Surgery is the only way to achieve a complete cure and remains the mainstay of treatment for all patients with primary carcinoid tumors.
However, because of the relatively indolent disease course of carcinoid tumors, many patients present with synchronous or metachronous metastatic lesions.
In fact, up to 75% of patients with carcinoid tumors develop hepatic metastases regardless of the location of the primary tumor.
Meeting the goals of carcinoid tumor management—namely, symptom control, biochemical control, objective tumor control, and quality-of-life improvement—in patients with widespread disease and/or hepatic metastases relies on a multidisciplinary treatment approach.
Surgical Debulking
Cytoreductive surgery, a mainstay in the management of widely metastatic disease, aims to control symptoms and improve survival by removing or destroying disseminated tumor metastases.
Although aggressive surgical debulking may not be curative, recent data suggest a significant palliative effect of cytoreduction.
In a meta-analysis of cytoreductive partial hepatectomy in patients with advanced, metastatic carcinoid disease, surgical debulking yielded a 5-year survival rate >70% and complete resolution of carcinoid symptoms in 86% of patients.
Likewise, in another recent study, cytoreductive therapy relieved 83% of patients of mesenteric ischemia resulting from carcinoid encasement of the mesentery.
Somatostatin Analogues
Somatostatin is a naturally occurring regulatory peptide that acts primarily as a negative regulator of a variety of different cell types, blocking processes such as hormone secretion, cell growth, and smooth muscle contraction.
The intracellular functions of somatostatin are initiated by the binding of the peptide to one or more of five different cell-surface receptor proteins—somatostatin subtype receptor (SSTR)-1 to SSTR-5—thereby activating one or more intracellular G-proteins and initiating biochemical signaling pathways.
To date, two analogues of somatostatin—octreotide, an octapeptide analogue of somatostatin with a relatively short half-life, and lanreotide, a long-acting somatostatin analogue—are commercially available for the treatment of carcinoid tumors.
While both analogues bind primarily to SSTR-2, SSTR-3, and SSTR-5, the clinical efficacy of each seems related only to binding of SSTR-2.
Though long-acting somatostatin analogues have been shown to be highly effective in reducing NET markers and controlling the symptoms of carcinoid syndrome, tumor regression by radiographic criteria is relatively rare (4%).
However, in a study by Aparacio and colleagues, somatostatin analogue therapy stabilized tumor growth in nearly 60% of patients over a period of 11 months.
Although treatment of patients with carcinoid tumors with daily s.c. injections of standard doses of somatostatin analogues may result in significant symptomatic or subjective responses, the median duration of response to standard somatostatin analogue treatment is 12 months.
The mechanism for this loss of therapeutic effect with repeated dosing of somatostatin analogue in carcinoid patients—also known as tachyphylaxis—is unknown, though many believe the phenomenon represents SSTR downregulation or desensitization as a result of prolonged high-dose somatostatin therapy.
Recent data by Corleto et al. suggest that single, low-dose administration of octreotide may avoid SSTR desensitization.
Systemic Chemotherapeutic Options
Besides somatostatin analogues, common chemotherapeutic options for metastatic carcinoid syndrome include interferon-alpha and cytotoxic agents.
The former has been shown to inhibit protein and hormone synthesis in tumor cells, inhibit angiogenesis, and stimulate the immune system.
Additionally, interferon-alpha has been shown to upregulate the expression of somatostatin receptors and may therefore act synergistically with somatostatin analogues in the treatment of classic carcinoid syndrome.
Cytotoxic agents are typically employed as first-line treatments for malignant gastrointestinal NETs with elevated proliferation indices (Ki-67 antibody >5%–10%).
Traditionally, single-agent cytotoxic treatments have produced limited benefit in patients with NETs, with response rates of <30%.
Therefore, combination therapies—the most common combination of streptozocin, 5-fluorouracil, and doxorubicin elicits a response rate >50% in malignant pancreatic tumors—are commonly used in the treatment algorithms of highly proliferating carcinoid tumors.
Management of Hepatic Metastases
Many studies have shown that liver resection can play an important role in patients with hepatic metastases from the primary carcinoid tumor, and surgical resection may result in symptom relief and prolonged survival.
Though no prospective data exist, retrospective data from Que et al. have demonstrated longer survival in patients with metastatic gastrointestinal carcinoid tumors when >90% of the hepatic metastases were resected.
Landry and colleagues confirmed this trend toward longer survival for patients who underwent surgical resection of hepatic metastases, citing a 5-year survival rate of nearly 75% in these patients.
In patients with hepatic carcinoid metastases who are not candidates for complete surgical resection, several potential therapies—including radiofrequency ablation (RFA) and hepatic chemoembolization—may be offered.
RFA provides a novel approach for those with limited hepatic involvement by using selective thermal coagulation of the tumor to destroy isolated metastases.
In a retrospective study of 73 patients with metastatic foregut or midgut carcinoid tumors or endocrine pancreatic tumors (EPTs), Eriksson and colleagues demonstrated apparently total clearance of liver metastases in 17%, 41%, and 46% of foregut carcinoids, midgut carcinoids, and EPTs, respectively.
Likewise, symptom improvement was noted in 71% of patients with carcinoid syndrome, and 75% also experienced a reduction in their 5-HIAA and CgA levels by at least 50%.
Similarly, though data in hepatic carcinoid metastases are limited to a few case reports and small series, several studies have demonstrated the effectiveness of RFA in the treatment of unresectable hepatocellular carcinomas and hepatic metastases of colon carcinoma.
Hepatic chemoembolization (HCE) may be used in those with unresectable but liver dominant carcinoid disease.
In a report of 20 patients with liver metastases from islet cell tumors of the pancreas or carcinoid tumors, Yao and colleagues demonstrated a significant radiographic response, stabilization of hepatic tumor burden, or improvement in clinical symptoms in 90% of their cohort.
The details of their technique for chemoembolization included cisplatin (10 mg/ml), doxorubicin (3 mg/ml), and mitomycin-C (10 mg/ml) combination therapy with either viscous collagen agent or ethiodol and polyvinyl alcohol particles in suspension.
Factors related to sustained responses for HCE included previous surgical debulking, more than four HCE procedures, and liver metastases 5 cm.
Radiolabeled Somatostatin Analogues
In recent years, several research groups in nuclear medicine and radiopharmacy have sought to develop radiolabeled receptor-binding somatostatin analogues that could act as vehicles to guide radioactivity to SSTR-expressing tissues, such as carcinoid metastases.
The first promising dodecanetetraacetic acid-chelated somatostatin analogue—90Y-1,4,7,10-tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid (DOTA)0,Tyr3, octreotide (90Y-DOTATOC)—employed the use of a radiolabeled somatostatin analogue couple with 90Y, a pure β-emitter.
In a phase II study to evaluate the tumor response of NETs to high-dose targeted irradiation with 90Y-DOTATOC, Waldherr and colleagues demonstrated an objective response rate of 38% in approximately 13 patients with EPTs; likewise, a significant reduction in clinical symptoms was noted in these patients.
More recently, treatment with 177Lu-DOTA0,Tyr3octreotate (177Lu-DOTATATE), a compound with greater SSTR-2 affinity, was shown to effect complete or partial tumor responses in nearly 30% of patients with neuroendocrine disease.
Importantly, 90Y-DOTATOC seems to be more effective in larger tumors whereas 177Lu-DOTATATE effects better tumor responses in smaller lesions; as such, combination therapies using both 90Y-DOTATOC and 177Lu-DOTATATE are currently being explored.
Future Targeted Therapies
It is well known that the growth, differentiation, phenotype, and hormonal expression of carcinoid tumors depend upon a network of cellular signaling cascades.
At this time, several pathways and individual molecules have been implicated in the tumorigenesis of carcinoids and are currently under evaluation.
Novel agents targeting vascular endothelial growth factor (VEGF) and mammalian target of rapamycin have been demonstrated to have promising activity in patients with advanced NETs.
Inhibition of angiogenesis by targeting VEGF is especially promising given the highly vascular nature of NETs.
In our own laboratory, recent data suggest the importance of alternative pathways, which include alterations in Raf-1/mitogen-activated protein kinase–extracellular signal–related kinase (ERK) kinase (MEK)/ERK activation, Notch1 activation, and glycogen synthase kinase-3β inhibition.