An official website of the United States government
Here's how you know
Official websites use .gov
A
.gov website belongs to an official
government organization in the United States.
Secure .gov websites use HTTPS
A lock (
) or https:// means you've safely
connected to the .gov website. Share sensitive
information only on official, secure websites.
As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with,
the contents by NLM or the National Institutes of Health.
Learn more:
PMC Disclaimer
|
PMC Copyright Notice
. 2013 Jul-Aug;6(4 Suppl 1):S27–S29.
Update on the Pathologic Classification and Grading of NETs
The optimal classification of epithelial neuroendocrine tumors (NETs) has been the subject of much discussion. Multiple different systems of terminology, grading, and staging have been used, some systems combining grading and staging parameters into a single prognostic classification. Recently, national and international consensus groups have attempted to standardize the classification of NETs, especially for those arising in the gastrointestinal tract and pancreas (GEP-NETs). Furthermore, recognition that certain classification criteria (such as proliferative rate) are a component of all the different systems allows the basic data necessary to predict outcome and tailor therapy to be included in pathology reports, even though a single uniform system of terminology may not be possible for every anatomic site.
Recent advances include the development of a standardized grading system for GEP-NETs, first proposed by the European Neuroendocrine Tumor Society (ENETS) and adopted by the World Health Organization in 2010. This system uses the proliferative rate, as determined by counting mitotic figures or determining the labeling percentage in immunohistochemical stains for Ki67, to separate NETs into three grades. The low and intermediate grade NETs constitute the well differentiated category, analogous to carcinoid tumor and atypical carcinoid tumor of the lung or thymus. The high grade category includes the poorly differentiated neuroendocrine carcinomas, small cell carcinoma and large cell neuroendocrine carcinoma. Although issues persist in measuring Ki67, such as the technique to determine the labeling percentage and the problem of intratumoral heterogeneity, the ENETS/WHO grading system allows accurate stratification of NETs into different prognostic groups.
Formal TNM-based staging systems have also been developed recently, both by the ENETS and by the AJCC. Both systems reflect the extent of invasion of the primary tumor, but there are differences between them regarding the tissue landmarks that define the T-stages. Thus, it remains important to include certain basic information in pathology reports, such as the size of the primary tumor, the structures involved, and the specific mitotic rate and Ki67 labeling index, in addition to specifying the stage and grade. A recent concensus group has proposed a “Minimum Data Set” of pathology information to include in reports, and national organizations such as the College of American Pathologists have published diagnostic checklists to help ensure all relevant data are reported. Studies can now focus on refining the criteria for grading and staging, which may differ among different primary sites.
Gastrointest Cancer Res. 2013 Jul-Aug;6(4 Suppl 1):S27–S29.
Prognostic Validity of the American Joint Committee on Cancer (AJCC) Staging Classification for Midgut Neuroendocrine Tumors
The American Joint Committee on Cancer (AJCC) staging manual has introduced a TNM staging classification for jejunal-ileal (midgut) neuroendocrine tumors (NETs). This classification has not been validated in a population consisting solely of midgut NETs.
Methods:
Patients with jejunal and ileocecal NETs treated at the Moffitt Cancer Center between 2000 and 2010 were assigned stages (I-IV) based on TNM staging classification. Kaplan-Meier analyses for overall survival (OS) were performed based on TNM stage and pathologic grade using log-rank tests. Survival time was measured from time of initial diagnosis until date of last contact or date of death. Multivariate modeling was performed using Cox proportional hazards regression.
Results:
We identified 691 patients with histologically-proven jejunal and ileocecal NETs. The AJCC classification in aggregate was highly prognostic for overall survival (P<0.00001). 5-year overall survival (OS) rates for stages I, II, III and IV were 100%, 100%, 91% and 72% respectively. The survival difference between stages III and IV was significant (p<0.00001); the difference between stages I/II versus III was not statistically significant (p=0.1). Among patients with stage IIIB tumors, 5-year survival rates were 95% for resectable tumors versus 78% for unresectable mesenteric tumors (P=0.02).
Conclusions:
Stages I and II midgut NETs are associated with identical survival rates and are unlikely to be prognostically distinct. Stage IIIB tumors are heterogeneous, with significant differences in survival observed between resectable mesenteric lymph nodes versus unresectable masses in the root of the mesentery. Revisions to the current AJCC staging classification may therefore be.
Gastrointest Cancer Res. 2013 Jul-Aug;6(4 Suppl 1):S27–S29.
RADIANT-4: A Randomized, Double-blind, Multicenter, Phase III Study of Everolimus Versus Placebo in the Treatment of Patients With Advanced Non-functional NET of GI or Lung Origin
The RAD001 In Advanced Neuroendocrine Tumors (RADIANT) series of clinical studies evaluated the benefits of everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor in patients with advanced neuroendocrine tumors (NET) of different origins and functionality. In the phase III RADIANT-3 study, everolimus significantly improved median progression-free survival compared with placebo (11 vs 4.6 months, P <.001) in patients with advanced pancreatic NET. In the phase III RADIANT-2 study, a combination of everolimus and octreotide provided some evidence of efficacy based on progression-free survival in patients with advanced functional NET (carcinoid) compared to octreotide alone, although the difference was not statistically significant. RADIANT-4 (NCT01524783) is designed to test everolimus in patients with advanced nonfunctional NET of gastrointestinal or lung origin, a patient group with a high unmet need not evaluated in either RADIANT-2 or RADIANT-3.
Methods:
RADIANT-4 is a prospective, multicenter, randomized, double-blind, parallel-group, placebo-controlled, phase III study with a target of 285 adults with histologically confirmed well-differentiated (G1 or G2) advanced (unresectable or metastatic) NET of gastrointestinal or lung origin, with no history of and no active symptoms related to carcinoid syndrome, and with radiologic progression in the last 6 months. Patients are randomized (2:1) to receive either everolimus 10 mg once daily or matching placebo. Both arms are receiving best supportive care. Randomization is stratified by prior somatostatin analog exposure, tumor origin, and WHO performance status. The primary objective of RADIANT-4 is to evaluate progression-free survival as per modified RECIST 1.0. Secondary objectives include evaluating overall survival, overall safety, quality of life, objective response rate, disease control rate, change in chromagranin A and neuron-specific enolase, and time to definitive deterioration in WHO performance status.
Results:
Enrollment began in May 2012 with completion expected in October 2013. An interim analysis (expected 21 months from the start) is planned when approximately 140 (80%) of the planned 176 progression-free survival events are reached. If the primary endpoint is met at either the interim or final analysis, the data monitoring committee may recommend unblinding and crossover for all patients receiving placebo.
Conclusions:
RADIANT-4 will provide important efficacy and safety information on everolimus in a large cohort of patients with advanced nonfunctional NET of gastrointestinal or lung origin.
Gastrointest Cancer Res. 2013 Jul-Aug;6(4 Suppl 1):S27–S29.
Above-Label Doses of Octreotide-LAR in Patients with Metastatic Small Intestinal Carcinoid Tumors
Octreotide LAR is indicated for treatment of the malignant carcinoid syndrome, and has been studied at doses of 10–30mg intramuscularly every 4 weeks. It has also been proven to delay time to progression of metastatic midgut carcinoid tumors at a dose of 30mg every 4 weeks. In clinical practice, higher doses are often prescribed for patients who experience refractory carcinoid syndrome (flushing and/or diarrhea) or tumor growth while on the maximal labeled dose. We performed a retrospective, longitudinal review of octreotide LAR administration at a tertiary institution to determine the frequency of ‘above-label’ dosing and outcomes.
Methods:
A retrospective chart-review was performed using a database of patients with metastatic small-bowel carcinoid tumors treated at the Moffitt Cancer Center between the years 2000 and 2010. Data included the maximal dose of octreotide LAR administered, reasons for change in dose or frequency (above the labeled dose of 30mg every 4 weeks), and clinical responses to dose change.
Results:
337 patients were considered evaluable, among whom 99 patients (27%) underwent at least one increase in dose or frequency of octreotide-LAR above the standard labeled dose. The most common maximal doses were 40mg every 4 weeks (37 patients), 60mg every 4 weeks (34 patients), and 30mg every 3 weeks (17 patients). The indications for dose increase were worsening carcinoid syndrome (60 patients), radiographic progression (33 patients) and rising urine 5-HIAA (6 patients). Among patients whose doses were increased for refractory carcinoid syndrome, 62% experienced improvement in diarrhea and 56% experienced improvement in flushing.
Conclusions:
In clinical practice, octreotide LAR is commonly prescribed in doses or schedules above the labled dose and frequency. Patients with refractory carcinoid syndrome appear to experience a clinical benefit from the change. Prospective data is needed to evaluate this strategy.
Gastrointest Cancer Res. 2013 Jul-Aug;6(4 Suppl 1):S27–S29.
Long-term, Open-label Everolimus in Patients With Pancreatic Neuroendocrine Tumors: Two Case Presentations From RADIANT-3
RAD001 In Advanced Neuroendocrine Tumors-3 (RADIANT-3) was a randomized, double-blind, multicenter, phase III clinical trial that evaluated everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), in patients with advanced pancreatic neuroendocrine tumors (pNET). Patients receiving everolimus experienced a significant prolongation of median progression-free survival (11 months vs 4.6 months; P < 0.001) when compared with patients on placebo. The study protocol allowed that upon radiologically confirmed progressive disease (PD), patients in the placebo arm could cross over to open-label everolimus. Described here are case presentations of two patients who were randomly assigned to the placebo arm of RADIANT-3 and crossed over to open-label everolimus after PD and maintained long-term stable disease (SD) while receiving everolimus.
Methods:
Both patients were white women with well-differentiated pNET with liver metastases initially diagnosed in December 2005. Patient A was 40 years of age at enrollment (March 2008) and had a WHO performance score of 1 and a history of carcinoid symptoms. Patient B was 71 years of age at enrollment (March 2008) and had a WHO performance score of 0 and a history of hyperkalemia, hypothyroidism, and anemia; she underwent radiofrequency ablation in May 2007 and portovenous embolization in September 2007. Neither patient received chemotherapy before randomization. PD was confirmed after 168 days in patient A (October 2008) and after 171 days in patient B (September 2008), and both initiated open-label everolimus (10 mg/day).
Results:
Both patients experienced SD after the initiation of everolimus. Patient A eventually halted everolimus therapy in November 2010 because of disease progression (25 months). Patient B continues to have stable disease as of February 2012, 41 months after initiation of everolimus. She also receives octreotide LAR (30 mg IM q28d). Suspected drug-related adverse events reported after the initiation of open-label everolimus included fatigue, weakness, and skin rash. All were grade 1 or 2, and none required dose adjustment.
Conclusions:
In the cases presented, each patient experienced PD on previous therapy and long-term SD on everolimus therapy. Adverse events with everolimus were mild and similar to those that have been previously reported.
