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Abstract
PRACTICE GUIDELINE SERIES Consensus recommendations for the diagnosis and management of well- differentiated gastroenterohepatic neuroendocrine tumours: a revised statement from a Canadian National Expert Group † ‡ W. Kocha MD,* J. Maroun MD, H. Kennecke MD, § || # C. Law MD, P. Metrakos MD, J.F. Ouellet MD, § ‡ R. Reid MD,** C. Rowsell MD, A. Shah MD, †† ‡‡ S. Singh MD MPH, S. Van Uum MD PhD, and §§ R. Wong MD well-differentiated gastroenterohepatic net s; treat- ABSTRACT ment and management of other ten s will be discussed Well-differentiated neuroendocrine tumours (net s— in a subsequent paper. previously called “carcinoid tumours”) are relatively In Canada, gastroenterohepatic n e t s represent rare tumours originating from the diffuse neuroen- less than 0.25% of oncology cases . Because of docrine system; they are found most often in the the relative rarity of these tumours, diagnostic and bronchial or gastrointestinal systems. In Canada, therapeutic approaches vary and are often based on gastroenterohepatic ten s represent less than 0.25% of individual physician experience. In recent years, a oncology cases. Because of the relative rarity of these number of European and North American groups have tumours, diagnostic and therapeutic approaches vary developed consensus guidelines for the diagnosis and are often based on individual physician experi- and management of well-differentiated gastroentero- 5–9 ence. A number of European and North American hepatic net s , and in 2006, Canadian consensus groups have developed consensus guidelines for the guidelines were published by a Canadian net expert diagnosis and management of well-differentiated group . The updated and expanded current Canadian gastroenterohepatic n e t s, and in 2006, Canadian guidelines are based on the consensus meeting held consensus guidelines were published by a Canadian at the European Neuroendocrine Tumour Society expert group. The updated and expanded current Ca- (enets ) meeting in Paris, France, in April 2008 and nadian guidelines are based on a consensus meeting are based on the most current literature. held in Paris, France, in 2008 and are based on the most current literature. 2. CONSENSUS PROCESS KEY WORDS Panel members included oncologists, surgeons, ra- diologists, and pathologists. The recommendations Carcinoid tumour, carcinoid syndrome, carcinoid arrived at represent evidence from the published heart disease, neuroendocrine tumours, guidelines, literature and the collective experience of the authors. clinical management, diagnosis, surgery Table i describes the criteria used to rate level of consensus. All recommendations in this document 1. INTRODUCTION fall into Category 2A, with the exception of the rec- ommendation for octreotide as an antiproliferative Well-differentiated neuroendocrine tumours (net s— agent, which falls into Category 1. previously called “carcinoid tumours”) are relatively rare tumours originating from the diffuse neu- 3. EPIDEMIOLOGY roendocrine system. They are found most often in the bronchial or gastrointestinal systems , with the The reported incidence of gastroenterohepatic net s gastrointestinal tract accounting for about two thirds, varies between 2.5 and 4.5 cases per 100,000 popu- 3,10 most of which originate in the small intestine (41.8%), lation in the United States . A trend toward rising rectum (27.4%), and stomach (8.7%) . The present incidence has been seen in recent years. For ex- article focuses on the treatment and management of ample, in Ontario, the incidence has risen from 2 per Copyright © 2010 Multimed Inc. Current On COl Ogy —VOlume 17, number 3 KOCHA et al. million population in 1964 to 22 per million in 2002 noting differences in biochemical and histochemical (Figure 1). Similar trends have been observed in the properties between tumours that originated in differ- 3,12 17 United States . Factors that have been hypothesized ent sites . The utility of this classifi cation was lim- to possibly account for this rising incidence are in- ited, because it did not further characterize tumours creased clinical awareness; more thorough pathologic based on their histologic appearance, prognosis, or evaluation, including the use of immunostaining clinical behaviour. for specifi c molecular markers related to net s [for The 1980 World Health Organisation ( w h o ) example, synaptophysin, chromogranin A (CgA)]; classifi cation scheme broadly applied the term “car- and the widespread use of proton pump inhibitors . cinoid” to tumours of the diffuse neuroendocrine Ongoing research and data collection will be impor- system, but subdivided them on the basis of granule- tant to clarify this potential change in incidence and staining techniques into enterochromaffi n-cell carci- to better understand potential causative factors. noids, gastrin-cell carcinoids, and other carcinoids. The appearance of these net s at the same time as With increasing use of newer diagnostic techniques, other malignancies (such as adenocarcinomas) has including biochemistry, immunohistochemistry, and 14–16 also been demonstrated . molecular biology, it has become apparent that this classi fication also does not adequately re flect the 4. PATHOLOGY AND CLASSIFICATION histopathologic diversity, functional behaviour, and prognosis of these tumours . 4.1 Classifi cation The most recent classifi cation system devised by the ohw emphasizes a prognosis-oriented de n fi ition Early net classifi cation systems focused primarily of gastroenterohepatic net s regardless of anatomic on embryologic origin (foregut, midgut, hindgut), site of origin: ● Well-differentiated net s able t i Categories of consensus ● Benign ● Uncertain malignant potential Category 1 Uniform consensus based on high-level evidence ● Well-differentiated neuroendocrine carcinomas that the recommendation is appropriate. ● Poorly-differentiated neuroendocrine carcinomas Category 2A Uniform consensus based on lower-level evidence, including clinical experience, that the Well-differentiated n e t s are often considered the recommendation is appropriate. “classical carcinoid” net and demonstrate a trabe- Category 2B Non-uniform consensus, but no major cular, insular, or ribbon-like architecture; minimal disagreement, based on lower-level evidence, cellular pleomorphism; and sparse mitotic activ- including clinical experience, that the ity. Well-differentiated neuroendocrine carcinomas recommendation is appropriate. (sometimes called “malignant carcinoids”) have Category 3 Major disagreement that the increased cellular pleomorphism and mitotic activ- recommendation is appropriate. ity, and may have punctate necrosis. Tumours with well-differentiated histologic features, but also more aggressive pathologic features such as angioinva- sion, also fall into this second category. Poorly dif- ferentiated neuroendocrine carcinomas show marked cellular pleomorphism, fields of necrosis, and brisk mitotic activity, and can be histopathologically similar to small-cell lung carcinoma. 4.2 Staging The checklists of the American Joint Committee on Cancer ( a J c c ) and the College of American Pathologists have not previously included nets of 20,21 the gastrointestinal tract . However, the aJcc included a n e t s classi fication in its latest itera- tion, released in late 2009 . Before that, enets proposed tumour, node, metastasis (TNM) staging and grading systems for foregut and midgut/hindgut 1,23 net s . The TNM stage is individualized by site, eigurf 1 Incidence of well-differentiated neuroendocrine tumours with separate classifi cations for gastric, duodenal (“carcinoid tumours”) in Ontario, 1964–2002 . Age-adjusted and proximal jejunal, pancreatic, distal jejunal and rates standardized to 1991 (rate per million population), by year of diagnosis. ileal, appendiceal, and colorectal tumours. This Current OnCOlOgy —VOlume 17, number 3 CANADIAN NET RECOMMENDATIONS proposed grading system includes proliferative image analysis may help to reduce inter-observer markers such as mitotic count and Ki-67 index. variability in Ki-67 assessment , but more research Prospective validation of this system is underway. is required in this area. Problematically, the two systems do not agree in It should be noted that, to ensure accurate Ki-67 terminology and classification. results, adequate biopsy material is required; a pa- thologist should be consulted before biopsy to ensure 4.3 Specimen Collection, Handling, and Analysis that an adequate sample is obtained. 4.3.1 Biopsy Specimens 4.4.1 Ki-67 as a Predictive and Prognostic Marker Biopsy specimens (needle core biopsies, endoscopic Although Ki-67 is frequently used to subclassify biopsies) of suspected net s should be immediately these tumours, there are no well-established, vali- placed in formalin for proper fixation and processed dated cut-off points. In the most recent TNM clas- according to routine laboratory protocols for small bi- sification of foregut net s, 3 groups are suggested: opsies. Currently, formalin-fixed paraffin-embedded ≤ 2%, 3%–20%, and >20%. Other authors suggest tissue for routine microscopic examination and im- that a level of ≥ 5% be considered indicative of munohistochemical staining are adequate to provide higher-proliferating tumours more likely to benefit diagnostic and prognostic information. from chemotherapy; other treatments—somatostatin analogs ( s s a s), interferon, and potentially, mam- 4.3.2 Resection Specimens malian target of rapamycin (mort ) inhibitors and Gross assessment of large resection specimens should anti-angiogenic therapy—are considered for tumours focus on the provision of prognostic information. with Ki-67 below 5% . Specimens should be properly fixed in formalin to Tumour heterogeneity and changes in prolifera- ensure good histologic detail and reliable immuno- tion between primary and metastatic sites may sig- histochemical staining. The following elements are nificantly alter the Ki-67 index and limit its utility. recommended for inclusion in pathology reports for The Ki-67 index should be used only as a guide; the well-differentiated net s : prognostic and predictive value of Ki-67 needs to be established in a prospective manner. The recent ● Tumour site publication on pathology reporting of nets indicated ● Histologic type (who classification) considerable disparity between the European and the ● Local tumour growth (T stage, size and involve- U.S. recommendations for Ki-67 reporting. The latter ment of adjacent organs) group felt that Ki-67 is not always necessary (reflect- ● Margins (proximal, distal, radial) ing current practice and capabilities). In the Canadian ● Lymphatic and vascular invasion context, it is recommended that the Ki-67 index (and ● Necrosis (focal or zonal) number of mitoses per 10 fph ) be consistently reported ● Lymph nodes (number with metastases/overall until further data clarify or resolve the contention. number examined) The clinical behaviour of the tumour should always ● Mitotic rate [per 10 high-power fields ( hpf )] be considered the guiding factor when choosing a ● Ki-67 index management strategy. ● Any other histochemical or immunohistochemical stains performed and the results 4.5 Other Immunohistochemical Stains ● A minimum data set for pathology reporting of nets has also recently been published . The typical architectural and cytologic features of net s are usually recognized on routine hematoxylin 4.4 Ki-67 Index and eosin preparations, but immunohistochemical stains can be useful adjuncts in confirming the neu- The Ki-67 index, a widely used marker for cell pro- roendocrine nature of a tumour, particularly in the liferation, is essential for the management of net s. setting of poor histologic differentiation. Commonly Among the commercial antibody tests available, used antibodies include cytosolic (neuron-specific the MIB-1 antibody is recommended by enets . enolase), small vesicle (synaptophysin), secretory The usefulness of Ki-67 stems from the fact that granule (CgA), and cell membrane (neural cell adhe- this protein is present and detectable in the nucleus sion molecule, CD56) markers. during all active phases of the cell cycle, but that it is absent from resting cells . As a guide to medical 4.6 Recommendations treatment of net s , Ki-67 is regarded as a prog- nostic factor for survival and a surrogate marker of Use of the 2007 who classification system is recom- biologic behaviour . mended to ensure consistency in nomenclature. It is recommended that the Ki-67 index be deter- Known or possible features of prognostic signifi- mined in 2000 tumour cells within areas of highest cance should be routinely reported as outlined earlier. 1,24 observed nuclear labelling . Computer-assisted The proposed TNM staging and grading system Current On COl Ogy —VOlume 17, number 3 KOCHA et al. proposed by enets may be used, with the caveat that Excess serotonin [metabolized to 5-hydroxy- this system still requires prospective validation. indoleacetic acid (5-hiaa )] appears to be the major 32,33 At high-volume centres, review of pathologic contributor to carcinoid syndrome . Carcinoid specimens is encouraged to maximize consistency syndrome arises primarily in the setting of hepatic in reporting and to ensure proper management. The metastases or because of primary lesions with direct College of American Pathologists provides a check- drainage into the systemic as opposed to the portal list online . circulation (primary ovarian net s, for instance). The severity of carcinoid syndrome may correlate with 5. CLINICAL MANIFESTATIONS urinary 5-hiaa levels . The clinical manifestations of gastroenterohepatic 5.2 Non-functional Tumours ten s can overlap with a number of benign conditions, potentially leading to significant delays in diagnosis. Local growth and metastasis—and also mesenteric Primary intestinal lesions may present asymptomati- fibrosis—may lead to abdominal discomfort, bowel 6,34 cally, with nonspecic fi abdominal complaints, or with obstruction, and diarrhea . However, in many symptoms related to mass effect or partial intestinal cases, non-functional tumours are asymptomatic, obstruction. Symptoms also depend on whether a and because they are slow-growing, they may go ten secretes biologically active hormones (serotonin, undetected until they have progressed to advanced vasoactive intestinal peptide, or gastrin, for instance) disease. Indeed, they are often found incidentally dur- 2,6,8,29 or whether it is non-functional . Owing to the ing surgery, and their neuroendocrine origin may be relatively slow-growing nature of many net s, and to recognized only after histologic examination. Some the nonspecic fi symptomatologies caused by hormone patients with these tumours should remain under overproduction, alternative diagnoses such as irritable watchful observation, because they may progress to bowel syndrome, colitis, menopause, and asthma are more aggressive disease that requires therapy. often reached in error because of a failure to consider a diagnosis of net . Primary care physicians should 6. BIOCHEMICAL MARKERS consider the possibility of ten in the appropriate clini- cal settings so that early diagnosis of these tumours The detection of substances specific for particular is not missed. types of net s can facilitate a more exact diagnosis and permit earlier detection, which may contribute to 5.1 Functional Tumours improved control of syndromes related to hormone oversecretion, such as carcinoid heart disease . Two Clinical suspicion of a functional net is commonly biochemical products that can be measured and used raised because of symptomatic manifestations of to aid in diagnosis and surveillance of well-differen- excess hormone production. The most frequently tiated gastroenterohepatic net s are 5-hiaa and CgA. observed is the carcinoid syndrome caused by high levels of circulating serotonin. Table ii presents 6.1 5-HIAA manifestations of the carcinoid syndrome, which can include facial u fl shing, diarrhea, and bronchoconstric- Serotonin released by functional tumours is metabo- 6,30–32 tion . Right-sided heart failure may be present lized by monoamine oxidases to 5-hiaa in the liver, at the time of diagnosis in long-standing carcinoid lungs, and brain. When measured in a 24-hour urine 6,30–32 syndrome . Flushing can be provoked by certain collection, 5-aaih has a sensitivity of 73% and a speci- drugs, some foods (for example, nuts and cheese), ficity of 100% for diagnosing well-differentiated func- 32 35 and alcohol . tional gastroenterohepatic net s . Levels of 5-hiaa may not be elevated in non-functional tumours. The 24-hour urinary 5- h i a a test is a part of able t ii Clinical manifestations of carcinoid syndrome standard testing for these tumours and is also highly sensitive for diagnosing and monitoring treatment of Clinical presentation Rate (%) Examples the carcinoid syndrome . Compared with patients having normal uri- Vasomotor symptoms 90 Facial flushing, telangiectasia, nary 5- h i a a levels, patients with elevated levels, chronic facial cyanosis, rhinitis whether symptomatic or not, tend to have a poorer 36–38 Increased intestinal 80 Diarrhea, borborygmia, prognosis . The severity of carcinoid syndrome motility abdominal pain symptomatology correlates with the level of 5-hiaa elevation. There is also evidence that long-standing Heart failure 40 Endocardial fibrosis, tricuspid insufficiency, significant elevations in 5- hiaa may be associated 39–42 pulmonary stenosis with carcinoid heart disease . Levels of 5-hiaa can also be used to assess bio- Bronchoconstriction 15 Asthma chemical response to ass s, with a 50% reduction from Current On COl Ogy —VOlume 17, number 3 CANADIAN NET RECOMMENDATIONS pretreatment levels and control of symptoms being marker because, unlike 5-aaih , CgA may be expressed indicative of response. However, because flushing by functional and non-functional tumours alike. is mediated by different hormones in foregut and The sensitivity of CgA for net s has been found 43,44,47 midgut tumours, some patients with a net will have to be 62.9%, and the specificity, 98.4% . Lev- symptoms of flushing with low or normal levels of els of CgA are elevated in 85%–100% of patients 43,44 5-hiaa . Although symptoms may be controlled with well-differentiated gastroenterohepatic n e t s, without normalizing urinary 5-hiaa , elevated 5-hiaa regardless of whether the tumour is functional or non- 48,49 has been associated with progression of carcinoid functional . In classical midgut net s, CgA levels 48,49 heart disease; it is therefore important to try to normal- are elevated to 100–1000 times normal . Serial ize this value . Some patients with elevated 5-hiaa CgA evaluations may be helpful in the monitoring of may be asymptomatic; the role of ssa s in this group both functional and non-functional net s either being of patients is controversial. observed or on therapy. The normal range for urinary 5- h i a a i s Table iv lists factors that may cause false eleva- 3–15 mg/24 h, but this figure may vary depending tions in CgA. on the laboratory. Practical challenges associated with 5-aaih testing include the inconvenience of collecting 6.3 Recommendations a 24-hour urine sample, and the fact that readings may be affected by certain foods and drugs (Table iii ). At diagnosis, 5-hiaa and CgA should be measured in all patients. 6.2 CgA In asymptomatic patients who have undergone complete resection and show no signs of disease, CgA Chromogranin A is found in the wall of secretory should be evaluated as part of annual surveillance. granules and is co-released with hormones. Chro- In patients with active functional disease, 5-hiaa mogranins are precursors of various biologically and CgA should be used to monitor treatment, to active peptides, and they may play a role in the pro- follow changes in symptomatology, to evaluate for gression and metastasis of net s . Measurement of tumour growth, and so on. circulating CgA is particularly useful as a biochemical 7. DIAGNOSTIC IMAGING able t iii Foods and drugs affecting 24-hour urinary 5-hydroxyin- 9,45,46 doleacetic acid Radiographic and nuclear imaging play an important role in the diagnosis and management of gastroen- Potentially causes terohepatic net s. False-positive results False-negative results 7.1 Conventional Imaging Drugs Acetaminophen Acetylsalicylic acid Ultrasonography, computed tomography ( c t ) im- aging, and magnetic resonance imaging (mri ) can Caffeine Adrenocorticotropic hormone be used for determining the anatomic location and Fluorouracil extent of tumours, and for monitoring response Levodopa Methysergide to treatment. Methyldopa Naproxen Phenothiazines Non-prescription serotonin 7.1.1 CT Ethyl alcohol Diazepam Triphasic ct of the liver at diagnosis should be Imipramine considered a standard component of the diagnostic Ephedrine imaging of net s, because the liver is the most com- Isoniazid Glycerol guaiacolate mon site of metastatic involvement and because of Monoamine oxidase Nicotine the wide availability of this diagnostic modality. inhibitors Phenobarbital Triphasic ct can also be used to evaluate tumours Tricyclic antidepressants before radiofrequency ablation and hepatic arterial Foods Avocado embolization, and it should be routinely used in the preoperative evaluation of potentially resectable Bananas Eggplant able t iv Factors causing false elevations in chromogranin A Pineapple Plums Inflammatory conditions Walnuts Renal insufficiency Plantain Type A gastritis Tomato Treatment with proton pump inhibitors Current On COl Ogy —VOlume 17, number 3 KOCHA et al. primary or metastatic lesions. Sequential evaluation 4–6 hours after the scan without interfering with the can assist in monitoring disease status in response to quality of the images. For patients treated with the therapy or in the surveillance setting. long-acting release (ral ) formulation, the scan should be performed just before the next lar administra- 7.1.2 Ultrasonography tion. However, in patients with severe functional Most guidelines for the diagnosis and management symptoms, data from several centres and the present of net s recommend the inclusion of ultrasonography group’s experience suggest that, in such situations, in the range of imaging modalities used to detect and somatostatin therapy can be maintained . 6,9 monitor ten s . This technique may serve as an adjunct to tc imaging in certain clinical situations—such as as- 7.2.2 MIBG Scintigraphy sessing tumour volume before radiofrequency ablation Meta-iodobenzylguanidine concentrates in gastro- 123 131 and hepatic arterial embolization, and differentiating enterohepatic net s, and I- or I-labelled mibg lesions with uncertain ct imaging characteristics. can be useful for staging, monitoring, and conduct- ing preoperative evaluations, particularly in cases 7.1.3 MRI in which an In-pentetreotide scan is negative or In detecting ten s of the pancreas, irm has a sensitivity unhelpful . Radiolabelled gbim testing may also be 50,51 of 74%–100% . The technique is not routinely useful for identifying patients that may be candidates recommended in gastroenterohepatic net s, although for radiolabelled mibg therapy (discussed later in 56,58–60 it can be used to characterize hepatic lesions before this article) . surgery if the diagnosis is not clear, and in general, To minimize the risk of false-negative scans, it it may be useful if ct or ultrasonography results are is important to ensure an adequate dose of I- or coni fl cting or unhelpful. Magnetic resonance imaging I-labelled gbim . Patients should also be questioned may also be used in particular cases when ct may be carefully about prescription and recreational drug contraindicated or less sensitive for disease detection; use; false-negative scans from interference with gbim in patients having contrast allergies or hepatic steato- uptake can be caused by the beta-blocker labetalol sis; and in consideration of possible liver resection or and by cocaine. tumour-debulking surgeries. About 10% of patients with a negative In- pentetreotide scintigraphy result have a positive gbim 7.2 Other Imaging Modalities scan. The latter technique is therefore recommended if In-pentetreotide scintigraphy is negative or if the 111 131 Other modalities—specifically, In-pentetreotide patient is a candidate for mibg I therapy. scintigraphy and meta-iodobenzylguanidine (mibg ) scintigraphy—are important for identifying and staging 7.2.3 PET tumours. Positron-emission tomography ( t e p ) imaging Imaging by pet is not routinely recommended for currently has a limited role in net management. net s because of the inherently low metabolic activ- ity of well-differentiated tumours, but it may be 7.2.1 In-Pentetreotide Scintigraphy used in cases in which other imaging techniques are 111 56,60,61 Scintigraphy using In-pentetreotide is the most contradictory or unhelpful . As neuroendocrine- important imaging investigation for identifying and specific markers become available, pet imaging has staging gastroenterohepatic net s. An In-labelled the potential to become a much more sensitive tech- s s a , pentetreotide, which shares the somatostatin nique. Indeed, a recent European study found that F- receptor–binding profile of octreotide, concentrates l -dihydroxyphenylalanine pet compared favourably in tumours with somatostatin receptor subtypes 2 with conventional imaging ; however, the utility of and 5, the subtypes most frequently expressed in this the technique is currently limited because of lack of tumour type . availability in Canada. Scintigraphy using In-pentetreotide can detect octreotide-avid lesions throughout the body, and 7.3 Recommendations therefore can assist in disease staging, preoperative evaluation, surveillance, and monitoring response to Baseline scanning at diagnosis should include one 52 111 therapeutic intervention . Available data also suggest or more of triphasic ct imaging of the liver, In- that somatostatin-avid disease on scintigraphy may pentetreotide scintigraphy, and mibg scintigraphy. imply a preferential benefit in disease control with Imaging modalities for postoperative evaluation or therapeutic doses of octreotide (discussed later in this for disease status monitoring in the metastatic setting 53–56 article), although long-term data are lacking . should include the most sensitive imaging modality It is generally suggested that octreotide therapy determined at diagnosis. Because of the highly vari- should be interrupted before scintigraphy. For pa- able clinical presentation of net s, and because of the tients treated with subcutaneous immediate-release individualization of therapeutic interventions, imaging ( i r ) octreotide, treatment should be stopped for intervals and modalities may both vary depending on 24 hours before the scan. Injections can be restarted the goals of care and the intensity of therapy. Current On COl Ogy —VOlume 17, number 3 CANADIAN NET RECOMMENDATIONS 8. ALGORITHM 9. SURGICAL MANAGEMENT The main goals of net management are increased Surgical management of gastroenterohepatic n e t s survival, symptom control, biochemical control (that can be performed with curative or palliative intent. is, lowering or even normalizing of 5-hiaa levels), Even in the setting of metastatic disease, most patients objective tumour control, and improvement in qual- benefit from primary tumour resection or tumour deb- ity of life. Figure 2 shows a suggested algorithm for ulking. In limited or locoregional disease, surgery has management in the Canadian context. curative potential and has also been found to improve figure 2 Suggested management algorithm for well-differentiated gastroenterohepatic neuroendocrine tumours. ned = no evidence of disease; ssa s = somatostatin analogs; a rf = radiofrequency ablation. Current On COl Ogy —VOlume 17, number 3 KOCHA et al. 26,48,63,64 survival for patients with metastatic disease . 9.2 Palliative Surgery As well, because of the intense mesenteric fibrotic changes elicited by primary lesions within the gastro- For patients with net s of the gastrointestinal tract in intestinal tract, primary disease resection will reduce whom complete resection is not possible, cytoreduc- or eliminate the risk of progressive symptomatology tive resection should be considered. The goals of from incomplete or complete bowel obstruction. Early non-curative surgery include stabilization or improve- intervention may also maximize the chance of suc- ment of symptoms and lowering or normalization of cessful surgery and reduce technical complications 5-hiaa levels. Palliative surgery in the appropriate from progressive fibrosis. If technically feasible, the clinical context can reduce tumour bulk, prevent or primary tumour should be removed by segmental delay complications from local or distant disease, and 2,26 resection, including lymphadenectomy. reduce 5-hiaa levels . A prophylactic cholecystectomy should be con- The rationale for palliative surgical intervention sidered in every patient undergoing surgery for net s derives from the fact that net s of the gastrointestinal of the digestive tract. This procedure mitigates the tract are usually slow-growing, and patients may biliary toxicity of ssa therapy and avoids chemical experience prolonged survival even with metastatic cholecystitis if transcatheter arterial chemoemboliza- disease. A meta-analysis of cytoreductive partial he- 48,65,66 tion (ace t ) is performed in the future . patectomy in patients with malignant ten s observed a Good communication between surgical and an- 5-year survival rate of 71% and complete resolution of esthesia teams is important to ensure that octreotide carcinoid syndrome symptoms lasting 4–120 months is administered perioperatively and intraoperatively. in 86% of cases . Intraoperative carcinoid crisis is a rare but serious Cytoreductive surgery can consist of a combina- aggravation of symptoms that can be provoked by tion of multiple techniques, such as hepatectomy, surgery or anesthesia in patients with functional tu- local ablative therapies (radiofrequency ablation, mours . Preoperative ass administration is required cryotherapy, or microwave therapy), intra-abdominal in cases of functional net s. In patients whose symp- organ resection, and bypass procedures . Patients toms are well controlled with a long-acting ssa , a considered for cytoreductive surgery should be as- supplemental dose of short-acting octreotide should sessed by a multidisciplinary team that includes both be given 1–2 hours before surgery, and in some cases, medical and surgical oncologic expertise to ensure an intraoperative intravenous (IV) infusion should coordination of care and exploration of case-specific be considered (bolus IV doses of 500–1000 μg, palliative options. repeated every 5 minutes until symptom control is Hepatic arterial embolization, with or without achieved) . Intraoperative signs and symptoms can chemotherapy, represents a further cytoreductive include refractory hypotension and can be treated option for patients who are not candidates for sur- with intraoperative intravenous octreotide infu- gery. A recent report of 122 patients undergoing this sions titrated to blood pressure control. For emer- procedure revealed radiographic tumour regression gency surgery, octreotide 500–1000 μg IV bolus in 82% of patients, with stabilization of disease in or 500 μg subcutaneously can be given 1–2 hours 12% . Median duration of ct response was 19 before the procedure, followed by an IV infusion of months; improvement in symptoms occurred in 92% 50–200 μg/h, if needed. of patients for a median duration of 13 months . In addition, recent reports suggest that radioemboliza- 9.1 Curative Surgery tion for unresectable metastatic liver net s may also be effective. In one study, 148 patients were treated Resection of the primary tumour should be accom- with 185 separate procedures. Imaging response was panied by careful intraoperative evaluation for syn- stable in 22.7% of patients, partial in 60.5%, and chronous tumours or metastatic disease in the liver. complete in 2.7%, with progressive disease occurring Resectable liver metastasis should be resected . in 4.9%. No radiation-induced liver failure occurred, In cases having borderline liver reserve, selec- and median survival was 70 months. The advantage tive portal-vein embolization is considered so as to of radioembolization appears to be a morbidity rate induce hypertrophy of the future remaining liver. lower than that seen with ace t . Short-acting ssa s Liver transplantation can also be considered in young must also be used immediately before and during patients (below 50 years of age) when the primary hepatic arterial embolization in patients with func- tumour originates in the gastrointestinal tract, is tional net s. drained by the venous portal system, and has been previously removed with curative intent, and when 9.3 Recommendations disease progression is controlled for at least 6 months before transplantation . Definitive resection of the primary tumour should No currently available data support the use of always be performed whenever technically feasible. adjuvant systemic or radioisotope treatment after Prophylactic cholecystectomy should be consid- complete resection. ered during surgery for net s. Current On COl Ogy —VOlume 17, number 3 CANADIAN NET RECOMMENDATIONS In patients with functional tumours, short-acting go beyond 60 mg based on perceived patient benefit. ass s should be given peri- and intraoperatively during Patients with “breakthrough” symptoms during the invasive surgery to prevent carcinoid crisis. 4th week of therapy may also be considered for injec- In patients with localized, locoregional, or resect- tions every 3 weeks. able metastatic disease, curative surgery should be Side effects may include nausea, abdominal pain, considered if technically and clinically feasible. flatulence, vomiting, and diarrhea, which usually If technically feasible and clinically appropriate, resolve within days of starting therapy. In patients cytoreductive surgery to achieve maximal debulking with steatorrhea, pancreatic enzyme therapy should and palliation of symptoms should be considered in be considered. Cholelithiasis and biliary sludge can all patients with unresectable metastatic disease. develop as a long-term complication in up to 50% of Surgical approaches should be individualized, patients . Bile acid colitis from previous terminal with the ultimate therapeutic decisions and approach- ileal resection should be treated with cholestyramine. es decided after a full multidisciplinary evaluation. Tachyphylaxis and resistance to ssa therapy can oc- Surgical treatment of complex cases should be cur, but other causes should be considered, including undertaken by surgeons having expertise and experi- progressive disease. ence with these tumours. Unresectable liver disease may be considered for Treatment of Asymptomatic Patients with Elevated ace t or radioembolization. 5-HIAA: Patients with elevated 5- a a i h levels remain 33,39–42,74,75 at risk for carcinoid heart disease . Case 10. MEDICAL MANAGEMENT series of patients with carcinoid heart disease have described an association between elevated 5-aaih and 10.1 SSAs the development and pathogenesis of carcinoid heart 33,39–42 disease . Therapy with ssa reduces circulating Somatostatin analogs bind selectively to somatosta- serotonin levels and may stabilize the progression of 74,75 tin receptors and are indicated in the management carcinoid heart disease . of symptomatic functional gastroenterohepatic net s Because elevated 5-hiaa is almost universally to lower hormone production, to provide symptom viewed as a predictor of cardiac complications and a control, and to reduce the risk of carcinoid crises and marker of tumour growth or progression, the consen- other severe events . sus of the present expert group was that all patients with elevated 5-hiaa levels (>70 mg/24 h)—even 10.1.1 Functional Tumours those who are asymptomatic—should be considered Somatostatin analogs have been used primarily to for ssa therapy. relieve symptoms of carcinoid syndrome; they can significantly improve symptoms in most patients by 10.1.2 Non-functional Tumours reducing or normalizing circulating 5-hiaa levels . The role of ssa s in non-functional disease has been As noted earlier, short-acting octreotide may also be under debate; however, recent evidence from the used to prevent carcinoid crisis during procedures Placebo-Controlled, Double-Blind, Prospective 5,26,48,63 such as surgery or hepatic arterial infusion . Randomized Study of the Effect of Octreotide lar in the Control of Tumour Growth in Patients with Treatment of Symptomatic Patients: Patients with Metastatic Neuroendocrine Midgut Tumours (dimorp ) symptomatic tumours should be treated with s s a trial has demonstrated the utility of octreotide lar in therapy to manage symptoms, reduce 5-hiaa levels, these patients for tumour stabilization. Based on the 4,48,72 and stabilize tumour growth . Treatment initia- promid data, asymptomatic patients with progres- tion usually involves subcutaneous administration sive disease should be monitored closely with serial of short-acting octreotide for 3–7 days to ensure 5-hiaa , imaging (ct and mri ), and CgA evaluations, tolerability, followed by administration of the more and they should be treated with octreotide lar (evi- convenient lar formulation . Lifelong treatment is dence: Level 1). likely. Octreotide is currently the only ssa approved for the treatment of ten s in Canada (other ass s can be Antitumour Effects: The results of the promid trial considered in cases of intolerance to octreotide): were presented in January 2009 and subsequently published . The intent of the study was to evalu- ● Octreotide ir : 100–500 μg subcutaneously three ate the potential antitumour effect of octreotide lar times daily in newly diagnosed, treatment-naïve patients with well-differentiated midgut net s, both functional and ● Octreotide ral : intramuscularly starting at 30 mg non-functional. Patients were randomized to receive every 4 weeks; titrate up as required octreotide l a r 30 mg or placebo intramuscularly The usual starting dose for octreotide lar of 30 mg every 4 weeks, and the primary endpoint was time every 4 weeks may be titrated up to 60 mg for break- to tumour progression ( p t t ). Overall, the results dem- through symptoms, if needed. It may be necessary to onstrated that octreotide lar significantly increased Current On COl Ogy —VOlume 17, number 3 KOCHA et al. ttp . Median ttp was 14.3 months [95% confidence temozolomide and thalidomide has also been shown interval (ci ): 11.0 to 28.8 months] for octreotide lar to be beneficial , but thalidomide is not currently compared with 6.0 months (95% i c : 3.7 to 9.4 months) available in Canada. for placebo. This effect represents a 66% reduction in Given their side-effects profiles, most cytotoxic disease progression (hazard ratio: 0.34; 95% ci : 0.20 therapies should be used only when they are most to 0.59; p = 0.000072). likely to have an effect. Cytotoxic therapy may be Tumour stabilization was shown in patients with considered to lower the proliferative capacity of functional and non-functional ten s, regardless of CgA highly proliferative disease, potentially improving levels. The effect was most evident in patients with the effectiveness of other treatment options, including hepatic loads below 10%; however, patients with a resection or debulking, hepatic arterial infusion, and hepatic tumour load above 10% experienced a clini-ssa , interferon alfa, or radioisotope therapy. cal benefit as well. The evidence is now sufficient to recommend 10.2.3 New Agents the use of octreotide lar for tumour stabilization in New agents such as imatinib and mort inhibitors newly diagnosed treatment-naïve patients with well- (for example, RAD001) are being evaluated. Anti- differentiated midgut n e t s. Octreotide l a r should angiogenic substances such as Endostatin (Entremed, be strongly considered for patients with fore- and Rockville, MD, U.S.A.), angiostatin, the new com- hindgut net s as well. pound 2004-01-13IZD6126, and a new ass that binds to somatostatin receptors 1, 2, 3, and 5 (SOM230) 10.2 Other Treatment Alternatives may also have future roles. 10.2.1 Interferon alfa 10.2.4 Other Agents Interferon alfa inhibits protein and hormone synthesis Other agents may be administered as required, depend- in tumour cells, inhibits angiogenesis, and stimulates ing on symptomatology. Examples include loperamide the immune system. It can be used for low-prolif- or diphenoxylate to treat diarrhea, and H1 or H2 block- erating n e t s, either alone or in combination with ers (or both) for histamine-secreting tumours. ssa s. Interferon therapy requires careful monitoring; toxicities include severe fatigue, neutropenia, hepa- 10.3 Recommendations totoxicity, autoimmune disorders, and depression or 6,32,77 other mental disturbances . The recommended For patients with symptomatic secretory tumours, doses for gastroenterohepatic net s are lower than for ssa s are the primary treatment. most other indications, and therefore tolerance may Octreotide lar is recommended to stabilize tu- be improved. mour growth in patients with asymptomatic progres- The recommended dose of interferon alfa is sive disease. 3–5 million units subcutaneously, 3–5 times per Somatostatin analogs should be used to prevent or week. The dose should be individually titrated, aim- treat carcinoid crises before, during, and after procedures ing for a reduction in leukocyte count to approxi- such as surgery and hepatic arterial embolization. mately 3×10 /L. Interferon alfa (alone or in combination with ass s) may A suggested dose (not yet established) for pe- be used for low-proliferating gastroenterohepatic net s. gylated interferon alfa is 75–150 μg subcutaneously Cytotoxic treatment may be a first-line treatment per week. for net s with a high proliferation index (Ki-67 ≥ 5%). 10.2.2 Cytotoxic Treatments 11. RADIATION THERAPY/RADIOISOTOPES Cytotoxic treatment is usually used for tumours with a high proliferative capacity (Ki-67 ≥ 5%); it is 11.1 Radiation Therapy of less use in low-proliferating gastroenterohepatic n e t s. Indeed, these tumours are often resistant to External radiation therapy has limited value in net s; chemotherapy, with tumour response rates of only it often results in fibrosis and may therefore interfere 10%–16% . with tumour evaluation. It may also cause loss of so- Streptozocin in combination with 5-fluorouracil matostatin receptors on tumour cell surfaces, thereby or doxorubicin is the most commonly reported regi- reducing the effectiveness of ssa therapy. For these men . Poorly differentiated ten s are associated with reasons, radiotherapy is recommended only for bone an up to 67% response rate to etoposide plus cispla- and brain metastases. tin, but prognosis is poor, with a 2-year survival rate 7,60,79 of less than 20% . Epirubicin, cisplatin, and 11.2 Radioisotope Therapy fluorouracil combination therapy has been used, but results with that regimen are inconclusive. There is Tumour-targeted treatment with radioactive oct- increasing evidence that regimens of temozolomide reotide derivatives [ In-d -Phe(1)-Tyr(3)-octreotide 80,81 111 90 plus capecitabine may be benec fi ial. A regimen of ( In-a d o t -octreotide) or Y-a d o t -octreotide and Current On COl Ogy —VOlume 17, number 3 CANADIAN NET RECOMMENDATIONS 177 131 40,42 Lu- a dot -octreotate] and with I-mibg have been in 20%–70% of patients with metastatic disease . associated with varied response rates and clinical It is associated with a mortality rate as high as 50% benefit. One large single-institution study of 310 of the mortality associated with these tumours, right 33,84 patients with gastroenteropancreatic n e t s treated ventricular failure being a major cause of death . with Lu- a dot -octreotate documented a 28% re- The role of serotonin in the development of sponse rate and a median overall survival from start carcinoid-related heart disease is controversial, of treatment of almost 4 years . Because of regu- but the indirect evidence appears compelling. latory constraints associated with the synthesis of Only patients with elevated 5-hiaa levels develop 177 39–42 Lu- a dot -octreotate, the treatment is not currently this complication ; serotonin receptors have 85–88 available in Canada. been identified in the heart ; experimentally, stimulation of these receptors causes cardiac cell 89–91 12. MONITORING AND FOLLOW-UP proliferation ; and two drugs, fen-phen and methysergide, can cause identical cardiac pathol- Generally, net s are slow-growing, but they may prog- ogy (both have chemical structures analogous to ress faster if they have a high Ki-67 index (≥5%) or are serotonin, and both can be shown to bind to heart poorly differentiated. Patients should be followed more serotonin receptors) . closely during the first year after diagnosis to estab- lish the “tempo” of the disease. If disease is stable or 13.1 Diagnosis gradually progressive, subsequent investigations may occur less frequently. Occasionally, net s may become Early diagnosis of carcinoid heart disease is essential. more aggressive, requiring a change in frequency of The symptoms of carcinoid heart disease may be so follow-up. If a patient’s status shows a significant clini- subtle as to be attributed to noncardiac causes; as a cal change, an increase in biomarkers, or new sites of result, it is advisable that patients with carcinoid syn- disease, a complete reassessment is required, and more drome have an echocardiogram at diagnosis. Patients frequent follow-up tests may be needed. who are predisposed to carcinoid heart disease should Routine evaluations to detect carcinoid heart have an annual echocardiogram and follow-up with disease in its early stages can improve prognosis . a cardiologist. Follow-up should include early echocardiograms for Carcinoid heart disease can appear in asymp- patients with elevated 5-hiaa . tomatic patients and in those with small increases Quality of life should also be regularly assessed in 5-hiaa , but it is more commonly associated with during treatment. A specific quality-of-life score is carcinoid syndrome and chronic elevation of 5-hiaa . currently being developed for patients with net s; at Carcinoid heart disease is likely to develop in pa- present, a useful tool is the European Organisation tients with longstanding elevations of 5-hiaa ; it is 39–42 for Research and Treatment of Cancer Quality of Life uncommon in patients without elevated 5-hiaa . Questionnaire–C30 . Asymptomatic patients with elevated 5-hiaa should Table v stratifies patients according to potential also be closely monitored for the development of risk of recurrence and outlines suggested follow- carcinoid heart disease. up schedules. 13.2 Prevention 12.1 Recommendations In patients at risk, routine examinations (for example, Patients should be stratified according to risk and fol- echocardiography, mri ) should be conducted every lowed accordingly—more frequently in the first year 6–12 months to detect cardiac involvement in its early after diagnosis to determine the “tempo” of disease, stages and to possibly initiate treatment . and then at regular intervals thereafter depending on Some indirect evidence supports the use of ssa s the risk of recurrence. to prevent or minimize carcinoid heart disease, but Patients with elevated 5-aaih (>70 mg/24 h) should the efficacy of such therapy has not been demon- be routinely evaluated for carcinoid heart disease. strated conclusively. Indeed, carcinoid heart disease may continue to progress even if 5-hiaa is carefully 13. CARCINOID HEART DISEASE controlled . Nevertheless, patients with elevated 5-hiaa levels should be strongly considered for oc- Carcinoid syndrome is associated with the release treotide therapy. of serotonin and other vasoactive substances by the tumour; exposure of the heart to high levels of these 13.3 Treatment substances can result in endocardial damage, most commonly involving the right side of the heart, includ- Once carcinoid heart disease is diagnosed, treatment ing the tricuspid valves, the pulmonary valves, and the should be initiated, and referral to a cardiologist endocardium. Heart failure is one of the most serious should be arranged. Treatment is generally initi- manifestations of carcinoid syndrome, and it occurs ated according to Canadian Cardiovascular Society Current On COl Ogy —VOlume 17, number 3 KOCHA et al. able t v Monitoring and follow-up Disease type Recommended follow-up Resected disease Low-risk All of: Risk of recurrence is low (for example, carcinoid appendix); follow-up is at the ● Primary < 2 cm discretion of the physician ● No nodal involvement ● Low Ki-67 (<5%) High-risk Any one or more of: Close follow-up tailored to the patient’s clinical presentation. ● Primary > 2 cm Year 1: ● Nodal involvement ● 5-hiaa every 3–6 months if functional tumour ● High Ki-67 (≥5%) ● CgA every 3–6 months ● ct ● If results are abnormal, further investigations, including In-pentetreotide scintigraphy or mibg (or both) as indicated Years 2–5: ● 5-hiaa every 3–6 months if functional tumour ● CgA every 6 months ● ct annually ● If abnormal re sults, further investigations, including In-pentetreotide scintigraphy or mibg (or both) as indicated Metastatic disease or post-debulking Close follow-up tailored to the patient’s clinical presentation. (post-resection where macroscopic residual Year 1: disease is not present) ● 5-hiaa every 3–6 months if functional tumour ● CgA every 3–6 months ● ct annually ● If disease progression is evident, further investigations, including In-pentetreotide scintigraphy or mibg (or both) as indicated Years 2 and 3: ● 5-hiaa every 6 months if functional tumour ● CgA every 6 months ● ct annually ● In-pentetreotide scintigraphy annually ● If disease progression is evident, further investigations, including In-pentetreotide scintigraphy or mibg (or both) as indicated Years 4 and 5: ● 5-hiaa annually ● CgA annually ● ct annually ● In-pentetreotide scintigraphy annually ● If disease progression is evident, further investigations, including In-pentetreotide scintigraphy or mibg (or both) as indicated Unresected disease Metastatic disease or post-debulking Close follow-up tailored to the patient’s clinical presentation. (where macroscopic residual disease Year 1: is present) ● 5-hiaa every 3–6 months if functional tumour ● c ga every 3 months ● ct every 6 months ● In-pentetreotide scintigraphy ● If abnormal results, further investigations, including In-pentetreotide scintigraphy or mibg (or both) as indicated Years 2–5: ● 5-hiaa every 4–6 months if functional tumour ● c ga every 4–6 months ● ct every 6 months ● In-pentetreotide scintigraphy annually ● Echocardiogram annually if 5-hiaa is elevated above 70 mg/24 h ● If disease progression is evident, further investigations, including In-pentetreotide scintigraphy or mibg (or both) as indicated 5-hiaa = 5-hydroxyindoleacetic acid; CgA = chromogranin A; ct = computed tomography; mibg = meta-iodobenzylguanidine. Current On COl Ogy —VOlume 17, number 3 CANADIAN NET RECOMMENDATIONS recommendations . Initial measures for heart fail- facilitated by the algorithm and the recommenda- ure should include education, risk-factor reduction, tions outlined in the present guideline—should be lifestyle modifications, restriction of salt and water developed early so as to minimize symptoms, slow intake, and monitoring of fluid balance and weight . tumour progression, and ultimately improve quality Patients with heart failure and a left-ventricular ejec- of life for the patient. tion fraction below 40% should be treated with an angiotensin converting-enzyme (a c e ) inhibitor in 15. ACKNOWLEDGMENTS combination with a beta-blocker unless a specific contraindication exists . Angiotensin receptor ii Editing and writing assistance was provided by antagonists may be used in those who cannot tolerate CME Solutions Canada. Funding was received from ace inhibitors . Digoxin (with or without nitrates), Novartis Pharmaceuticals Canada (Montreal, QC). diuretics, and spironolactone may be added in those The funding source was not involved in the design with New York Heart Association class iii –iv heart of the article, nor in the analysis and interpretation failure and persistent symptoms . Some patients of data. with carcinoid heart disease may benet fi from cardiac valve replacement , but the correct timing of surgi- 16. CONFLICT OF INTEREST DISCLOSURES cal valve replacement is not clear. As well, cardiac surgeons may be reluctant to treat patients with can- All authors received support from Novartis for travel cer. Nevertheless, adequate treatment of right-sided to and participation in the consensus meeting. In the heart failure has been associated with improvements past, several authors have received honoraria or travel in symptomatology and quality of life . reimbursements for educational work, speaking en- gagements, or consultancy: WK (Novartis, Pfizer, Ca- 13.4 Recommendations nadian Medical Protective Association, AstraZeneca), JM (Novartis, Roche, Sano– fi Aventis), HK (Novartis, Patients with carcinoid syndrome should have an Pfizer, Roche, Sanofi–Aventis), JFO (Novartis), CR echocardiogram at diagnosis. All patients should have (Novartis), SVU (Novartis), RW (Novartis). an annual echocardiogram. Referral to a cardiologist or cardiac surgeon should be arranged if cardiac abnor- 17. REFERENCES malities are diagnosed. Early intervention with octreotide should be con- 1. 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Journal
Current Oncology – Multidisciplinary Digital Publishing Institute
Published: Jun 1, 2010
Keywords: carcinoid tumour; carcinoid syndrome; carcinoid heart disease; neuroendocrine tumours; guidelines; clinical management; diagnosis; surgery