Small intestinal “carcinoid” or well-differentiated grade 1 (G1) neuroendocrine tumors (NETs) can have an insidious onset or be diagnosed serendipitously at the time of surgery, during the workup for another disorder, or during a screening test. The absence of carcinoid syndrome symptoms would imply a nonfunctional status, confirmed by a careful history.[1] The presence of nonspecific symptoms such as fatigue and intermittent pain may be disease-related, but their insidious nature usually accounts for misdiagnosis or a delay in diagnosis. When nonspecific symptoms increase in intensity or frequency, and the correct diagnosis is made, symptoms have commonly been present for 5 to 7 years. Early disease confined to lymph nodes may be discovered at the time of appendectomy, cholecystectomy, or a colonoscopy that includes an inspection of the distal ileum.
Initial Evaluation
Management of patients presenting with primary metastatic small intestinal carcinoid tumor without carcinoid syndrome includes a careful patient history to determine the source and duration of presenting symptoms. Identifying factors that provoke or improve symptoms is key in determining whether a patient is truly nonfunctional. A physical examination is useful to detect facial telangiectasia, wheezing, cardiac murmurs, abdominal tenderness, organomegaly, lymphadenopathy, and edema of the lower extremities. Laboratory evaluation includes a complete blood count (CBC); comprehensive metabolic panel (CMP); assessment of chromogranin A levels; and a 5-hydroxyindoleacetic acid (5-HIAA) assay, performed via 24-hour urine collection or plasma measurement using a Z-tube containing stabilizers.[2] Clinical staging is complete with imaging following either “liver protocol” abdominal and pelvic CT scans, or MRI scans and OctreoScan (In111 pentetreotide) as appropriate, if better visualization of small tumors and hepatic masses is necessary. The use of 68Ga-DOTATATE conjugated peptides for positron emission tomography (PET)/CT imaging will replace In111 pentetreotide in the near future.[3] Pathologic staging following either a percutaneous biopsy or surgery is definitive with regard to the diagnosis and prognosis.
Tumor grade and stage are the key predictors of outcome.[4] The majority of well-differentiated intestinal NETs are grade 1, whereas pancreatic NETs are commonly grade 2. Grades can be assessed using the mitotic index or a proliferative marker such as Ki-67 or MIB-1.[5]
Treatment
A G1 metastatic well-differentiated intestinal NET is initially approached based on the clinical circumstances that brought the patient to medical attention. Asymptomatic patients require education about the natural history of the disease, as well as treatment options and prognosis. Control of tumor-related symptoms is central to improving quality and quantity of life. At the time of progression or if the patient presents with 30% to 80% hepatic involvement, antitumor therapy or debulking procedures should be initiated.
The Watch-and-Wait Approach
Asymptomatic patients with less than 20% to 30% hepatic involvement can be considered for observation only. It may be several months to years before systemic therapy is necessary, since clinical assessment (interval history and physical examination, CBC, CMP, and biochemical markers) occurs quarterly and radiographic scans are repeated every 6 months.[5,6] As the disease progresses, patients may develop symptoms related to the overproduction and release of hormonal and vasoactive substances. Patients may experience other tumor-related symptoms independent of amine or peptide oversecretion, including right upper quadrant abdominal pain, weight loss, and fatigue.
Surgery and Radiofrequency Ablation
Following an “R0” surgical resection with involvement of regional lymph nodes, adjuvant therapy is not indicated. Metastatic disease is usually confined to abdominal lymph nodes and/or the liver, although peritoneal and pelvic implants need to be carefully excluded as sites of metastasis. While removal of an asymptomatic primary in patients with metastatic disease is controversial, a retrospective, nonrandomized, single-institution study indicated better progression-free survival (PFS) and overall survival outcomes with primary resection.[7] Thorough patient education about potential symptoms and careful follow-up after surgery are essential. Ideally, surgical debulking is performed electively and accompanied by a cholecystectomy to avoid cholelithiasis/cholecystitis, potential long-term complications of somatostatin analog therapy. Resecting or ablating hepatic disease at the time of a primary resection is potentially associated with greater risks and a longer hospital stay.
Radiotherapy
G1 NETs are generally considered to be refractory to closed-source radiotherapy; however, the experience with open-source radiation is quite different. Peptide receptor radiotherapy (PRRT) using 177Lu-octreotate or 90Y-DOTATATE is effective; it is available in Europe and at select centers in North America for patients whose NETs show significant uptake on the OctreoScan.[8] For somatostatin receptor–negative tumors, 131I-metaiodobenzylguanidine (MIBG) therapy may be an option.[9] Brachytherapy using 90Y microspheres intrahepatically may also be an option if the disease progresses or symptoms worsen.[10]
KEY POINTS
Management of Metastatic Small Intestinal Carcinoid Tumor (Grade 1) Without Carcinoid Syndrome
- A watch-and-wait approach is an initial option for the patient with “low bulk” asymptomatic metastatic grade 1 small intestinal NETs presenting without carcinoid syndrome.
- Serial biochemical measurements (eg, urinary/plasma 5-HIAA and chromogranin A levels) may be useful in assessing efficacy and detecting progression.
- An OctreoScan at the time of diagnosis allows for the evaluation of occult sites that may influence the initial care plan, guide surveillance, and establish whether PRRT is a future therapeutic option.
- Initiation of therapy with somatostatin analogs is recommended prior to surgical procedures (such as an exploratory laparotomy for obstructive intestinal symptoms despite the absence of carcinoid syndrome).
- The assessment of disease bulk is critical in determining if and when a locoregional approach should be combined with systemic therapy.
- At the time of clinical or radiographic progression, targeted therapy should be initiated with somatostatin analogs or mTOR inhibitors, or the patient should be enrolled in a clinical trial evaluating CA4P or pazopanib.
5-HIAA = 5-hydroxyindoleacetic acid; CA4P = combretastatin A4 phosphate (also known as fosbretabulin tromethamine); mTOR = mammalian target of rapamycin; NET = neuroendocrine tumor; PRRT = peptide receptor radiotherapy.
Hepatic Artery Embolization or Chemoembolization
Locoregional therapy is effective in debulking hepatic disease and is usually considered during the course of managing metastatic G1 intestinal NETS. The selection of “bland” embolization or chemoembolization is based on individual center preference, since no head-to-head comparison data are available.[11] When the hepatic disease is diffuse, embolization procedures are generally preferred over 90Y microspheres or radiofrequency ablation. These procedures may also be considered earlier in management, in cases when there is more than 30% but less than 80% hepatic involvement.
Chemotherapy/Targeted Agents
Somatostatin analogs
Octreotide and lanreotide are somatostatin analogs approved for symptom control and tumor control, respectively, in patients with carcinoid syndrome.[12-14] Retrospective studies and clinical trials of these agents have demonstrated both symptom and tumor control in G1 intestinal NETs. In cases of flushing, secretory diarrhea, wheezing, or disease progression, initiating a depot formulation of a somatostatin analog improves symptoms and delays the time to a second progression.[12,14]
Mammalian target of rapamycin (mTOR) inhibitors
The double-blind, randomized, placebo-controlled phase III RADIANT-2 trial, evaluating the mTOR inhibitor everolimus vs placebo in combination with octreotide, did not meet the prespecified statistical significance threshold for its primary endpoint[15]; however, preliminary results from the RADIANT-4 trial focused on everolimus in G1 intestinal NETs did demonstrate significant delay in PFS.[16]
Capecitabine and temozolomide
Cytotoxic chemotherapy is sometimes used in good-performance patients as a late option. Early data from the CAPTEM trial of combination therapy with capecitabine and temozolomide need confirmation in larger trials before this approach can be embraced as a standard of care.[17]
Bisphosphonates/denosumab
A small percentage of G1 intestinal NETs metastasize to the bone as a late manifestation. The indications for prescribing these osteoclast inhibitors are similar to those for other neoplasms and relate to the number and location of metastases.
Telotristat etiprate
5-Hydroxytryptophan inhibitors, such as telotristat etiprate, decrease serotonin blood levels and offer another mechanism to improve quality of life by controlling symptoms refractory to treatment with somatostatin analogs.[18] The pivotal phase III TELESTAR trial (ClinicalTrials.gov identifier NCT01677910) met its primary endpoint. This new class of drugs will become integrated into the standard-of-care management of G1 intestinal NETs. The further lowering of blood serotonin levels may reduce the fibrotic or cicatricial reaction that is common in the heart and mesentery.
Clinical Trials
Current efforts are directed toward enrolling patients with progressive G1 intestinal NETs into clinical trials evaluating fosbretabulin tromethamine (CA4P), a vascular disrupting agent, and pazopanib, an oral tyrosine kinase inhibitor (TKI) used in the treatment of kidney cancer and soft tissue sarcomas.[19,20]
Survival outcomes in patients with G1 intestinal NETs have improved since the introduction of the somatostatin analogs in the mid-1980s.[21] Combining hormonal therapy with locoregional procedures; PRRT; mTOR inhibitors; and, possibly, TKIs that target c-KIT, platelet-derived growth factor, fibroblast growth factor, and vascular endothelial growth factor receptors offers additional therapeutic options to further improve survival rates among patients who initially present with metastatic disease without carcinoid syndrome.
Financial Disclosure:Dr. Lowell receives clinical research support from Lexicon and OxiGene.
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