Gastrointestinal Carcinoid Tumors Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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Gastrointestinal Carcinoid Tumors Treatment

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of gastrointestinal carcinoid tumors. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

  • Cellular classification.
  • Staging.
  • Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

General Information

The majority of carcinoid tumors are slow-growing tumors that can be treated and often cured, especially in early stages.[1] The occurrence of metastasis from carcinoid tumors relates directly to the size of the primary tumor (lesions 1 cm or less rarely metastasize; lesions greater than 2 cm frequently metastasize). They are classified as neuroendocrine or amine precursor uptake and decarboxylation tumors. Rarely, they may be a part of the multiple endocrine neoplasia syndrome type 1. Carcinoid tumors may arise from various sites, most commonly the gastrointestinal tract and the lung. The appendix, small bowel, and rectum account for over 90% of surgical cases occurring in the gastrointestinal tract. Small bowel carcinoids may occur in multiple sites in the same patient. Symptoms may be chronic, suggesting partial obstruction or intussusception. Carcinoid tumors, except those originating in the rectum, produce a variety of endocrine substances, the most frequent of which are serotonin (5-hydroxytryptamine) and kallikrein (an activator of bradykinin release). The diagnosis of carcinoid syndrome (a syndrome associated with flushing, diarrhea, bronchoconstriction, cardiac valvular lesions, and telangiectasia) is aided by demonstrating elevated 24-hour urinary 5-hydroxyindoleacetic acid levels. This test is not useful in the diagnosis of carcinoids at a curable stage, except in some rare cases in which the tumor arises from a site outside of the gastrointestinal tract, such as the lung.[2,3,4,5,6,7] Blood chromogranin A assay may also be a useful, though nonspecific, confirmatory test for carcinoid or neuroendocrine tumors.[8] Primary carcinoids of the extrapelvic colon are uncommon, typically present with metastatic disease, and have a poor prognosis.[9,10] Patients with carcinoid tumor are at increased risk for synchronous or metachronous second malignancies. The most common site for a second primary malignancy is the gastrointestinal tract.[11]

The relatively rare carcinoid syndrome relates to the release of bioactive substances, but precise pharmacologic mechanisms are still unclear. Because of efficient hepatic metabolism of vasoactive amines, the carcinoid syndrome rarely occurs in the absence of liver metastases. Exceptions are circumstances where venous blood draining from tumors enters directly into the systemic circulation (for example, pulmonary and ovarian primaries, and pelvic or retroperitoneal involvement by metastatic or locally invasive small bowel carcinoids or extensive bone metastases).

Surgical resection is the standard curative modality. If the primary tumor is localized and resectable, 5-year survival rates are excellent (70%-90%). Even in patients with distant metastasis, the disease is usually very indolent, with median survivals of 2 years or more. When necessary, excellent palliation may be achieved by bypass surgery or resection of large hepatic metastases that may produce the carcinoid syndrome. Radiation therapy has a minor role in patients with regionally unresectable disease and may palliate the pain of bone metastasis. Patients with carcinoid syndrome can usually be effectively palliated by injections of somatostatin analogue two to three times a day. A long-acting somatostatin analogue that can be given as an injection once a month, with equivalent efficacy, is now available.[12]

Patients with symptomatic metastatic carcinoid disease are appropriate candidates for clinical trials examining combination chemotherapy, since single-agent standard chemotherapy provides minimal palliation. However, chemotherapeutic drug combinations occasionally do offer long-lasting (in excess of 1 year) palliation. In patients with the carcinoid syndrome, palliation is sometimes obtained with pharmacologic agents that suppress production or block the action of vasoactive amines; of particular interest is a somatostatin analogue.[13] Some patients benefit from the use of interferon alpha. Toxic effects associated with interferon treatment that frequently outweigh therapeutic gains can occur in some patients, but these effects are reversible once treatment has been discontinued and usually do not occur with smaller doses. Anecdotal reports of biologic activity indicate that some patients may respond to combined octreotide and interferon alpha treatment.[14] Patients with asymptomatic metastases that cannot be resected for cure will often remain symptom-free for long periods of time.

References:

1. Moertel CG: Karnofsky memorial lecture. An odyssey in the land of small tumors. J Clin Oncol 5 (10): 1502-22, 1987.
2. Kulke MH, Mayer RJ: Carcinoid tumors. N Engl J Med 340 (11): 858-68, 1999.
3. Mani S, Modlin IM, Ballantyne G, et al.: Carcinoids of the rectum. J Am Coll Surg 179 (2): 231-48, 1994.
4. Moertel CG, Weiland LH, Nagorney DM, et al.: Carcinoid tumor of the appendix: treatment and prognosis. N Engl J Med 317 (27): 1699-701, 1987.
5. Martin JK Jr, Moertel CG, Adson MA, et al.: Surgical treatment of functioning metastatic carcinoid tumors. Arch Surg 118 (5): 537-42, 1983.
6. Moertel CG: Treatment of the carcinoid tumor and the malignant carcinoid syndrome. J Clin Oncol 1 (11): 727-40, 1983.
7. Delcore R, Friesen SR: Gastrointestinal neuroendocrine tumors. J Am Coll Surg 178 (2): 187-211, 1994.
8. Roberts LJ, Anthony LB, Oates JA: Disorders of vasodilator hormones: carcinoid syndrome and mastocytosis. In: Wilson JD, Foster DW, Kronenberg HM, et al., eds.: Williams Textbook of Endocrinology. 9th ed. Philadelphia, Pa: W.B. Saunders Company, 1998, 1711-1731.
9. Spread C, Berkel H, Jewell L, et al.: Colon carcinoid tumors. A population-based study. Dis Colon Rectum 37 (5): 482-91, 1994.
10. Modlin IM, Sandor A: An analysis of 8305 cases of carcinoid tumors. Cancer 79 (4): 813-29, 1997.
11. Gerstle JT, Kauffman GL Jr, Koltun WA: The incidence, management, and outcome of patients with gastrointestinal carcinoids and second primary malignancies. J Am Coll Surg 180 (4): 427-32, 1995.
12. 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 (2): 600-6, 1999.
13. 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.
14. Frank M, Klose KJ, Wied M, et al.: Combination therapy with octreotide and alpha-interferon: effect on tumor growth in metastatic endocrine gastroenteropancreatic tumors. Am J Gastroenterol 94 (5): 1381-7, 1999.

Cellular Classification

There is no histologic difference between carcinoids arising in various sites or between metastasizing and nonmetastasizing lesions. Carcinoid tumors are neuroendocrine tumors composed of uniform, round, or polygonal cells. Immunohistochemistry reveals the presence of neuron-specific enolase (NSE) and chromogranin. Electron microscopy shows neurosecretory granules. Morphologic features suggesting malignancy (cellular pleomorphism, hyperchromatic nuclei, necrosis, high mitotic activity) can occasionally be seen. Such cases are designated as atypical carcinoids and usually have an aggressive clinical course. Carcinoids are classified by their embryologic relationship to the foregut (the anterior part of the alimentary canal, from the mouth to the intestine or to the entrance of the bile duct), midgut (the middle part of the alimentary canal, from the stomach or entrance of the bile duct to or including the large intestine), or hindgut (the posterior part of the alimentary canal, including the rectum and sometimes the large intestine), which is correlated with clinical behavior and the secretion or nonsecretion of various neuroendocrine peptides. Proximal carcinoids may secrete histamine-like peptides causing a pink flush and bronchoconstriction. Peptide secretions of midgut carcinoids cause a cyanotic (purplish) flush, diarrhea, and hypotension. Hindgut carcinoids usually do not secrete syndrome-producing peptides.

Stage Information

There is no accepted staging system for carcinoid tumors.

Localized Gastrointestinal Carcinoid Tumors

Appendiceal Carcinoids

For patients with appendiceal carcinoid tumors less than 1.5 cm in greatest diameter, appendectomy is adequate treatment with cure rates of essentially 100%.[1] No follow-up management is required if the tumor is confined within the wall of the appendix. Tumors 1.5 to 2 cm in diameter can be treated by simple appendectomy or more aggressive surgical treatment. Tumors 2 cm or greater in diameter are less common, but must be considered malignant. Invasion of the mesoappendix does not alter prognosis, but invasion of the cecum mandates more extensive resection. When right hemicolectomy is performed, a lymphadenectomy, as performed for colon cancer, is appropriate.

Rectal Carcinoids

For patients with rectal carcinoid tumors 1 cm or less in diameter, simple fulguration or local excision is adequate treatment. Cure rates of essentially 100% may be anticipated, and no follow-up management is required.[2]

Tumors 2 cm or larger should be considered malignant and should be treated by an appropriate cancer operation, but sphincter-preserving procedures are preferred when possible. Otherwise, standard therapy includes abdominoperineal resection.

Tumors 1 to 2 cm in diameter can be treated either by local excision or by more radical resection. The decision should be based on actual size of the tumor, extent of invasion, and necessity for abdominal perineal resection versus a sphincter-preserving resection, and estimated operative risk. If local excision is elected, the patient should be carefully followed.

Small Bowel Carcinoids

For patients with small bowel carcinoid tumors less than 1 cm in diameter, conservative local resection is sufficient. For tumors greater than 1 cm in diameter, excision of a wedge of mesentery containing regional nodes is indicated.[3] Patients with tumors 1.5 to 2 cm or larger are at risk for recurrence; however, a standard surveillance program has not been established. A search for multiple primary lesions should be made in all patients with small bowel carcinoids.

Gastric, Pancreatic, and Colon Carcinoids

Carcinoids of other sites in the gastrointestinal tract are rare. Optimal management of localized disease is aggressive surgical resection, although carcinoid tumors of the stomach and colon are typically less often localized than those in other gastrointestinal sites.[4,5]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with localized 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. Roggo A, Wood WC, Ottinger LW: Carcinoid tumors of the appendix. Ann Surg 217 (4): 385-90, 1993.
2. Mani S, Modlin IM, Ballantyne G, et al.: Carcinoids of the rectum. J Am Coll Surg 179 (2): 231-48, 1994.
3. Moertel CG: Karnofsky memorial lecture. An odyssey in the land of small tumors. J Clin Oncol 5 (10): 1502-22, 1987.
4. Spread C, Berkel H, Jewell L, et al.: Colon carcinoid tumors. A population-based study. Dis Colon Rectum 37 (5): 482-91, 1994.
5. Maurer CA, Baer HU, Dyong TH, et al.: Carcinoid of the pancreas: clinical characteristics and morphological features. Eur J Cancer 32A (7): 1109-16, 1996.

Regional Gastrointestinal Carcinoid Tumors

Patients with carcinoid tumors with gross regional lymphatic metastasis or local extension should be treated by aggressive surgical resection. If all visible malignant disease can be removed, long-term survival rates will be excellent.[1] However, late recurrences (after 5 or 10 years) do occur, implying the need for prolonged follow-up.

There is no known effective surgical adjuvant treatment and none should be attempted except as part of a clinical trial.

If the regional disease is found to be unresectable, palliative surgery, such as partial resection, cryoablation, radiofrequency ablation, or hepatic artery chemoembolization should be considered. Treatment should be customized for each patient depending on the growth of the tumor and/or development of symptoms since some patients with asymptomatic, unresectable disease will frequently have many months or even years of comfortable life with no further treatment.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with regional 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: Karnofsky memorial lecture. An odyssey in the land of small tumors. J Clin Oncol 5 (10): 1502-22, 1987.

Metastatic Gastrointestinal Carcinoid Tumors

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]

Carcinoid Syndrome

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.[10,11,12,13]

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]

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:

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.
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.
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.
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.
5. Oberg K: Advances in chemotherapy and biotherapy of endocrine tumors. Curr Opin Oncol 10 (1): 58-65, 1998.
6. Öberg K: Carcinoid Tumors: Current Concepts in Diagnosis and Treatment. Oncologist 3 (5): 339-345, 1998.
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.
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.
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.
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.
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.
13. Kvols LK: The carcinoid syndrome: a treatable malignant disease. Oncology (Huntingt) 2 (2): 33-41, 1988.
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.
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.
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.
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.
18. Moertel CG: Karnofsky memorial lecture. An odyssey in the land of small tumors. J Clin Oncol 5 (10): 1502-22, 1987.

Recurrent Gastrointestinal Carcinoid Tumors

The prognosis for any treated carcinoid patient with progressive or recurrent disease is poor. Deciding on further treatment depends on many factors, including prior treatment, site of recurrence, and individual patient considerations. Attempts at reresecting slow growing tumors (e.g., repeat or multiple liver resections) are worthy of consideration after extensive evaluation, since successful further reduction of tumor volume may provide long-term palliation. Recurrence in any single site may also be potentially resectable. Clinical trials are appropriate and should be considered when possible.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent 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.

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Changes to This Summary (05 / 16 / 2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

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Date Last Modified: 2008-05-16

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