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Medical Management of Carcinoid Neoplasms: Present and Future Considerations

Medical Management of Carcinoid Neoplasms: Present and Future Considerations

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.[6] 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.[8] Therapeutic 111In-pentetreotide is currently available in some centers for patients with progressive disease and symptoms 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 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.

References

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 tumors—A condensed overview of diagnosis and treatment. Ann Oncol 10(suppl 2):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 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 1):59-68, 2000.

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, 2000.

 
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