Carcinoid Tumors of the GI Tract
Carcinoid tumors typically arise from components derived from the primitive gut, lungs, and, rarely, the gonads. Approximately 85% of all carcinoids originate from the gut, predominantly the appendix, followed by the small bowel and the rectum.
These tumors have the propensity to cause considerable morbidity by virtue of creating a syndrome of hormonal excess. For example, although the majority of carcinoids are hormonally inert, these neoplasms may produce excessive amounts of serotonin (from dietary tryptophan(Drug information on tryptophan)), prostaglandins, kinins (secondary to kallikrein release), and a variety of other hormones, which may account for the "carcinoid syndrome." SEER data suggest an increase in the incidence of carcinoid tumors between 1973 and 1990.
Signs and Symptoms
Symptoms of carcinoid tumors are often long-term and vague. The majority of patients diagnosed with carcinoid tumors can have their symptoms (of varying intensity) tracked for one year prior.
Flushing
The most common sign of the carcinoid syndrome is flushing, which is often triggered by alcohol(Drug information on alcohol), catecholamines, or emotional stress. It ranges in severity from a minor annoyance to profound vasodilatation with nearsyncope and hypotension. Diarrhea
Diarrhea
Diarrhea is also common and is due to GI hypermotility. It usually occurs after meals and is rarely voluminous, bulky, or foul smelling.
Abdominal cramps
Diarrhea may be associated with crampy pain, although other etiologies for the pain must be considered, including bowel obstruction due to tumor or mesenteric fibrosis.
Bronchospasm
Patients may also develop bronchospasm, which may be mediated by histamine. This problem is often associated with flushing, although it is less common.
Cardiac disease
A late finding is right-sided valvular heart disease, although left-sided lesions may be noted occasionally. The fibrous deposits may lead to tricuspid insufficiency and/or pulmonary stenosis. Valve replacement is rarely necessary. Because the disease remains undiagnosed in many patients, a cardiac evaluation should be performed in all patients who have carcinoid syndrome.
Symptom triad
If there is sufficient shunting of dietary tryptophan from niacin to serotonin synthesis, patients may present with diarrhea, dermatitis, and dementia. However, this symptom triad is rare if patients maintain adequate intake of a balanced diet.
Diagnosis
Diagnostic studies include CT/MRI of the abdomen and a 24-hour urine test for 5-hydroxyindoleacetic acid. Some radiologists prefer to obtain a triple-phase CT scan of the liver to detect these highly vascular liver metastases.
Octreotide scanning
111Indium octreotide(Drug information on octreotide) scintigraphy (OctreoScan) has a higher sensitivity for detecting pancreatic tumors and is superior to CT or MRI for detecting metastatic disease, particularly extrahepatic disease. One study suggests that 111indium octreotide scintigraphy can reduce costs by avoiding unnecessary surgeries. Also, a positive scan may predict which patients may benefit from treatment with somatostatin(Drug information on somatostatin) analogs (eg, octreotide). Initial studies with a new peptide tracer, 111indium 1,4,7,10-tetraazacyclododecane-N,N,N',N'-tetraacetic acid-lanreotide, suggest high tumor uptake and a more favorable dosimetry than is seen with 111indium diethylene triamine pentaacetic acid-d-[Phe1]-octreotide. Other scans of increasing interest include 68Ga-DOTA-1-Nal3-octreotide (68Ga-DOTANOC) and 68Ga-DOTA-D-Phe1-Tyr3-octreotate (68Ga-DOTATATE). PET scans are rarely useful, particularly in well differentiated or moderately differentiated tumors.
TNM staging of neuroendocrine tumorsStaging and Prognosis
Staging
Carcinoid tumors are staged according to local spread of disease, nodal status, and distant metastatic involvement, using the AJCC TNM system (Table 3).
The site of tumor origin is potentially prognostic, because most appendiceal carcinoids (75%) are < 1 cm when found and are usually cured by resection. Similarly, rectal carcinoids are usually small and completely resectable for cure.
In contrast, small bowel carcinoids tend to present at a more advanced stage, and approximately one third have multicentric primary lesions. However, if the disease is completely resectable, patients have a 20-year survival rate of 80%; patients with unresectable intra-abdominal or hepatic metastases have median survival durations of 5 and 3 years, respectively.
• Gastric carcinoids—Types I and II are often multifocal, associated with an elevated gastrin level, and relatively indolent, whereas type III gastric carcinoids are solitary, have a normal gastrin level, and have a more aggressive clinical course.
Treatment
The management of carcinoid tumors focuses not only on treating bulky disease, as with other solid malignancies, but also on treating the complications of hormonal excess.
Treatment of bulky disease
Surgery.
• Appendiceal carcinoids—For tumors that are found incidentally in the appendix and that are probably between 1 and 2 cm, appendectomy is the treatment of choice. For tumors > 2 cm, a right hemicolectomy and lymph node dissection are appropriate.
Small intestines and rectal carcinoids should be resected with a wedge lymphadenectomy to evaluate nodal disease. Small distal rectal tumors (< 2 cm) can undergo local excision via transanal techniques. Duodenal lesions should be locally excised if they are small (< 2 cm), with radical resection reserved for larger tumors.
• Tumor debulking—Liver resection or ablation of liver metastases with cryotherapy or radiofrequency techniques is useful in patients with limited extrahepatic disease and/or symptomatic carcinoid syndrome. Tumor debulking can protect liver functional reserve and improve quality of life.
• Liver transplantation—Liver transplantation may be of benefit in highly select patients without extrahepatic disease whose cancer progresses after other therapeutic interventions.
Preoperative and intraoperative considerations. All patients with metastatic, hormonally active carcinoid tumors require echocardiograms before any surgical intervention to evaluate for valvular disease. Furthermore, patients will require preoperative treatment with octreotide either subcutaneously or intravenously. Administration of intravenous octreotide is the preferred method of managing carcinoid crisis. All patients undergoing operative intervention should have a cholecystectomy, because octreotide use can promote the development of gallstones. Also, regional therapy for the liver with the use of embolic material, can cause acute cholecystitis.
Radiation. Carcinoid tumors are modestly responsive to radiation therapy and frequently are palliated with this modality. Overall, treatment with higher radiation doses (29-52 Gy) has been associated with higher response rates (40%-50%) than has treatment with lower doses (10%).
A single-arm study (Bushnell JL Jr. et al: J Clin Oncol 2010) of 90yttrium-edotreotide administered to 90 symptomatic patients with carcinoid tumor refractory to octreotide resulted in stable disease or response for 74% of patients.
Chemotherapy. Since carcinoid tumors tend to be resistant to most chemotherapeutic agents, there are no standard regimens for the treatment of unresectable tumors.
• Single agents—Agents that have reported activity include 5-FU, doxorubicin, and recombinant human interferon alfa-2a(Drug information on interferon alfa-2a) and alfa-2b. However, the response rate with these agents is in the range of 10% to 20%, the response duration is < 6 months, and complete remission is rare.
• Combination regimens—Combination chemotherapy regimens represent little improvement over single-agent therapy, with response rates ranging from 25% to 35%, response durations < 9 months, and rare complete remissions.
• New agents—Antiangiogenic approaches and the recognition of other potential biologic targets have contributed to the development of a number of early-phase clinical trials incorporating bevacizumab with temozolomide and with FOLFOX chemotherapy, temozolomide and capecitabine(Drug information on capecitabine), sunitinib (Sutent), sorafenib(Drug information on sorafenib) (Nexavar), vatalanib, imatinib(Drug information on imatinib), thalidomide, temsirolimus, and everolimus. Phase III trials are planned or ongoing to further evaluate sunitinib and everolimus. The SWOG is currently coordinating an Intergroup randomized phase III trial comparing depot octreotide (Sandostatin LAR) plus interferon alfa-2b(Drug information on interferon alfa-2b) vs depot octreotide plus bevacizumab(Drug information on bevacizumab) in advanced carcinoid patients with poor prognoses.
Management of poorly differentiated (high-grade or anaplastic) neuroendocrine tumors and metastatic disease and postresection therapy for isolated resectable disease consists of the same systemic treatment as that used for small-cell lung cancer.
Treatment of symptoms
Somatostatin analogs.
• Octreotide—The most active agent is the somatostatin analog octreotide. Even though native somatostatin is effective in controlling many symptoms, due to its short half-life (< 2 minutes), this agent would have to be administered via continuous infusion to be clinically useful. However, octreotide may be administered subcutaneously every 8 to 12 hours, facilitating outpatient therapy. The initial dose of octreotide is 100 to 600 µg/d in two to four divided doses, although the effective dose varies between patients and must be titrated to the individual patient's symptoms. The most commonly used dose and schedule of somatostatin in the depot formulation is given at monthly doses of 20 mg or higher.
Octreotide not only is useful in managing the chronic problems of the carcinoid syndrome, but it also is effective in treating carcinoid crisis (volume-resistant hypotension), which may be precipitated by surgery or effective antitumor treatment.
Octreotide is well tolerated, although chronic treatment may be associated with cholelithiasis, increased fecal fat excretion, fluid retention, nausea, and glucose intolerance. Occasional objective antitumor responses have been observed in patients who have received octreotide; the median duration of symptomatic improvement is 1 year. One report evaluating the cost-effectiveness of octreotide suggested that it may double survival time. Other somatostatin analogs, including lanreotide(Drug information on lanreotide), pasireotide and vapreotide, are under investigation. A sustained-release formulation of lanreotide (Somatuline Depot) is specifically indicated for the long-term treatment of patients with acromegaly who have responded inadequately to surgery and/or radiotherapy or for whom surgery and/or radiotherapy is not an option.
Patients who demonstrate disease resistance with somatostatin analog treatment alone may benefit from combination therapy with interferon-alfa and this somatostatin analog.
• Radiolabeled somatostatin analogs—A promising experimental treatment approach involves the use of octreotide or other somatostatin analogs conjugated to radioisotopes (eg, 111indium or 90yttrium or 177 lutetium) in patients whose tumors express somatostatin receptors (eg, those with a positive OctreoScan result). This approach allows targeted in situ radiotherapy by taking advantage of internalization of the radioligand into the cell to produce DNA damage and cell death, with little effect on normal tissue. Initial reports have shown favorable results with this technique.
Other agents. Other agents that have been used for symptomatic management include histamine type 1 (H1)- and H2-receptor antagonists, methoxamine (Vasoxyl), cyproheptadine, and diphenoxylate with atropine. The symptom complex of diarrhea, dermatitis, and dementia may be prevented or treated with supplemental niacin.
Bisphosphonate therapy should be considered for patients with bone metastases.
Hepatic arterial embolization. Hepatic arterial embolization with such products as Ivalon or Gelfoam, with or without chemotherapy (chemoembolization), is an option for patients with either a carcinoid tumor or an islet-cell carcinoma who have predominant liver metastases or who are symptomatic. These lesions often are hypervascular, and, thus, peripheral hepatic embolization may provide symptomatic relief in some patients. It is unclear whether this therapy has any effect on patient survival.
Other liver-directed therapeutic strategies include RFA for select patients and 90yttrium microspheres.
