter of concern rather how long can a "drug/agent" contest the biological menace of NETs {euphe-mistically referred to as progression-free survival (PFS) has taken the centre stage [5]}.…”

“…This has led to a change in the "end point" of efficacy of a treatment thereby accommodating different visions of efficacy [5]. No longer is the overall survival (OS) of homo sapiens "with NET" a principal matter of concern rather how long can a "drug/agent" contest the biological menace of NETs {euphe-mistically referred to as progression-free survival (PFS) has taken the centre stage [5]}. The paradox of increased PFS without increase in OS remains to be explained!…”

“…For grade 3 neuroendocrine cancers, even fewer treatment options are available, and conventional archaic cytotoxic chemotherapy schemes are usually applied [5,22].…”