Much progress in the diagnosis and management of
well-differentiated neuroendocrine malignancies is evident over the past 2
decades. Initial medical intervention using somatostatin analogs such as
octreotide acetate in the immediate and sustained release formulations (Sandostatin
and Sandostatin LAR Depot) is standard for the symptomatic stage IV
patient.[1,2] Somatostatin analogs provide effective hormonal suppression for
carcinoid neoplasm, pancreatic islet cell malignancies, and pituitary adenomas.
Somatostatin inhibits various cellular processes including
secretion, proliferation, motility, and vaso-constriction. One or more of the five somatostatin receptors (sst 1 through sst
5) belonging to the heptahelical G protein-coupled receptor family mediate
somatostatin’s effect. These five receptors are present in normal and tumor
cells with the expression of each receptor being receptor subtype- and cell
type- specific. The antiangiogenic and growth factor inhibitory actions of
octreotide potentially allow somatostatin receptor "negative" tumors
to be targets of its action, alone or in combination with other agents.
Because the survival rate has increased since the
introduction of somatostatin analogs for patients with carcinoid syndrome, the
use of these agents in patients who are asymptomatic but with progressive
radiographic disease is an option prior to instituting cytotoxic therapy. After
obtaining a medical history, performing the physical examination, and reviewing
a spiral, hyperdynamic computed tomography scan or magnetic resonance imaging
with gadolinium and radiolabeled octreotide scanning with 111In-pentetreotide (OctreoScan, Mallinkrodt Imaging), staging can be assessed.[3-5] For biochemical
markers, 24-hour urinary 5-HIAA and/or blood levels of chromogranin A are
interchangeable and assist in patient assessments between imaging intervals.
After biotherapy is initiated with agents such as somatostatin analogs and/or
interferon, the patient can be observed for control of symptoms and disease.
Should progression occur, investigative approaches or additional cytoreductive
measures inclusive of, but not limited to, radiofrequency ablation, surgical
debulking, and hepatic artery chemoembolization can be considered.[5,7]
Progress over the next decade will take advantage of specific
molecular pathways that are being characterized as contributing to the
phenotypic or genotypic aspects of neoplasia. Additional options in targeting
the somatostatin receptor will include analogs and their associated radiolabeled
counterparts that have different binding characteristics than octreotide.
is currently available in some centers for patients with progressive disease and
symptoms after other modalities have failed. 90Y-DOTA-D-Phe(1)-Tyr(3)-octreotide
(OctreoTher) may become available in the future and offer a "cocktail"
approach in providing greater symptom control and potentially improved survival.
Agents that target specific growth pathways, including the
epidermal growth receptor blockers such as cetuximab (Erbitux, IMC-C225),
trastuzumab (Herceptin), and ZD1839 (Iressa), as well as drugs that induce
apoptosis, block angiogenesis and specific enzymatic pathways, and inhibit
signal transduction and mitosis, are being developed and offer additional
clinical investigative opportunities for patients with carcinoid neoplasm and
other well-differentiated neuroendocrine malignancies.[4,8] With advances in
diagnosis, monitoring, and medical and surgical management, it is predictable
that the median survival of stage IV carcinoid patients may increase from 6.7
years to more than 10 years over the next decade.
1. Rubin J, Ajani J, Schirmer W, et al: Octreotide acetate
long-acting formulation versus open-label subcutaneous octreotide acetate in
malignant carcinoid syndrome. J Clin Oncol 17:600-606, 1999.
2. Roberts LJ II, Anthony LB, Oates JA: Disorders of
vasodilator hormones: the carcinoid syndrome and mastocytosis, in Williams RH,
Foster DW, Kronenberg HE, et al (eds): Williams Endocrinology, 9th ed, pp
1711-1132. Philadelphia, WB Saunders, 1998.
3. Slooter GD, Mearadji A, Breeman WA, et al: Somatostatin
receptor imaging, therapy and new strategies in patients with neuroendocrine
tumours. Br J Surg 88:31-40, 2001.
4. Oberg K: Neuroendocrine gastrointestinal tumorsA
condensed overview of diagnosis and treatment. Ann Oncol 10(suppl
5. Caplin ME, Buscombe JR, Hilson AJ, et al: Carcinoid tumour.
Lancet 352:799-805, 1998.
6. Anthony LB, Vance D, Rubin J, et al: 5-HIAA and
chromogranin A biochemical markers in the management of carcinoid syndrome:
Results from a randomized multi-institutional clinical trial (abstract 664). Proc
Am Soc Clin Oncol 21:167a, 2002.
7. Ahlman H, Wangberg B, Jansson S, et al: Interventional
treatment of gastrointestinal neuroendocrine tumours. Digestion 62(suppl
8. Eriksson B, Oberg K: Summing up 15 years of somatostatin
analog therapy in neuroendocrine tumors: Future outlook. Ann Oncol
10(suppl 2):S31-S38, 1999.
9. McCarthy KE, Woltering EA, Anthony LB: In situ radiotherapy with
111In-pentetreotide: State of the art and perspectives. Q J Nucl Med 44:88-95,