1 Department of Endocrine Oncology, University Hospital, Uppsala, Sweden; 2 University of South Florida, Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 3 Center for Gastroenterology, Royal Free Hospital, London, UK; 4 II School of Medicine, Ospedale Sant, Andrea, Università degli Studi di Roma La Sapienza, Rome, Italy; 5 Department of Internal Medicine, Section of Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands; 6 Departimento di Patologica e Medicina di Laboratorio, Sezione di Anatomica, Patologica, Universita degli Studi, Panua, Italy; 7 Hospital Beaujon, Service de Gastroenterologie, Clichy, France; 8 Lousiana University, Health Service Center, New Orleans, LA, USA; 9 Medizinische Klinik M.S., Head of Department, Hepatologie und Gastroenterologie, Berlin, Germany
Received 22 December 2003; accepted 27 January 2004
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ABSTRACT |
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Key words: gastroenteropancreatic system, lanreotide, neuroendocrine tumors, octreotide, somatostatin, somatostatin analogs, tumor markers, imaging
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Introduction |
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Critical aspects of the pathology report |
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To do this, several parameters should be assessed, including tumor size, invasion of nearby tissue or wall, invasion beyond the submucosa, angioinvasion, perineural space invasion, solid, organoid structure, presence of necrosis, more than two mitoses per high power field, Ki67 index >2%, loss of chromogranin A (CgA) immunoreactivity, argyrophilia or hormone expression.
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Critical aspects of tumor markers |
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Several radio-immunoassay procedures for analyzing CgA have been developed in recent years and some assays are also commercially available. CgA is a very stable molecule and no special precautions are needed to store the serum or plasma. The levels of CgA are significantly elevated in most types of NETs, but particularly high levels are encountered in classical mid-gut NETs where levels of CgA may be increased 100- to 1000-fold.
Treatment with somatostatin analogs significantly reduces plasma CgA levels, especially in patients with classical mid-gut NETs. This change probably reflects an inhibition of both hormone synthesis and release from the tumor cells rather than a reduction in tumor mass. Therefore, changes in plasma CgA concentrations should be interpreted with care. In cases of progressive disease during treatment with somatostatin analogs, increased plasma levels of CgA may reflect a loss of secretory control and/or tumor growth. Interestingly, in some cases of tumor progression, CgA levels start to increase before changes in tumor size can be detected using computerized tomography (CT) or magnetic resonance imaging (MRI) [3]. Serotonin (5-HT) is an important marker for mid-gut NETs, which appears to be co-stored with CgA in secretory granules in NET cells and released upon stimulation. In contrast to its metabolite, urinary 5-hydroxy indole acetic acid (5-HIAA), determination of plasma levels of 5-HT is not useful in clinical practice.
In patients with pancreatic NETs, measurement of peptide levels is also critical. In cases where unusual symptoms are present or a multiple endocrine neoplasia (MEN) syndrome is suspected, a panel of peptide levels may be helpful. Clearly, if MEN syndromes are suspected these peptide level measurements should include simultaneous measurement of PTH, if the calcium is elevated and pituitary hormones or amines secreted by the adrenals. Suitable assay kits are commercially available or can be obtained from research laboratories.
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Definitions of functional and non-functional digestive NETs |
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Which markers should be used in the clinic? |
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Both CgA and 5-HIAA are important markers for diagnosing mid-gut NETs.
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Imaging modalities commonly used in NETs |
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Surgical considerations |
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Cytoreductive surgery, which includes tumor resection, radiofrequency ablation and cryotherapy, is designed to either remove or destroy tumor in an effort to control clinical symptoms and enhance patient survival. Whenever possible, gross tumors are removed from the primary site and regional lymphatics. For islet cell tumors such as insulinomas, this may require little more than simple enucleation, though for clearly malignant tumors, more aggressive surgical approaches including pancreatoduodenectomy may be warranted. Many patients with NETs receiving cytoreductive procedures on the liver will have been treated with somatostatin analogs, or will be future candidates for long-term somatostatin analog therapy. Since a common side-effect of somatostatin analog therapy is cholelithiasis, whenever a surgical procedure is planned that requires abdominal exploration, a cholecystectomy should be performed in anticipation of somatostatin or embolic therapy.
The goal of cytoreductive surgery is to improve symptoms by controlling peptide/amine excess, to improve the quality of life and extend survival. Partial hepatectomy for metastatic gastrointestinal or pancreatic NETs has proved to be an effective way of controlling symptoms. Recently, a meta-analysis summarizing 26 years of medical literature on cytoreductive procedures on NETs was published [21]. The mean 5-year survival rates in mid-gut NET patients undergoing cytoreduction and in patients with metastatic islet cell tumors following partial hepatectomy were well over 50%. Overall, 5-year survival of patients following orthotopic liver transplantation for metastatic NET was 50% and median survival was 5.1 years. Survival following orthotopic liver transplantation for NETs or conventional cancers was also high.
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Hepatic arterial chemoembolization |
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Symptomatic responses were obtained in most patients, while tumor shrinkage was observed in about half of the patients with progressive disease before chemoembolization.
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The use of interferon treatment in NETs |
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Symptomatic and biochemical responses are seen in 50% of patients, with significant tumor reduction in 1015%. The most severe side-effects are flu-like symptoms and autoimmune phenomena (e.g. thyroiditis).
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The role of chemotherapy in patients with NETs |
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Comments on the roles of chemotherapy in different NETs
Although most NET cells are endodermally derived and possess similar, unique morphology, there appear to be considerable differences in chemosensitivity in relation to primary tumor location. There has been progress in the treatment of some of these rare tumors (e.g. pancreatic NETs), while in others we are continuing to use therapies that have remained unchanged for many years. Exciting developments in the manipulation of the cellular regulation of endocrine secretion may enable us to retard the growth of the malignant cells without the toxicity of chemotherapy. Large-scale cooperative studies are urgently required to evaluate new therapeutic modalities fully. Patients with these rare neoplasms should be entered into prospective clinical trials whenever possible.
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Therapy with somatostatin analogs |
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Since native somatostatin has only limited clinical usefulness due to the need for intravenous administration, the short duration of action (half-life <3 min) and the post-infusion rebound hypersecretion of hormones [24, 25], synthetic somatostatin analogs were developed. Octreotide was the first such analog. Its elimination half-life after subcutaneous administration is 2 h and rebound hypersecretion of hormones does not occur [23]. Somatostatin and its analogs exert their effects through interaction with somatostatin receptor (sst) subtypes 15 (sst1 to sst5). Native somatostatin binds with high affinity to all somatostatin subtypes, whereas octreotide binds with a high affinity to sst2 and with a somewhat lower affinity to the sst3 and sst5 receptors [26]. Other cyclic analogs with very similar affinity and activity profiles, such as lanreotide, have been developed (Table 1) [23].
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Tumors and metastases that bear sst2 or sst5 can be visualized in vivo after injection of radiolabeled octapeptide analogs such as 111In-pentetreotide [OctreoScan® ([111In-DTPA0]octreotide)] and [111In-DOTA0]lanreotide [35, 36]. Radiolabeled octapeptide analogs such as 111In-pentetreotide [90Y-DOTA0,Tyr3]octreotide (OctreoTher®), [177Lu-DOTA0Tyr3]octreotate, [111In-DOTA0]lanreotide and [90Y-DOTA0]lanreotide, can also be used for radiotherapy of sst2- and sst5-positive advanced or metastatic endocrine tumors [3640].
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Practical aspects of octreotide therapy |
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Patients benefiting from treatment with octreotide include those with functional NETs of fore- and mid-gut origin. Glucagonomas, VIPomas and to a lesser extent gastrinomas and metastatic insulinomas are examples of functioning pancreatic endocrine tumors amenable to treatment with octreotide. Selection of patients is based on a positive OctreoScan® or, less frequently, a suppression test where a >50% decrease in peptide/amine levels is seen 12 h after administration of 100 µg octreotide s.c. Other syndromes where octreotide may provide benefit include ectopic adreno-corticotropic hormone (ACTH) secretion with Cushings syndrome, oncogenic osteomalacia, and hypercalcemia due to the secretion of ectopic parathyroid hormone-related peptide.
A more controversial area concerns the treatment of patients with non-functioning endocrine tumors of the GEP system.
Common adverse effects of treatment with somatostatin analogs include nausea, abdominal cramps, loose stools, mild steatorrhea (presumably resulting from transient inhibition of pancreatic exocrine secretion and malabsorption of fat) and flatulence. These symptoms start within hours of the first s.c. injection, are dose-dependent, and usually subside spontaneously within the first few weeks of treatment. There may be local pain and erythema at the injection site. Impaired glucose tolerance or even overt diabetes mellitus (resulting from transient inhibition of insulin secretion) have also been observed during therapy with somatostatin analogs [23]. A very rare side-effect is gastric atony [41]. Because of these adverse events, administration of the IR formulation is recommended before the administration of the intramuscular depot formulation.
The risk of developing gallstones and/or gallbladder sludge in patients with metastatic gut NETs or malignant islet cell tumors undergoing therapy with somatostatin analogs approaches 50% [42]. The prevalence of somatostatin analogue-induced gallstones in acromegalic patients varies geographically and may be influenced by dietary, environmental or racial factors. The formation of gallstones during somatostatin analogue therapy probably involves inhibition of gallbladder contraction and emptying, inhibition of the secretion of cholecystokinin, and increased intestinal and biliary production of deoxycholic acid. It has been suggested that gallstone development in patients receiving somatostatin analogs for metastatic gastrointestinal or pancreatic NETs is dose-dependent. Despite the high incidence of new gallstones in patients receiving somatostatin analogs, only 1% of patients develop acute symptoms requiring cholecystectomy.
In patients with metastatic gut NETs or malignant islet cell tumors undergoing somatostatin analogue therapy, cholecystectomy should be performed if the patient is undergoing surgery for bowel resection or cytoreductive surgery.
When should somatostatin analog treatment be started?
There are accepted as well as more controversial indications for beginning somatostatin analog therapy. The accepted indications for the use of a somatostatin analog include: patients with peptide-/amine-induced syndromes with clinical symptoms, and patients with progression of metastatic disease even without a syndrome. The peri-operative use of somatostatin analogs is critical in the prevention of carcinoid crisis. More controversial indications include: use after debulking procedures such as surgical, radiofrequency ablation or embolization; adjuvant treatment with octreotide in patients who have no evidence of residual disease; and an asymptomatic patient at the time of diagnosis of metastatic disease.
How should octreotide be prescribed for optimal symptom control?
The optimum approach for using this drug is to initiate therapy in the form of s.c. injections of the IR formulation for 37 days to test for tolerability before giving the LAR formulation i.m. The s.c. injections should be continued for 14 days after the LAR injection since therapeutic levels are not achieved until that time. It is important to emphasize to the patient that the IR octreotide should be used for breakthrough symptoms after the start of LAR treatment. The use of this as rescue medication is vital to optimize control of the symptoms.
The initial dose of IR octreotide may range from 100 to 500 µg s.c., two to four times daily. A reasonable starting dose is 150 µg s.c. three times daily (t.i.d.). Some investigators prefer continuous s.c. infusion of octreotide by pump at a dose of 10002000 µg daily. The dose of IR octreotide may be escalated until maximum control of symptoms is achieved by doubling the dose at 3- or 4-day intervals.
The majority of patients will prefer the convenience of once monthly injections with the LAR formulation. Most new patients are initially treated with the 20 mg dose of LAR. There is little if any role for 10 mg LAR in NET patients. As a general rule, if the total IR dose is 200600 µg/day, LAR 20 mg should be tried, and if total IR dose is 7501500 µg/day, LAR 30 mg should be tried. The LAR doses range from 20 to 60 mg every 28 days.
Supplementary administration with the IR form of octreotide in patients escaping anti-secretory response is often required during long-term treatment with LAR. If it is necessary to give the patient rescue doses of IR octreotide three or four times per week, increase the LAR dose to 30 mg/4 weeks, or reduce the interval between administrations of the depot formulation (e.g. 20 mg every 3 weeks). Furthermore, the temporal occurrence of hypersecretion during the 4-week dosing interval should be considered. For example, if the rescue s.c. therapy is required during the week before the next injection of LAR, then a reduction of the dosing interval by 1 week is advisable. On the other hand, if the need for rescue medication occurs sporadically throughout the month then increasing the dose stepwise by 10 mg/month up to 60 mg/month should be tried. Doses of LAR >60 mg/month are rarely of added value. At this juncture one could consider resuming s.c. injection, switching to a continuous infusion pump or adding a new agent.
The duration of therapy with octreotide is usually lifelong unless unmanageable side-effects occur or there is a total loss of symptom control.
How should a patient on somatostatin analog therapy be followed?
A complete history and physical examination should be performed every 3 months. The patient should be examined using conventional imaging studies (CT/MRI or ultrasonography) every 6 months. Patients with progressive disease should be scanned before therapy and every 3 months until stability is seen for two consecutive scans.
Annual OctreoScans® are controversial, but they may be indicated when new symptoms appear. Biochemical parameters (tumor markers) are repeated every 36 months. For gastrointestinal NET patients, this includes CgA and a 24-h urine collection for determination of 5-HIAA. For pancreatic NETs, the predominant peptide should be measured every 36 months. It is of note that patients with non-functional gastrointestinal as well as pancreatic NET tumors may develop functional hormone secretion during tumor progression.
Responses to octreotide therapy are defined according to three categories: symptomatic, biochemical and objective (radiologic). Symptomatic responses are reductions in hypersecretion-related/hormonally mediated symptoms such as diarrhea or hypoglycemia, and in non-functional NETs they are reduction in tumor bulk-related symptoms such as upper abdominal pain, and improvement in quality of life or performance status. Biochemical responses are defined as a 50% decrease in tumor (serum/urine) markers. The importance of biochemical responses is controversial, but an early and dramatic reduction in markers may portend a more durable response to octreotide [43]. Objective responses according to World Health Organization and RECIST (response evaluation criteria in solid tumors) criteria are rare with octreotide. However, in about one-third of the patients who show progressive disease before somatostatin analog therapy, stable disease is observed after initiation of treatment [44].
What is the role of SRS in the follow-up of patients with NETs?
In contrast to sectioning imaging procedures (e.g. CT, ultrasound and MRI), SRS may show early evidence, based on the whole body scan, of additional lesions not revealed by other procedures. SRS may also provide evidence of a local biological response versus an anatomical response, e.g. necrosis. Thus, the loss of the SRS signal in a given lesion as well as the detection of additional lesions in other organs missed using conventional imaging procedures may affect therapeutic management.
To obtain optimal SRS scans, treatment with octreotide should be interrupted in patients on chronic therapy. For patients treated with s.c. IR octreotide, treatment should be stopped for 24 h before the scan. It can be restarted 46 h after the OctreoScan® injection without interfering with the quality of the images. For patients treated with the LAR formulation, the scan should be performed just before next LAR administration. However, in patients with severe functional symptoms, data from several centers suggest that maintenance of somatostatin therapy does not influence SRS results.
What is the role of octreotide in patients receiving radiolabeled somatostatin therapy?
As with SRS, therapy with unlabeled octreotide should be stopped before the administration of radiolabeled somatostatin analogs. Theoretically, occupation of the binding sites for somatostatin prevents the receptor sites from being occupied when the radionuclide/peptide combination is administered. We recommend stopping the IR form of octreotide for 24 h before radiotherapy. For patients receiving the depot formulations of octreotide, treatment should be interrupted >2 months before radiotherapy. In this situation, the patient can switch to the IR formulation.
How should octreotide be administered during invasive procedures?
The use of octreotide before invasive procedures is important to prevent carcinoid crisis. In patients in whom symptoms are well controlled by LAR 20/30 mg, a supplementary bolus dose of 250500 µg octreotide should be given s.c. within 12 h before the procedure. For emergency surgery in therapy-naïve patients with functional NETs, a 5001000 µg i.v. bolus of octreotide or 500 µg s.c. should be given 12 h before the procedure.
The recommended intra-operative use of octreotide for carcinoid crisis with hypotension is bolus i.v. doses of 5001000 µg, with treatment repetition at 5-min intervals until control of symptoms is achieved. Alternatively, following an i.v. bolus dose, continuous i.v. infusion of octreotide at a dose of 50200 µg/h may be given. In any patient who has required supplemental dosing during a procedure, the post-operative dose would be 50200 µg/h for 24 h, followed by resumption of the preoperative treatment schedule.
Do patients with NETs develop drug resistance?
Resistance to octreotide in terms of symptom control and/or tumor growth can be defined in several ways: (i) primary absolute failure to achieve symptomatic and/or tumor growth control in spite of dose escalations; (ii) secondary failure of response to dose escalations after initial control of symptoms and/or tumor growth; and (iii) in spite of excellent symptom control of functional symptoms, an increase in tumor size or tumor markers. In the latter case, additional treatment options such as hepatic arterial chemoembolization or local thermal ablation of hepatic metastases may be considered. During these procedures octreotide therapy should be continued for symptom control. Also, the addition of interferon or even chemotherapy could be considered. Most importantly, consideration should be given to referring the patient for participation in experimental protocols.
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The use of octreotide as therapy for paraneoplastic syndromes |
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Are there alternative treatments when octreotide therapy fails? |
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Due to its potent anti-secretory actions, octreotide is one of the few oncologic drugs that is continued in the face of tumor progression. Furthermore, it may be used with other modalities without additional toxicity.
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FOOTNOTES |
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