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Gastrointestinal carcinoid tumor


Table of Contents

GENERAL INFORMATION
CELLULAR CLASSIFICATION
STAGE INFORMATION
TREATMENT OPTION OVERVIEW
LOCALIZED GASTROINTESTINAL CARCINOID TUMOR
Appendiceal carcinoids
Rectal carcinoids
Small bowel carcinoids
Gastric, pancreatic, and colon carcinoids
REGIONAL GASTROINTESTINAL CARCINOID TUMOR
METASTATIC GASTROINTESTINAL CARCINOID TUMOR
Carcinoid syndrome
RECURRENT GASTROINTESTINAL CARCINOID TUMOR

GENERAL INFORMATION

Many carcinoid tumors behave like benign tumors and can be treated and often cured, especially in early stages.[1] The occurrence of metastasis from carcinoid tumor relates directly to the size of the primary tumor (lesions 1 centimeter or less rarely metastasize; lesions greater than 2 centimeters 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. These usually slow-growing tumors may arise from various sites, although 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 tumor with distant metastases is aided by demonstrating elevated 24-hour urinary 5-hydroxyindoleacetic acid levels, but this test is not useful in diagnosis of carcinoids at a curable stage or of rectal carcinoids at any stage.[2-7] Primary carcinoids of the extrapelvic colon are uncommon, typically present with metastatic disease, and have a poor prognosis.[8,9] 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.[10]

The relatively rare malignant carcinoid syndrome (flush, diarrhea, bronchoconstriction, cardiac valvular lesions, arthropathy, and telangiectasia) relates to the release of endocrine 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 from large tumor masses drains directly into the systemic circulation (for example, pulmonary and ovarian primaries, and pelvic or retroperitoneal involvement by metastatic or locally invasive small bowel carcinoids).

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. For such patients, 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 2 to 3 times a day.

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.[11] A few patients benefit from the use of interferon alfa, but responses have been generally transient and accompanied by toxic effects that frequently outweigh therapeutic gains. Patients with asymptomatic metastases that cannot be resected for cure will often remain symptom-free for long periods of time. There is no evidence that treatment during this time will prolong survival.

References:

  1. Moertel CG: An odyssey in the land of small tumors. Journal of Clinical Oncology 5(10): 1503-1522, 1987.

  2. Kulke MH, Mayer RJ: Carcinoid tumors. New England Journal of Medicine 340(11): 858-868, 1999.

  3. Mani S, Modlin IM, Ballantyne G, et al.: Carcinoids of the rectum. Journal of the American College of Surgeons 179(2): 231-248, 1994.

  4. Moertel CG, Weiland LH, Nagorney DM, et al.: Carcinoid tumor of the appendix: treatment and prognosis. New England Journal of Medicine 317(27): 1699-1701, 1987.

  5. Martin JK, Moertel CG, Adson MA, et al.: Surgical treatment of functioning metastatic carcinoid tumors. Archives of Surgery 118(5): 537-542, 1983.

  6. Moertel CG: Treatment of the carcinoid tumor and the malignant carcinoid syndrome. Journal of Clinical Oncology 1(11): 727-740, 1983.

  7. Delcore R, Friesen SR: Gastrointestinal neuroendocrine tumors. Journal of the American College of Surgeons 178(2): 187-211, 1994.

  8. Spread C, Berkel H, Jewell L, et al.: Colon carcinoid tumors: a population-based study. Diseases of the Colon and Rectum 37(5): 482-491, 1994.

  9. Modlin IM, Sandor A: An analysis of 8305 cases of carcinoid tumors. Cancer 79(4): 813-829, 1997.

  10. Gerstle JT, Kauffman GL, Koltun WA: The incidence, management, and outcome of patients with gastrointestinal carcinoids and second primary malignancies. Journal of the American College of Surgeons 180(4): 427-432, 1995.

  11. Gorden P, Comi RL, Maton PN, et al.: 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. Annals of Internal Medicine 110(1): 35-50, 1989.


CELLULAR CLASSIFICATION

There is no histologic difference between carcinoids arising in various sites or between metastasizing and nonmetastasizing lesions. Carcinoids are classified by their embryologic relationship to the foregut, midgut, or hindgut which is correlated with clinical behavior.


STAGE INFORMATION

There is no accepted staging system for carcinoid tumors.


TREATMENT OPTION OVERVIEW

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.


LOCALIZED GASTROINTESTINAL CARCINOID TUMOR


Appendiceal carcinoids

For appendiceal carcinoid tumors less than 1.5 centimeters 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 to the mucosa of the appendix. Tumors 1.5 to 2 centimeters in diameter can be treated by simple appendectomy or more aggressive surgical treatment. Tumors 2 centimeters or greater in diameter are rare, 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 rectal carcinoid tumors 1 centimeter 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 centimeters 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 abdomino-perineal resection.

Tumors 1 to 2 centimeters 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 small bowel carcinoid tumors less than 1 centimeter in diameter, conservative local resection is sufficient. For tumors greater than 1 centimeter in diameter, excision of a wedge of mesentery containing regional nodes is indicated.[3] Patients with tumors 1.5 to 2 centimeters 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 quite 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]

References:

  1. Roggo A, Wood WC, Ottinger LW: Carcinoid tumors of the appendix. Annals of Surgery 217(4): 385-390, 1993.

  2. Mani S, Modlin IM, Ballantyne G, et al.: Carcinoids of the rectum. Journal of the American College of Surgeons 179(2): 231-248, 1994.

  3. Moertel CG: An odyssey in the land of small tumors. Journal of Clinical Oncology 5(10): 1503-1522, 1987.

  4. Spread C, Berkel H, Jewell L, et al.: Colon carcinoid tumors: a population-based study. Diseases of the Colon and Rectum 37(5): 482-491, 1994.

  5. Maurer CA, Baer HU, Dyong TH, et al.: Carcinoid of the pancreas: clinical characteristics and morphological features. European Journal of Cancer 32A(7): 1109-1116, 1996.


REGIONAL GASTROINTESTINAL CARCINOID TUMOR

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 resection removing all accessible disease or bypass, should be carried out. Chemotherapy is not indicated except in symptomatic tumors when symptoms are due to the bulk of the tumor mass. Patients with asymptomatic, unresectable disease will frequently have many months or even years of comfortable life with no further treatment.

References:

  1. Moertel CG: An odyssey in the land of small tumors. Journal of Clinical Oncology 5(10): 1503-1522, 1987.


METASTATIC GASTROINTESTINAL CARCINOID TUMOR

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 or cryosurgery 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 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 or 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]

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

5. 131I-MIBG: Therapeutic doses of iodine-131-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 alfa and octreotide, alone and in combination, have been reported to have activity.[5]


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 non-resection surgical ablative techniques include cryosurgery 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.[6,7] Such treatment may also be given in conjunction with systemic chemotherapy in selected patients.[8] 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: Diarrhea will frequently respond to standard antidiarrheal medications.

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.[9-12]

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 are drugs to be specifically avoided in these patients since they will exacerbate the syndrome by inhibiting serotonin degradation.

4. Interferon alfa preparations may have a role in controlling symptoms of the carcinoid syndrome or in arresting tumor growth.[13] These benefits have generally been transient and accompanied by toxic effects that frequently outweigh therapeutic gains,[14] although interferon alfa has been reported to re-induce symptom control in patients who have failed octreotide.[15] The combination of interferon alfa and continuous- infusion fluorouracil has demonstrated antitumor and/or antihormonal activity and, similar to other drug regimens, can provide useful palliation.[16] Combination of interferon alfa and octreotide has also been reported to have activity.[5]

5. Protocols using chemotherapy combinations should be considered for symptomatic patients.[17]

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): 227-232, 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. American Journal of Surgery 169(5): 523-528, 1995.

  3. Schupak KD, Wallner KE: The role of radiation therapy in the treatment of locally unresectable or metastatic carcinoid tumors. International Journal of Radiation Oncology, Biology, Physics 20(3): 489-495, 1991.

  4. Taal BG, Hoefnagel CA, Valdes Olmos RA, et al.: Palliative effect of metaiodobenzylguanidine in metastatic carcinoid tumors. Journal of Clinical Oncology 14(6): 1829-1838, 1996.

  5. Oberg K: Advances in chemotherapy and biotherapy of endocrine tumors. Current Opinion in Oncology 10(1): 58-65, 1998.

  6. Carrasco CH, Charnsangavej C, Ajani J, et al.: The carcinoid syndrome: palliation by hepatic artery embolization. American Journal of Roentgenology 147(1): 149-154, 1986.

  7. Moertel CG, May GR, Martin JK, et al.: Sequential hepatic artery occlusion (HAO) and chemotherapy for metastatic carcinoid tumor and islet cell carcinoma (ICC). Proceedings of the American Society of Clinical Oncology 4: 80, 1985.

  8. Moertel CG, Johnson CM, McKusick MA, et al.: The management of patients with advanced carcinoid tumors and islet cell carcinomas. Annals of Internal Medicine 120(4): 302-309, 1994.

  9. Kvols LK, Moertel CG, O'Connell MJ, et al.: Treatment of the malignant carcinoid syndrome: evaluation of a long-acting somatostatin analogue. New England Journal of Medicine 315(11): 663-666, 1986.

  10. Kvols LK, Martin JK, Marsh HM, et al.: Rapid reversal of carcinoid crisis with a somatostatin analogue. New England Journal of Medicine 313(19): 1229-1230, 1985.

  11. Gorden P, Comi RL, Maton PN, et al.: 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. Annals of Internal Medicine 110(1): 35-50, 1989.

  12. Kvols LK: The carcinoid syndrome: a treatable malignant disease. Oncology (Huntington NY) 2(2): 33-40, 1988.

  13. Oberg K, Norheim I, Lind E, et al.: Treatment of malignant carcinoid tumors with human leukocyte interferon: long-term results. Cancer Treatment Reports 70(11): 1297-1304, 1986.

  14. Moertel CG, Rubin J, Kvols LK: Therapy of metastatic carcinoid tumor and the malignant carcinoid syndrome with recombinant leukocyte A interferon. Journal of Clinical Oncology 7(7): 865-868, 1989.

  15. Tiensuu Janson EM, Ahlstrom H, Andersson T: Octreotide and interferon alfa: a new combination for the treatment of malignant carcinoid tumours. European Journal of Cancer 28(10): 1647-1650, 1992.

  16. 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. Journal of Clinical Oncology 13(6): 1486-1492, 1995.

  17. Moertel CG: An odyssey in the land of small tumors. Journal of Clinical Oncology 5(10): 1503-1522, 1987.


RECURRENT GASTROINTESTINAL CARCINOID TUMOR

The prognosis for any treated carcinoid patient with progressing, recurring, or relapsing disease is poor. Deciding on further treatment depends on many factors, including the prior treatment, site of recurrence, as well as individual patient considerations. Attempts at re-resecting 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.

Date Last Modified: 10/1999



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