Medical Management of Carcinoid Neoplasms: Present and Future Considerations

September 1, 2002

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.

Much progress in the diagnosis and management ofwell-differentiated neuroendocrine malignancies is evident over the past 2decades. Initial medical intervention using somatostatin analogs such asoctreotide acetate in the immediate and sustained release formulations (Sandostatinand Sandostatin LAR Depot) is standard for the symptomatic stage IVpatient.[1,2] Somatostatin analogs provide effective hormonal suppression forcarcinoid neoplasm, pancreatic islet cell malignancies, and pituitary adenomas.

Somatostatin inhibits various cellular processes includingsecretion, proliferation, motility, and vaso-constriction. One or more of the five somatostatin receptors (sst 1 through sst5) belonging to the heptahelical G protein-coupled receptor family mediatesomatostatin’s effect. These five receptors are present in normal and tumorcells with the expression of each receptor being receptor subtype- and celltype- specific. The antiangiogenic and growth factor inhibitory actions ofoctreotide potentially allow somatostatin receptor "negative" tumorsto be targets of its action, alone or in combination with other agents.

Because the survival rate has increased since theintroduction of somatostatin analogs for patients with carcinoid syndrome, theuse of these agents in patients who are asymptomatic but with progressiveradiographic disease is an option prior to instituting cytotoxic therapy. Afterobtaining a medical history, performing the physical examination, and reviewinga spiral, hyperdynamic computed tomography scan or magnetic resonance imagingwith gadolinium and radiolabeled octreotide scanning with 111In-pentetreotide (OctreoScan, Mallinkrodt Imaging), staging can be assessed.[3-5] For biochemicalmarkers, 24-hour urinary 5-HIAA and/or blood levels of chromogranin A areinterchangeable and assist in patient assessments between imaging intervals.[6]After biotherapy is initiated with agents such as somatostatin analogs and/orinterferon, the patient can be observed for control of symptoms and disease.Should progression occur, investigative approaches or additional cytoreductivemeasures inclusive of, but not limited to, radiofrequency ablation, surgicaldebulking, and hepatic artery chemoembolization can be considered.[5,7]

Progress over the next decade will take advantage of specificmolecular pathways that are being characterized as contributing to thephenotypic or genotypic aspects of neoplasia. Additional options in targetingthe somatostatin receptor will include analogs and their associated radiolabeledcounterparts that have different binding characteristics than octreotide.[8]Therapeutic 111In-pentetreotideis currently available in some centers for patients with progressive disease andsymptoms after other modalities have failed.[9] 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 theepidermal growth receptor blockers such as cetuximab (Erbitux, IMC-C225),trastuzumab (Herceptin), and ZD1839 (Iressa), as well as drugs that induceapoptosis, block angiogenesis and specific enzymatic pathways, and inhibitsignal transduction and mitosis, are being developed and offer additionalclinical investigative opportunities for patients with carcinoid neoplasm andother well-differentiated neuroendocrine malignancies.[4,8] With advances indiagnosis, monitoring, and medical and surgical management, it is predictablethat the median survival of stage IV carcinoid patients may increase from 6.7years to more than 10 years over the next decade.

References:

1. Rubin J, Ajani J, Schirmer W, et al: Octreotide acetatelong-acting formulation versus open-label subcutaneous octreotide acetate inmalignant carcinoid syndrome. J Clin Oncol 17:600-606, 1999.

2. Roberts LJ II, Anthony LB, Oates JA: Disorders ofvasodilator hormones: the carcinoid syndrome and mastocytosis, in Williams RH,Foster DW, Kronenberg HE, et al (eds): Williams Endocrinology, 9th ed, pp1711-1132. Philadelphia, WB Saunders, 1998.

3. Slooter GD, Mearadji A, Breeman WA, et al: Somatostatinreceptor imaging, therapy and new strategies in patients with neuroendocrinetumours. Br J Surg 88:31-40, 2001.

4. Oberg K: Neuroendocrine gastrointestinal tumors—Acondensed overview of diagnosis and treatment. Ann Oncol 10(suppl2):S3-S8, 1999.

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 andchromogranin A biochemical markers in the management of carcinoid syndrome:Results from a randomized multi-institutional clinical trial (abstract 664). ProcAm Soc Clin Oncol 21:167a, 2002.

7. Ahlman H, Wangberg B, Jansson S, et al: Interventionaltreatment of gastrointestinal neuroendocrine tumours. Digestion 62(suppl1):59-68, 2000.

8. Eriksson B, Oberg K: Summing up 15 years of somatostatinanalog therapy in neuroendocrine tumors: Future outlook. Ann Oncol10(suppl 2):S31-S38, 1999.

9. McCarthy KE, Woltering EA, Anthony LB: In situ radiotherapy with111In-pentetreotide: State of the art and perspectives. Q J Nucl Med 44:88-95,2000.