Treatment Option Overview
Standard treatments for patients with gastrointestinal (GI) carcinoid tumors include the following:
- Somatostatin analogs.
- Treatment of hepatic metastases.
- Management of carcinoid-related fibrosis.
- Symptomatic therapy.
Treatments being tested in clinical trials include the following:
- Molecular-targeted therapies.
- Therapies for symptomatic relief.
- Antifibrotic therapies.
The only potential curative therapy for GI carcinoids, which may be possible in as many as 20% of patients, is resection of the primary tumor and local lymph nodes.[2-4] Endoscopic surgery may be suitable for some tumors depending on the location, number, size, and degree of malignancy. Resection of nonhepatic tumor primaries is associated with increased median survival ranging from 69 to 139 months.[5,6] However, the extent of resection depends on the site of origin of a given tumor, the involvement of surrounding structures, and the extent of metastases.
The development of long-acting and depot formulations of somatostatin analogs has been important in the amelioration of symptoms of carcinoid syndrome. The result has been a substantial improvement in quality of life with relatively mild adverse effects.[1,7] The inhibitory effects of somatostatin on neurotransmission, motor and cognitive functions, smooth muscle contractility, glandular and exocrine secretions, intestinal motility, and absorption of nutrients and ions are mediated by cyclic adenosine monophosphate inhibition.[8,9] Experimentally, somatostatin has been shown to have a cytostatic effect on tumor cells. This effect involves hyperphosphorylation of the retinoblastoma gene product and G1 cell cycle arrest, in addition to somatostatin receptor (SSTR) subtype 3 [sst(3)]-mediated (and to a lesser extent, SSTR subtype [sst(2)]-mediated) apoptosis.[10-12] Somatostatin also appears to have some antiangiogenic properties. However, only a small number of patients treated with somatostatin analog therapy experience partial tumor regression.[1,4]
Currently available somatostatin analogs display high affinity for sst(2) and SSTR subtype 5, low affinity for SSTR subtype 1 and SSTR subtype 4, and medium affinity for sst(3). (Refer to the Somatostatin Receptor Scintigraphy section in the General Information About Gastrointestinal Carcinoid Tumors section of this summary for more information.) Octreotide, a short-acting somatostatin analog and the first biotherapeutic agent used in the management of carcinoid tumors, exhibits beneficial effects that are limited to symptom relief, with about 70% of patients experiencing resolution of diarrhea or flushing. [1,4]
In the treatment of carcinoids, lanreotide, a long-acting somatostatin analog administered every 10 to 14 days, has an efficacy similar to that of octreotide and an agreeable formulation for patient use. The effects of lanreotide on symptom relief are comparable to those of octreotide, with 75% to 80% of patients reporting decreased diarrhea and flushing; however, there appears to be little improvement in tumor responses over shorter-acting octreotide. Depot formulations include long-acting repeatable (LAR) octreotide and a slow-release depot preparation of lanreotide. One study comparing subcutaneous short-acting octreotide with monthly LAR octreotide reported an increased median survival from the time of metastatic disease diagnosis (143 months vs. 229 months in favor of the LAR form), representing a 66% lower risk for death among patients treated with the LAR formulation. A randomized, controlled study in metastatic midgut neuroendocrine tumors showed improved time to tumor progression with monthly LAR octreotide compared with placebo. (Refer to the Jejunal and Ileal carcinoids section in the Treatment Option Overview section of this summary.)
The typical duration of treatment with somatostatin analogs is approximately 12 months because of the development of tachyphylaxis (reported less frequently with long-acting formulations) and/or disease progression.[15-17] In the management of carcinoid crises, intravenous somatostatin analogs are effective; crises are usually precipitated by anesthesia, surgical interventions, or radiologic interventions. Adverse effects of somatostatin analog administration include:[19,20]
- Loose stools.
- Cardiac conduction abnormalities and arrhythmias.
- Endocrine disturbances (e.g., hypothyroidism, hypoglycemia, or, more commonly, hyperglycemia).
- Gastric atony (rarely).
Biliary sludge and cholelithiasis occur in as many as 50% of the patients, but few patients (1%–3%) develop acute symptoms requiring cholecystectomy.
The most researched interferon in the treatment of carcinoid disease is interferon-alpha (IFN-alpha); comparable to somatostatin analogs, the most pronounced effects of IFN-alpha are inhibition of disease progression and symptom relief, with approximately 75% of patients reporting the resolution of diarrhea or flushing. IFN-alpha, similar to other IFNs studied in the treatment of carcinoids (e.g., IFN-gamma and human leukocyte interferon), has substantial adverse effects, including alopecia, anorexia, fatigue, weight loss, fever, a flu-like syndrome, and myelosuppression; however, IFN-alpha may show greater antitumor activity than somatostatin analogs. Both single-agent and multiagent chemotherapeutics appear to have little role in the management of these essentially chemoresistant tumors; no protocol has shown objective tumor response rates greater than 15%.
Treatment of Hepatic Metastases
The management of hepatic metastases may include surgical resection; hepatic artery embolization; cryoablation and radiofrequency ablation (RFA); and orthotopic liver transplantation. In one large review of 120 carcinoid patients, a biochemical response rate of 96% and a 5-year survival rate of 61% were reported for patients whose hepatic metastases were resected surgically. The 5-year survival rate without surgical therapy is approximately 30%. For hepatic artery embolization, the most frequently used single agent is gelatin powder; and, in more than 60 patients with carcinoid tumors, the use of gelatin powder resulted in 34% and 42% of patients achieving biochemical and tumor-diminution responses, respectively.[23-25] Trials using transcatheter arterial occlusion with chemoembolization have also been performed, with the most thoroughly researched combination involving hepatic artery ligation with gelatin foam and doxorubicin (4 trials and 66 patients), resulting in biochemical responses in 71% of patients and tumor regression in approximately 50% of patients. However, the duration of response can be short lived after embolization, and embolization may be associated with adverse effects that range from transient symptoms (e.g., pain, nausea, fever, and fatigue), which occur in 30% to 70% of patients, to liver enzyme abnormalities, which occur in as many as 100% of patients (i.e., transaminitis and postembolization syndrome), to florid and potentially lethal carcinoid crisis with massive release of vasoactive substances.
In one prospective trial, 80 RFA sessions were performed in 63 patients with neuroendocrine hepatic metastases (including 36 carcinoids), and 92% of the patients reported at least partial symptom relief. In the same 63 patients, 70% had significant or complete relief at 1 week postoperatively, with a perioperative morbidity of 5%; duration of symptom control was 11 ± 2.3 months, and median survival time was 3.9 years after the first RFA. There are few trials of cryoablation of hepatic metastases, and the results of liver transplantation for metastatic disease are disappointing, reflecting the typically advanced disease states of transplant recipients.
Information about ongoing clinical trials is available from the NCI Web site.
The four radionuclide conjugates most commonly used in the treatment of carcinoid disease are 131I-MIBG (iodine-131-meta-iodobenzylguanidine), indium-111, yttrium-90, and lutetium-177, with the latter three bound to a variety of somatostatin analogs. However, the median tumor response rate for the patients treated with 131I-MIBG is less than 5%, although the modality appears somewhat more effective in achieving biochemical stability (~50%) or tumor stability (~70%). Although 111In-labeled somatostatin analogs are the most commonly studied radiopeptides to date, largely reflecting their availability, and with therapeutic benefits similar to 131I-MIBG, the most promising advance in radiopeptide therapeutics has been the development of 177Lu-octreotate, which emits both beta and gamma radiation. In the largest patient series treated to date with lutetium-labeled somatostatin analogs (n = 131; 65 with GI carcinoids), remission rates were correlated positively with high pretherapy octreotide scintigraphy uptake and limited hepatic tumor load. In patients with extensive liver involvement, median time to progression was shorter (26 months) compared with patients who had either stable disease or tumor regression (>36 months).
Management of Carcinoid-Related Fibrosis
Bowel obstruction secondary to peritoneal fibrosis is the most common presenting symptom of small intestinal carcinoids. Heart failure secondary to right-sided valvular fibrosis represents a serious extraintestinal manifestation of carcinoid fibrosis and occurs in 20% to 70% of patients with metastatic disease; it accounts for as much as 50% of carcinoid mortality.[28,29] Currently, there is no effective pharmacologic therapy for either clinical problem. In the instance of bowel obstruction, surgical lysis of the adhesions often is technically demanding because of the cocoon-like effects of extensive fibrosis stimulated by the various tumor-derived growth factors. Valvular replacement usually is required to manage carcinoid heart disease.
In addition to the use of long-acting depot formulations of somatostatin analogs as the principal agents in the amelioration of carcinoid symptoms, the nonspecific supportive care of patients includes:
- Advising them to avoid factors that induce flushing or bronchospastic episodes including the following:
- Ingestion of alcohol, certain cheeses, capsaicin-containing foods, and nuts.
- Stressful situations.
- Some kinds of physical activity.
- Diarrhea may be treated with conventional antidiarrheal agents such as loperamide or diphenoxylate; more pronounced diarrhea may be treated with the 5-HT receptor subtype 2 antagonist cyproheptadine, which is effective in as many as 50% of patients and may also help alleviate anorexia or cachexia in patients with a malignant carcinoid syndrome.
- Histamine 1 receptor blockade with fexofenadine, loratadine, terfenadine, or diphenhydramine may be of benefit in treating skin rashes, particularly in histamine-secreting gastric carcinoid tumors.
- Bronchospasm can be managed with theophylline or beta-2 adrenergic receptor agonists such as albuterol.
Carcinoid crisis is manifested by profound flushing, extreme blood pressure fluctuations, bronchoconstriction, dysrhythmias, and confusion or stupor lasting hours or days and may be provoked by induction of anesthesia or an invasive radiologic procedure.[18,31] This potentially fatal condition can occur after manipulation of tumor masses (including bedside palpation), administration of chemotherapy, or hepatic arterial embolization. In contrast with the treatment of other causes of acute hypotension, the use of calcium and catecholamines should be avoided in carcinoid crisis because these agents provoke the release of bioactive tumor mediators that may perpetuate or worsen the situation. Plasma infusion and octreotide are used for hemodynamic support. For the most part, the use of somatostatin analogs has replaced other pharmacologic maneuvers in the treatment of crises, and their use has been associated with increased survival rates. Prophylactic use of subcutaneous octreotide or the administration of a depot somatostatin analog in a timely fashion before any procedures are undertaken is mandatory to prevent the development of a crisis.
Various therapies targeting vascular endothelial growth factor (VEGF), platelet-derived growth factor receptor, and mammalian target of rapamycin (mTOR) are in development.[1,33] Therapeutic agents under investigation include the VEGF monoclonal antibody, bevacizumab; VEGF tyrosine kinase inhibitors, sunitinib, vatalanib, and sorafenib; and the mTOR inhibitor, everolimus (RAD001).
General Therapeutic Approaches
As might be expected, therapeutic approaches to GI carcinoids vary according to anatomical location. In 2004, a consensus statement regarding the diagnosis and treatment of GI neuroendocrine tumors was published on behalf of the European Neuroendocrine Tumor Society, which details site-specific approaches to the treatment of GI carcinoids.
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- Plöckinger U, Rindi G, Arnold R, et al.: Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS). Neuroendocrinology 80 (6): 394-424, 2004. [PUBMED Abstract]
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- Lambert P, Minghini A, Pincus W, et al.: Treatment and prognosis of primary malignant small bowel tumors. Am Surg 62 (9): 709-15, 1996. [PUBMED Abstract]
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- Aparicio T, Ducreux M, Baudin E, et al.: Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours. Eur J Cancer 37 (8): 1014-9, 2001. [PUBMED Abstract]
- Kölby L, Persson G, Franzén S, et al.: Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg 90 (6): 687-93, 2003. [PUBMED Abstract]
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