Abstract
Simple SummaryTumor resistance, both primary and acquired, is leading to increased complexity in the nonsurgical treatment of patients with advanced panNENs, which would be greatly helped by reliable prognostic/predictive factors. The importance in identifying resistance is being contributed to by the increased array of possible treatments available for treating resistant advanced disease; the variable clinical course as well as response to any given treatment approach of patients within one staging or grading system, the advances in imaging which are providing increasing promising results/parameters that correlate with grading/outcome/resistance, the increased understanding of the molecular pathogenesis providing promising prognostic markers, all of which can contribute to selecting the best treatment to overcome resistance disease. Several factors have been identified that have prognostic/predictive value for identifying development resistant disease and affecting overall survival (OS)/PFS with various nonsurgical treatments of patients with advanced panNENs. Prognostic factors identified for patients with advanced panNENs for both OS/PFSs include various clinically-related factors (clinical, laboratory/biological markers, imaging, treatment-related factors), pathological factors (histological, classification, grading) and molecular factors. Particularly important prognostic factors for the different treatment modalities studies are the recent grading systems. Most prognostic factors for each treatment modality for OS/PFS are not specific for a given treatment option. These advances have generated several controversies and new unanswered questions, particularly those related to their possible role in predicting the possible sequence of different anti-tumor treatments in patients with different presentations. Each of these areas is reviewed in this paper.Purpose: Recent advances in the diagnosis, management and nonsurgical treatment of patients with advanced pancreatic neuroendocrine neoplasms (panNENs) have led to an emerging need for sensitive and useful prognostic factors for predicting responses/survival. Areas covered: The predictive value of a number of reported prognostic factors including clinically-related factors (clinical/laboratory/imaging/treatment-related factors), pathological factors (histological/classification/grading), and molecular factors, on therapeutic outcomes of anti-tumor medical therapies with molecular targeting agents (everolimus/sunitinib/somatostatin analogues), chemotherapy, radiological therapy with peptide receptor radionuclide therapy, or liver-directed therapies (embolization/chemoembolization/radio-embolization (SIRTs)) are reviewed. Recent findings in each of these areas, as well as remaining controversies and uncertainties, are discussed in detail, particularly from the viewpoint of treatment sequencing. Conclusions: The recent increase in the number of available therapeutic agents for the nonsurgical treatment of patients with advanced panNENs have raised the importance of prognostic factors predictive for therapeutic outcomes of each treatment option. The establishment of sensitive and useful prognostic markers will have a significant impact on optimal treatment selection, as well as in tailoring the therapeutic sequence, and for maximizing the survival benefit of each individual patient. In the paper, the progress in this area, as well as the controversies/uncertainties, are reviewed.
Highlights
A significant percentage of patients with both functional pancreatic neuroendocrine neoplasms (panNENs) syndromes [insulinoma, Zollinger-Ellison syndrome (ZES), other malignant functionalpanNENs) (F-panNEN) and nonfunctional panNENs (NF-panNENs) cannot be cured by surgical resection at presentation, or develop advanced disease on follow-up, which is not surgically curable, and which markedly reduces their survival and requires anti-tumor therapies [1–10]
This review primarily concentrated on reports consisting of patients with panNENs, and includes reports that have a large proportion of panNEN patients
This paper reviews in detail the recent progress, as well as the current situation and remaining controversies/uncertainties in attempting to identify predictive/prognostic factors for identification of resistance manifested by an decreasing effectiveness of each of the available nonsurgical therapeutic agents used in the treatment of patients with advanced panNENs
Summary
A significant percentage of patients with both functional panNEN syndromes [insulinoma, Zollinger-Ellison syndrome (ZES), other malignant functionalpanNENs) (F-panNEN) and nonfunctional panNENs (NF-panNENs) cannot be cured by surgical resection at presentation, or develop advanced disease on follow-up, which is not surgically curable, and which markedly reduces their survival and requires anti-tumor therapies [1–10]. The above controversies and uncertainties underlying the treatment/management of patients with advanced panNENs, especially related to the increasing role of resistant to treatment, have led to the emergence of a need for the development/establishment of sensitive and useful prognostic markers predictive for the clinical effects/outcomes of each specific therapeutic option for several reasons (Table 1) The availability of such prognostic markers will help clinicians select the optimal therapeutic agent at a particular time and to tailor treatment sequences for each individual patient, because the anti-tumor activity and toxicity can vary markedly between each therapeutic option, resulting in different clinical outcomes [18,25,26,61,73,102–104,106]. Is there a synergistic anti-tumor effect combining/sequencing these therapeutic agents?
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