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Information from PDQ -- for Health Professionals
Gastrointestinal carcinoid tumor
208/01064
** 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 syndrome (carcinoid tumor with distant metastases) is
aided by demonstrating elevated 24-hour urinary 5-hydroxyindoleacetic acid
levels. This test is not useful in 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.[2-7] Blood chromogranin A assay may
also be a useful, though non-specific, 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 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 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. 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. 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
alfa. 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 alfa 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: 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. Roberts LJ, Anthony LB, Oates JA: Disorders of vasodilator hormones:
carcinoid syndrome and mastocytosis. In: Wilson JD, Forster DW,
Kronenberg HM, et al.: Williams Textbook of Endocrinology. Philadelphia;
W.B. Sanders Company, 9th ed., 1998, 1711-1731.
9. 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.
10. Modlin IM, Sandor A: An analysis of 8305 cases of carcinoid tumors.
Cancer 79(4): 813-829, 1997.
11. 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.
12. Rubin J, Ajani J, Schirmer W, et al.: Octreotide acetate long-acting
formulation versus open-label subcutaneous octreotide acetate in
malignant carcinoid syndrome. Journal of Clinical Oncology 17(2):
600-606, 1999.
13. 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.
14. Frank M, Klose KJ, Wied M, et al.: Combination therapy with octreotide
and alpha-interferon: effect on tumor growth in metastatic endocrine
gastoenteropancreatic tumors. American Journal of Gastroenterology
94(5): 1381-1387, 1999.
** 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 (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 non-secretion 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.
** 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 within
the wall 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 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 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 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 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.
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, 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
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.[5,6]
-- 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 non-resection 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 alfa 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 alfa has been reported to
re-induce symptom control in patients who have failed octreotide.[16] 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.[17] 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.[18]
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. Oberg 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. American Journal of
Roentgenology 147(1): 149-154, 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). 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. Annals of
Internal Medicine 120(4): 302-309, 1994.
10. 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.
11. 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.
12. 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.
13. Kvols LK: The carcinoid syndrome: a treatable malignant disease.
Oncology (Huntington NY) 2(2): 33-40, 1988.
14. 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.
15. 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.
16. 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.
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. Journal of Clinical
Oncology 13(6): 1486-1492, 1995.
18. 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: 01/2002
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* This information from PDQ is reviewed regularly by members of the PDQ *
* Editorial Boards. If you have specific comments on the content of this *
* information, direct them to: PDQ Editorial Board, CIPS/NCI, 6116 *
* Executive Boulevard, Suite 3002B, MSC-8321, 20892-8321, fax: 301-480-8105.*
* *
* The PDQ database also contains listings of clinical trial protocols and *
* directories of organizations and physicians who treat cancer patients, *
* but this information is not available through CancerMail. For more *
* information on accessing PDQ, consult the CancerMail Contents List. *
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