Carcinoid Syndrome
Current Clinical Trials

Since carcinoid tumors are frequently indolent in growth, and asymptomatic, not all patients require treatment of metastatic disease at diagnosis. A period of observation may allow for a decision to be made concerning optimal supportive care or antitumor treatments.

Treatment options for distant metastasis:

1. Surgical treatment: Surgical treatment may frequently provide effective palliation (even in the presence of known distant metastasis with or without malignant carcinoid syndrome), particularly through bypass or palliative resection of obstructing small bowel tumors. Heroic attempts at surgical debulking, however, are not indicated except for hepatic resection in patients with the carcinoid syndrome (see section on Carcinoid Syndrome). Although liver metastases are usually multiple and neither bulky nor clustered, multiple wedge resections, cryosurgery, or radiofrequency ablation of the lesions can be considered in patients with carcinoid syndrome.



2. Chemotherapy: Although activity with a variety of single agents and drug combinations has been reported (fluorouracil, doxorubicin, dacarbazine, cyclophosphamide, fluorouracil + streptozocin, and etoposide + cisplatin [1]), response rates seldom exceed 30%. Complete responses are uncommon. Duration of response is usually short, although occasional remissions lasting a year or more have been noted. Otherwise, there is little evidence that chemotherapy contributes to patient survival. Chemotherapy should be used only for palliation in symptomatic patients who should be included in clinical trials aimed at developing new, more effective treatment. Continuous infusion of agents such as floxuridine into the hepatic artery has not been prospectively tested in large series of patients.



3. Chemoembolization: Hepatic artery infusion with fluorouracil, doxorubicin, mitomycin, or cisplatin, combined with embolization of the hepatic artery with collagen fibers or other material (i.e., gelfoam, lipiodol, or poly vinyl alcohol) has been reported to decrease tumor bulk of liver metastases from carcinoid tumors by 50% or more in as many as 60% of patients.[2] Palliative embolizations that prove effective may be repeated if symptoms return.



4. Radiation therapy: The role of radiation therapy in the management of patients with carcinoid tumors with distant metastasis is restricted to symptomatic palliation.[3] Although the tumor persists, painful bone metastases can be palliated.



5. I¹³¹-MIBG: Therapeutic doses of iodine¹³¹-labeled metaiodobenzylguanidine (MIBG) and unlabeled MIBG have been evaluated, with reduction of symptoms found in preliminary studies.[4]



6. Biological modification (immunotherapy): Low-dose interferon alpha and octreotide, alone and in combination, have been reported to have activity.[5,6]

Treatment options associated with metastatic carcinoid tumor:

1. Surgical treatment: Surgery may sometimes be of considerable value in the patient who has large or extensive hepatic metastases involving surgically accessible areas of the liver (single or multiple). Recurrent hepatic metastases (after previous resection) should be considered for resection if the lesions are placed in an area where resection can be done with minimal morbidity. Alternate nonresective surgical ablative techniques include cryosurgery, radiofrequency ablation, and percutaneous alcohol injections. For very carefully selected patients with indolent disease and symptomatic carcinoid heart disease, valve replacement may be indicated.



2. Hepatic artery ligation or embolization: For patients with bulky or symptomatic hepatic metastases, hepatic artery ligation or embolization can cause substantial tumor necrosis. Toxic effects of embolization are frequent and can be severe, especially if the entire liver is treated at one time. Reactions may be attenuated if multiple treatment sessions are possible at intervals of several weeks or months. These include abdominal pain, fever, nausea and transient worsening of the syndrome. However, many patients have subsequent symptomatic relief.[7,8] Such treatment may also be given in conjunction with systemic chemotherapy in selected patients.[9] Intra-arterial chemotherapy via the hepatic artery can cause regression of lesions in selected patients. These regressions tend to be durable as long as treatment is continued.



3. Pharmacologic management: Somatostatin analogue (octreotide) has been demonstrated to relieve symptoms of malignant carcinoid syndrome in the great majority of patients, with significant reduction of 5-hydroxyindoleacetic acid (5-HIAA) levels. Tumor reduction is rarely seen.[10-13]

   Patients benefit from specific pharmacologic interventions that either suppress production of vasoactive amines or block their peripheral effects. These agents include cyproheptadine and H2-receptor blockers.

   Monoamine oxidase inhibitors and adrenergic agonists are drugs to be specifically avoided in these patients since they will exacerbate the syndrome by inhibiting serotonin degradation or producing carcinoid syndrome crisis.




4. Interferon alpha preparations may have a role in controlling symptoms of the carcinoid syndrome or in arresting tumor growth.[14] These benefits have generally been transient and accompanied by toxic effects that frequently outweigh therapeutic gains,[15] although interferon alpha has been reported to reinduce symptom control in patients who did not respond to octreotide.[16] The combination of interferon alpha and continuous-infusion fluorouracil has demonstrated antitumor and/or antihormonal activity and, similar to other drug regimens, can provide useful palliation.[17] Combination of interferon alpha and octreotide has also been reported to have activity.[5]



5. Clinical trials using chemotherapy combinations should be considered for symptomatic patients.[18]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with metastatic gastrointestinal carcinoid tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Moertel CG, Kvols LK, O'Connell MJ, et al.: Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 68 (2): 227-32, 1991.  [PUBMED Abstract]
   
   
2. Diaco DS, Hajarizadeh H, Mueller CR, et al.: Treatment of metastatic carcinoid tumors using multimodality therapy of octreotide acetate, intra-arterial chemotherapy, and hepatic arterial chemoembolization. Am J Surg 169 (5): 523-8, 1995.  [PUBMED Abstract]
   
   
3. Schupak KD, Wallner KE: The role of radiation therapy in the treatment of locally unresectable or metastatic carcinoid tumors. Int J Radiat Oncol Biol Phys 20 (3): 489-95, 1991.  [PUBMED Abstract]
   
   
4. Taal BG, Hoefnagel CA, Valdes Olmos RA, et al.: Palliative effect of metaiodobenzylguanidine in metastatic carcinoid tumors. J Clin Oncol 14 (6): 1829-38, 1996.  [PUBMED Abstract]
   
   
5. Oberg K: Advances in chemotherapy and biotherapy of endocrine tumors. Curr Opin Oncol 10 (1): 58-65, 1998.  [PUBMED Abstract]
   
   
6. Öberg K: Carcinoid Tumors: Current Concepts in Diagnosis and Treatment. Oncologist 3 (5): 339-345, 1998.  [PUBMED Abstract]
   
   
7. Carrasco CH, Charnsangavej C, Ajani J, et al.: The carcinoid syndrome: palliation by hepatic artery embolization. AJR Am J Roentgenol 147 (1): 149-54, 1986.  [PUBMED Abstract]
   
   
8. Moertel CG, May GR, Martin JK, et al.: Sequential hepatic artery occlusion (HAO) and chemotherapy for metastatic carcinoid tumor and islet cell carcinoma (ICC). [Abstract] Proceedings of the American Society of Clinical Oncology 4: 80, 1985. 
   
   
9. Moertel CG, Johnson CM, McKusick MA, et al.: The management of patients with advanced carcinoid tumors and islet cell carcinomas. Ann Intern Med 120 (4): 302-9, 1994.  [PUBMED Abstract]
   
   
10. Kvols LK, Moertel CG, O'Connell MJ, et al.: Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med 315 (11): 663-6, 1986.  [PUBMED Abstract]
    
    
11. Kvols LK, Martin JK, Marsh HM, et al.: Rapid reversal of carcinoid crisis with a somatostatin analogue. N Engl J Med 313 (19): 1229-30, 1985.  [PUBMED Abstract]
    
    
12. Gorden P, Comi RJ, Maton PN, et al.: NIH conference. Somatostatin and somatostatin analogue (SMS 201-995) in treatment of hormone-secreting tumors of the pituitary and gastrointestinal tract and non-neoplastic diseases of the gut. Ann Intern Med 110 (1): 35-50, 1989.  [PUBMED Abstract]
    
    
13. Kvols LK: The carcinoid syndrome: a treatable malignant disease. Oncology (Huntingt) 2 (2): 33-41, 1988.  [PUBMED Abstract]
    
    
14. Oberg K, Norheim I, Lind E, et al.: Treatment of malignant carcinoid tumors with human leukocyte interferon: long-term results. Cancer Treat Rep 70 (11): 1297-304, 1986.  [PUBMED Abstract]
    
    
15. Moertel CG, Rubin J, Kvols LK: Therapy of metastatic carcinoid tumor and the malignant carcinoid syndrome with recombinant leukocyte A interferon. J Clin Oncol 7 (7): 865-8, 1989.  [PUBMED Abstract]
    
    
16. Tiensuu Janson EM, Ahlström H, Andersson T, et al.: Octreotide and interferon alfa: a new combination for the treatment of malignant carcinoid tumours. Eur J Cancer 28A (10): 1647-50, 1992.  [PUBMED Abstract]
    
    
17. Andreyev HJ, Scott-Mackie P, Cunningham D, et al.: Phase II study of continuous infusion fluorouracil and interferon alfa-2b in the palliation of malignant neuroendocrine tumors. J Clin Oncol 13 (6): 1486-92, 1995.  [PUBMED Abstract]
    
    
18. Moertel CG: Karnofsky memorial lecture. An odyssey in the land of small tumors. J Clin Oncol 5 (10): 1502-22, 1987.  [PUBMED Abstract]
    
    

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