Metastatic Gastrointestinal Carcinoid Tumors
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:
- 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.
- 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.
- 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.
- 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.
- I131-MIBG: Therapeutic doses of iodine131-labeled metaiodobenzylguanidine
(MIBG) and unlabeled MIBG have been evaluated, with reduction of symptoms found
in preliminary studies.[4]
- Biological modification (immunotherapy): Low-dose interferon alpha and
octreotide, alone and in combination, have been reported to have activity.[5,6]
Carcinoid Syndrome
Treatment options associated with metastatic carcinoid tumor:
- 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.
- 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.
- 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.
- 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]
- Clinical trials using chemotherapy combinations should be considered for
symptomatic patients.[18]
Current Clinical Trials
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
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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.
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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.
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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.
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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.
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Oberg K: Advances in chemotherapy and biotherapy of endocrine tumors. Curr Opin Oncol 10 (1): 58-65, 1998.
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Öberg K: Carcinoid Tumors: Current Concepts in Diagnosis and Treatment. Oncologist 3 (5): 339-345, 1998.
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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.
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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.
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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.
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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.
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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.
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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.
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Kvols LK: The carcinoid syndrome: a treatable malignant disease. Oncology (Huntingt) 2 (2): 33-41, 1988.
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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.
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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.
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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.
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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.
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Moertel CG: Karnofsky memorial lecture. An odyssey in the land of small tumors. J Clin Oncol 5 (10): 1502-22, 1987.
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