PDQ® Treatment Health Professionals
Many carcinoid tumors behave like benign tumors and can be treated and often cured, especially in early stages. 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.
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. 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.
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.
There is no accepted staging system for carcinoid tumors.
The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.
For appendiceal carcinoid tumors less than 1.5 centimeters in greatest diameter, appendectomy is adequate treatment with cure rates of essentially 100%. 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.
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.
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.
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. 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.
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]
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. 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.
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:
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 ), 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.
4. Radiation therapy: The role of radiation therapy in the management of carcinoid tumor with distant metastasis is restricted to symptomatic palliation. 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.
6. Biological modification (immunotherapy): Low-dose interferon alfa and octreotide, alone and in combination, have been reported to have activity.
Treatment options associated with metastatic carcinoid tumor:
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. 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. These benefits have generally been transient and accompanied by toxic effects that frequently outweigh therapeutic gains, although interferon alfa has been reported to re-induce symptom control in patients who have failed octreotide. 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. Combination of interferon alfa and octreotide has also been reported to have activity.
5. Protocols using chemotherapy combinations should be considered for symptomatic patients.
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