Resource Library: Neuroendocrine Tumor Clinical Press

A Nomogram to Assess Small-Intestinal Neuroendocrine Tumor ('Carcinoid')

Modlin IM, Gustafsson BI, Pavel M, Lawrence B, Svejda B, Kidd M

Abstract: Most information available to determine neuroendocrine tumor behavior reflects univariate assessment of factors or is anecdotal or experience based. There currently exists no objective multivariate analysis of indices that defines SI Neuroendocrine Tumor (NET) prognosis. A key unmet need is the lack of a rigorous mathematical-based tool – a nomogram – for the assessment of parameters that define progress, determine prognosis and can guide therapy. Since prediction of Neuroendocrine Tumor (NET) behavior is a critical criterion in determining clinical strategy, we constructed a Neuroendocrine Tumor (NET) nomogram (Modlin Score) for prognosis prediction, patient group comparisons and a guide for stratification of treatment and surveillance. External validation and amplification by identification of additional indices, e.g. molecular biomarkers, are necessary. The development of a mathematically validated nomogram provides a platform for objective assessment of SI Neuroendocrine Tumor (NET) disease, a finite basis for precise prognostication and a tool to guide management strategy.

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The Clinical Relevance of Chromogranin A as a Biomarker for Gastroenteropancreatic Neuroendocrine Tumors

Lawrence B, Gustafsson BI, Kidd M, Pavel M, Svejda B, Modlin IM

An accurate tumor marker is a critical tool in tumor management because it establishes an uncertain diagnosis, offers a basis for individual prognostication, signals response to therapy, and identifies relapse. In classical terms, a high-quality tumor marker should represent a biologic attribute unique to the tumor cell or its local environment. Although this has proved manageable in a homogenous tumor population, the goal has been difficult to attain in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) because they comprise an extremely heterogeneous group of cancers. Thus, the conundrum of identifying a global marker for NETs has remained a considerable technical challenge.

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Gastroenteropancreatic Neuroendocrine Tumours

Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV, Caplin M, Delle Fave G, Kaltsas GA, Krenning EP, Moss SF, Nilsson O, Rindi G, Salazar R, Ruszniewski P, Sundin A.

Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are fairly rare neoplasms that present many clinical challenges. They secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass eff ects. Investigation and management should be highly individualised for a patient, taking into consideration the likely natural history of the tumor and general health of the patient. Management strategies include surgery for cure (which is achieved rarely) or for cytoreduction, radiological intervention (by chemoembolisation and radiofrequency ablation), chemotherapy, and somatostatin analogues to control symptoms that result from release of peptides and neuroamines. New biological agents and somatostatin-tagged radionuclides are under investigation.

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Gastrointestinal Neuroendocrine (Carcinoid) Tumours: Current Diagnosis and Management

Modlin IM, Moss SF, Oberg K, Padbury R, Hicks R, Gustafsson BI, Wright NA, Kidd M

The term carcinoid (carcinoma-like) was introduced byOberndorfer in 1907 to describe a tumor of the gastroin-testinal tract that was less aggressive than adenocarcinoma. The earliest clear description of carcinoid syndrome (flushing, diarrhoea, and bronchospasm) and carcinoid heart disease waspublished in the early 1950s. At the same time, the first systemicbiogenic amine producing these symptoms, 5-hydroxytryptamine,was identified, and the neuroendocrine origin of carcinoid tumors was established.

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Systemic Therapeutic Options for Carcinoid

Pavel M, Kidd M, Modlin IM.

"Carcinoids" are mostly slow-growing neuroendocrine neoplasms (NENs) with low proliferativeactivity. A wide range of therapeutic options with variable efficacy exist, including locoregional ablative strategies. Thereafter, some patients may not require medical therapy for years depending on the rate of progression or recurrence. However, the majority of patients require systemic treatment and therein lies the dilemma, since no antiproliferative agent is currently approved for carcinoids. Somatostatin analogs (SSAs), and to a lesser extent interferon-alpha, are standard therapy for carcinoids associated with the carcinoid syndrome. These drugs have some antiproliferative efficacy. SSAs rarely lead to tumor remission but may modestly prolong time to tumor progression. Chemotherapy is of limited value in carcinoids with low proliferation indices but may be useful in higher grade tumors. Peptide receptor-targeted radionuclide therapy may be of benefit and is mostly used after medical therapies fail. However, it is considered an investigational modality. More recently, targeted drugs such as mammalian target of rapamycin (mTOR) inhibitors and anti-angiogenics have been investigated. Objective remissions are rare. Their value remains to be rigorously elucidated. Increased efficacy requires a better understanding of the underlying tumor biology and identification of molecular pathological criteria to allow appropriate preselection of candidates for targeted therapies.

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Development of a "nomogram" that can be used to predict metastasis probability and assess outcome facilitates development of a management strategy.

Numerous biomarkers have been proposed. Chromogranin A (CgA) is, by default, the most widely used in NET disease despite its unreliability.

The alterations in NET incidence from different sites demonstrate annualized percentage changes (APC) of 3-8%; these tumors are significantly increasing in incidence.

A range of imaging modalities are available to identify NETs. The most sensitive are based on utilizing knowledge of tumor biology and cell function e.g., somatostatin receptor and Octreoscan.

A variety of therapeutic strategies are associated with different outcomes. Surgery (when feasible and if the tumor is localized) appears to be the most effective therapy that translates into predictable and significant survival advantage.