throbber
Annals of Oncology 15 (Supplement 4): iv293 – iv298, 2004
`
`doi:10.1093/annonc/mdh942
`
`Management of neuroendocrine tumours
`
`K. O¨ berg
`
`Department of Endocrine Oncology, University Hospital, Uppsala, Sweden
`
`Introduction
`
`Neuroendocrine (NE) tumours of the gastrointestinal tract and
`pancreas constitute about 2% of all malignant tumours. They
`include a number of different tumours, derived from cells of
`the diffuse NE cell system [1]. The largest group of NE
`tumours are the so-called carcinoids, with an incidence of
`about 2.5/100 000 [2], which by tradition have been divided
`into foregut, midgut and hindgut tumours. This old classi-
`fication is based on the embryonic origin of the different
`tumours, where the foregut primaries have been located in
`the lung, thymus, gastric mucosa; the midgut with primary
`tumours in the ileum, caecum and proximal colon; and the
`hindgut with the primaries in the distal colon and rectum. This
`old classification is now about to be abandoned, and a more
`tumour-based classification has emerged. The new World
`Health Organization (WHO) classification now indicates five
`subtypes [3]:
`
`1 well-differentiated endocrine tumour
`2 well-differentiated endocrine carcinoma
`3 poorly differentiated endocrine carcinoma
`4 mixed exocrine and endocrine carcinomas
`5 tumour-like lesions.
`
`This classification can be used for all types of NE tumour; not
`only for carcinoids.
`A classical midgut carcinoid will, in the new terminology,
`be classified as a well-differentiated endocrine carcinoma of
`the ileum, whereas a benign insulin-producing tumour of the
`pancreas will be a well-differentiated endocrine tumour of the
`pancreas. The differentiation between different tumour types
`is based on histomorphology, tumour size and the presence or
`absence of local invasion and/or metastases. This new classifi-
`cation of NE tumours is a step forward, although the former
`classification of carcinoid tumours into foregut, midgut and
`hindgut remains clinically available and is still used in many
`clinical studies. It will take some time for the new classifi-
`cation to be generally accepted.
`NE tumours exhibit substantial differences in terms of geno-
`type and phenotype. Foregut carcinoids mainly located in the
`lung but also endocrine pancreatic tumours, frequently show
`loss of 11q, which represent a characteristic genetic alteration
`in these tumours. Both typical and atypical carcinoids of the
`lung show loss of heterozygosity at 11q13, harbouring the
`multiple endocrine neoplasia type 1 (MEN-1) gene. Atypical
`carcinoids also show loss of heterozygosity at 3p14 – p21.3.
`
`q 2004 European Society for Medical Oncology
`
`Recent studies have shown that carcinoid tumours of the lung
`and the gastrointestinal
`tract may develop via different
`molecular pathways. Inactivation of one of several tumour
`suppressor genes on chromosome 18 may be important for the
`biological behaviour of gastrointestinal
`tumours. Familial
`midgut carcinoids are rare but bronchial carcinoids as well as
`endocrine pancreatic tumours and gastric carcinoids may be
`part of a MEN-1 syndrome [4, 5].
`
`Clinical presentation
`
`The different NE tumours may be divided into functioning
`and non-functioning tumours. Functioning tumours present
`clinically with symptoms related to overproduction of hor-
`mones and amines such as midgut carcinoids with carcinoid
`syndrome, gastrinoma with Zollinger – Ellison’s syndrome,
`insulinoma with hypoglycaemic symptoms, glucagonoma with
`glucagonoma syndrome and VIPoma with watery diarrhoea –
`hypokalaemia – achlorhydria (WDHA) syndrome.
`Non-functioning tumours produce and secrete peptides that
`do not cause any distinct clinical symptom. The majority of
`endocrine pancreatic tumours is non-functioning tumours
`(40 – 45%).
`The classical carcinoid syndrome includes flushing (80%),
`diarrhoea (70%), abdominal pain (40%), valvular heart disease
`(30 – 40%), telangiectasia (25%), wheezing (15%) and pellagra-
`like skin lesions (5%).
`The flushing observed in patients with classical carcinoid
`syndrome has usually a pink to red colour and involves the
`face or upper trunk. It lasts for a few minutes and may be
`triggered by alcohol, physical exercise, mental stress and
`tyramine-containing foods such as chocolates, walnuts and
`bananas.
`The atypical carcinoid syndrome that is seen in bronchial
`carcinoids has a purple rather than pink colour with telang-
`iectasias, hypertrophy of the skin of the face, headache,
`lacrimation, hypotension, cutaneous edema and bronchocon-
`striction.
`Carcinoid heart disease is characterized by plaque-like
`fibrous endocardial
`thickening that classically involves the
`right side of the heart, occurring in 50 – 70% of patients with
`a carcinoid syndrome. Haemodynamically significant heart
`disease is seen in about 5 – 10% of patients [6, 9, 10].
`Zollinger – Ellison’s
`syndrome is
`related to a gastrin-
`producing tumour located either in the pancreas (45 – 50%) or
`in the duodenum (35 – 55%). These tumours produce gastrin,
`
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`iv294
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`which stimulates high acid output with recurrent gastritis
`and gastric ulcers. Nowadays with the use of proton-pump
`inhibitors severe ulcer disease is very rare.
`Insulinoma or hypoglycaemic syndrome is characterized by
`neuroglycopenia, particularly in the morning or after exercise,
`blurred vision and sometimes even psychosis. Secondary to
`low blood glucose the patient might develop palpitations and
`sweating.
`WDHA syndrome or VIPoma syndrome is characterized by
`severe secretory diarrhoea up to 10 – 15 l/day, hypercalcaemia,
`hypokalaemia, achlorhydria, flushing and diabetic glucose
`tolerance.
`Glucagonoma syndrome is very often present with typical
`necrolytic migratory erythema but also anaemia and thrombo-
`sis. About 50% of the patients also show mild diabetes melli-
`tus [6 – 8].
`Non-functioning tumours of the intestine present with large
`abdominal masses, bleeding from the gastrointestinal
`tract
`and/or intestinal obstruction. Non-functioning endocrine pan-
`creatic tumours become very large until they cause abdominal
`discomfort, pain and liver enlargement. Sometimes they also
`cause jaundice [8].
`
`Biochemical diagnosis of NE tumours
`
`Since the majority of NE tumours secretes peptides and
`amines,
`these can be used as markers both for diagnosis
`and monitoring of therapy.
`The most
`important
`tumour marker is chromogranin A,
`which is a glycoprotein stored in the secretory granules of
`tumour cells and is released together with other peptides and
`amines. The level of chromogranin A is increased in 70 – 90%
`of all NE tumours. The sensitivity and specificity are approxi-
`mately 92% and 96%, respectively.
`Another marker
`is pancreatic polypeptide, which is
`increased in 50 – 60% of patients with endocrine pancreatic
`tumours and a somewhat lower number in carcinoid of the
`gastrointestinal tract. The specificity and sensitivity is lower
`for this marker.
`Another tumour marker is human chorionic gonadotropin
`(HCG) a-subunit, which is particularly useful to determine the
`malignant potential of a NE tumour.
`A specific marker for patients with a carcinoid syndrome
`the 24 h urinary level of 5-hydroxyindoleacetic acid
`is
`(5-HIAA), a metabolite of serotonin with a sensitivity of 73%
`and specificity of 100%. The urine should be collected under
`dietary restrictions, excluding bananas, chocolate, tea, coffee,
`walnuts and pecan.
`Patients with foregut carcinoid tumours rarely secrete sero-
`tonin but may release adrenocorticotropic hormone (ACTH),
`growth hormone releasing hormone (GHRH) or histamine
`[11 – 14].
`Serum gastrin together with measurement of the basal and
`stimulated acid output are the best diagnostic tools for gastri-
`noma. Sometimes a secretin infusion test measuring gastrin is
`necessary to demonstrate a gastrinoma.
`
`For the diagnosis of an insulin-producing tumour, measure-
`ment of fasting serum insulin and blood glucose might be
`sufficient, but sensitivity can be improved by analysing pro-
`insulin and C-peptide as well. Sometimes 24 – 72 h fasting is
`necessary to diagnose an insulinoma.
`VIPoma is demonstrated by measuring plasma vasoactive
`intestinal peptide (VIP), which is significantly elevated in
`most patients.
`Plasma glucagon is elevated in most patients with a
`glucagonoma.
`Non-functioning tumours may present with a high chromo-
`granin A level as well as pancreatic polypeptide and HCG-a
`subunit [7, 8].
`
`Imaging of NE tumours
`
`A unique feature of NE tumour cells is the expression of
`peptide hormone receptors on their surface. These receptors
`may be targets for both diagnosis and therapeutic procedures.
`The majority of NE tumour cells expresses somatostatin
`receptors particularly receptor subtypes 2 and 5. They are the
`basis for somatostatin receptor scintigraphy (Octreoscan). This
`procedure is actually the most important staging procedure for
`NE tumours since 55 – 95% of these tumours express somato-
`statin receptors. Somatostatin receptor scintigraphy has a diag-
`nostic accuracy of 83% and a positive predictive value of
`100%. It has a higher sensitivity than I-131-metaiodobenzyl-
`guanidine (MIBG) scanning
`Undifferentiated anaplastic NE tumours with a high pro-
`liferation capacity lack somatostatin receptors and may give
`a negative somatostatin receptor scintigraphy. These tumours
`can be diagnosed by positron emission tomography (PET)
`scanning with [18F]-2-deoxy-2-fluoro-D-glucose (18-FDG).
`Another PET tracer with high sensitivity for well-differen-
`tiated hormone-producing NE tumours is C11-5HTP, with
`very high sensitivity and specificity. Tumours with a size of
`2 mm can be visualized by this method.
`Besides imaging by radionucleotides, computed tomography
`(CT) scan or magnetic resonance imaging (MRI) as well as
`ultrasonography should always be performed to visualize the
`precise location and size of the lesion for evaluation during
`treatment. Most recently a combined PET – CT camera has
`been developed, which makes a computerized fusion image of
`both methods.
`For endocrine tumours of the pancreatic head, endoscopic
`ultrasonography is particularly useful. Other
`localization
`procedures are bronchoscopy, gastroscopy and colonoscopy
`[7, 8, 15 – 18].
`
`Treatment of NE tumours
`
`Surgery
`
`The clinical management of metastatic NE tumours requires a
`multi-modal approach including surgery and other means of
`cytoreductive treatment, radiotherapy and medical treatment.
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`Surgery remains the treatment of choice and is the only
`approach that can achieve a complete cure in patients with NE
`tumours. In cases of metastases, surgery has been used to
`improve hormone-mediated symptoms, quality of life and sur-
`vival in certain groups of patients, as well as to reduce tumour
`bulk and prevent further local and systemic effects. Surgical
`resection of primary tumours as well as lymph nodes and liver
`metastases can improve survival. In addition, surgery can also
`be employed after medical treatment to achieve substantial
`tumour reduction in an attempt to maximize the disease-free
`interval. Surgery and thermal ablation (radiofrequency treat-
`ment) are new promising methods for treatment of liver
`metastases. Significant clinical improvement and reduction in
`tumour size have been reported.
`Liver transplantation has been suggested in selected patients
`without residual extrahepatic manifestations. However, long-
`term results are not that encouraging at the moment and liver
`transplantation should be reserved for a very few patients,
`where other means of therapy cannot control
`the disease
`[7, 19, 20].
`
`Embolization and chemoembolization
`
`A significant number of patients have liver metastases at diag-
`nosis. Therefore treatment aimed at reducing the tumour bulk
`in the liver may significantly improve quality of life and survi-
`val. Such procedures include embolization of liver metastasis
`with or without concomitant cytotoxic agents (chemoemboli-
`zation). Chemoembolization is embolization combined with
`intra-arterial administration of chemotherapy.
`By chemoembolization, the concentration of chemothera-
`peutic drugs may reach a higher local concentration and their
`action may be more effective due to the cellular tumour
`
`Table 1. Cytotoxic therapy for carcinoid tumours
`
`Drug
`
`Regimen
`
`iv295
`
`ischaemia. Contraindications for liver embolization include
`complete portal vein obstruction and hepatic insufficiency.
`If liver metastases are the only site of metastasis, emboli-
`zation may be the first-line treatment
`in patients with NE
`tumours poorly responsive to biological treatment or systemic
`cytotoxic treatment.
`in
`Chemoembolization gives symptomatic improvement
`75 – 100%, biochemical responses in 57 – 90% and significant
`tumour reduction in 35 – 80% of patients with NE tumours.
`The response duration is between 8 and 40 months.
`Side effects are usually mild and transient nausea, vomiting,
`abdominal pain, mild fever and raised liver enzymes. Patients
`with extensive disease may suffer necrosis of the tumour with
`carcinoid crises. Other rare but important complications are
`acute renal
`failure (hepato-renal syndrome), peptic ulcer
`bleeding and necrosis of the gall bladder [21, 22].
`
`Radiotherapy
`
`External radiotherapy has limited value in the treatment of NE
`tumours. It is reserved mainly for treatment of brain meta-
`stases and pain related to bone metastases.
`Tumour-targeted radiolabelled somatostatin analogues have
`been used during the past few years with some encouraging
`results. The various compounds used are 111indium-DTPA-
`octreotide, 90yttrium-DOTA-octreotide, 90yttrium-DOTATOC
`and MAURITIUS, all giving a symptomatic improvement in
`40% of the patients, biochemical responses in 24 – 30% and
`significant tumour reduction in 5 – 10%.
`To overcome the limitation of administering radiotherapy to
`non-octreotide avid lesions and lack of uptake due to tumour
`heterogeneity, several other isotopes such as 177lutetium and
`186rhenium are being examined.
`177Lu-DOTA-octreotate
`
`Number of
`patients
`
`Overall
`response (%)
`
`Median duration
`(months)
`
`Single agents
`
`Doxorubicin
`
`5-Fluorouracil
`
`Streptozotocin
`
`Dacarbazine
`
`Cisplatin
`
`Combinations
`
`Streptozotocin
`
`+5-Fluorouracil
`
`Streptozotocin
`
`+Doxorubicin
`
`Streptozotocin
`
`+Cyclophosphamide
`
`Etoposide
`
`+Cisplatin
`
`60 mg/m2 every 3 – 4 weeks
`500 mg/m2/day 5 every 5 weeks
`500 – 1500 mg/m2/day 5 every 3 – 5 weeks
`250 mg/m2/day 5 every 4 – 5 weeks
`45 – 90 mg/m2 every 3 – 4 weeks
`
`81
`
`30
`
`14
`
`15
`
`16
`
`21
`
`17 – 26
`
`0 – 17
`
`13
`
`6
`
`6
`
`3
`
`2
`
`4.5
`
`4.5
`
`500 mg/m2/day 5 every 3 – 6 weeks
`400 mg/m2/day 5 every 3 – 6 weeks
`1000 mg/m2/week 4
`25 mg/m2/week then every 2 weeks
`
`500 mg/m2/day every 6 weeks
`
`100 mg/m2 once every 3 weeks
`130 mg/m2/day 3
`45 mg/m2/day on day 2 and 3,
`repeat cycle every 4 weeks
`
`175
`
`7 – 33
`
`3 – 7
`
`10
`
`24
`
`13
`
`40
`
`39
`
`0
`
`5
`
`6.5
`
`–
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`iv296
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`shows a high tumour uptake with a very good ratio of tumour
`to kidney uptake. This isotope has recently been administered
`to 80 patients with a variety of progressive NE tumours and
`49% showed a partial response [23 – 25].
`
`Medical treatment
`
`treatment of NE tumours includes treatment with
`Medical
`both chemotherapy and biological agents, such as somatostatin
`analogues and interferon (IFN)-a.
`
`Chemotherapy
`
`Chemotherapy has been considered the gold standard for treat-
`ment of most NE tumours. However,
`its use is usually
`reported in a limited number of patients and with variable
`criteria for assessment of antitumour response.
`Cytotoxic treatment is predominantly used in patients with
`tumours with a high proliferative capacity shown by a pro-
`liferation index of >10 – 15% measured by the antibody Ki67
`and with a large tumour burden. Patients with a classical mid-
`gut carcinoid with a low proliferating capacity (Ki67 usually
`<2%) do not benefit from cytotoxic treatment.
`The most common chemotherapy for the treatment of endo-
`crine pancreatic tumours is a combination of streptozotocin
`plus 5-fluorouracil or doxorubicin. Response rates are between
`40% and 70%. In classical midgut carcinoids the same combi-
`nation induces responses of short duration in <10%.
`
`Table 2. Chemotherapy of endocrine pancreatic tumours
`
`No. of
`patients
`
`Objective
`response (%)
`
`Duration
`(months)
`
`Streptozotocin + 5-fluorouracil
`
`170
`
`Streptozotocin + doxorubicin
`
`Cisplatinum + etoposide
`
`Dacarbazine
`
`Paclitaxel
`
`50
`
`14
`
`11
`
`15
`
`45 – 63
`
`40 – 69
`
`50
`
`9
`
`7
`
`18 – 36
`
`12 – 24
`
`9
`
`6
`
`5
`
`For anaplastic tumours with a high proliferative capacity
`(Ki67 > 15%) combinations of cisplatin and etoposide have
`been useful with a response rate of 67% and a tendency to
`prolonged survival [26, 27]. Newer cytotoxic agents such as
`paclitaxel and gemcitabine have not been of substantial value.
`Results of phase II studies with different chemotherapeutic
`regimens are shown in Tables 1 and 2.
`
`Somatostatin analogues
`
`The rationale for the clinical use of somatostatin analogues
`is based on the identification of high-affinity somatostatin
`receptors in 80 – 90% of NE tumours. Regular octreotide at a
`subcutaneous daily dose of 200 – 450 mg is associated with a
`median 60% symptomatic, 70% biochemical and 8% tumour
`response. A limited number of patients has been reported with
`partial tumour regression during treatment with somatostatin
`analogues and very few cases have shown complete tumour
`regression. However, a high number of patients reached
`disease stabilization.
`(Sandostatin
`Slow release
`formulations of octreotide
`LARw) and somatuline (Somatuline Autogelw) have been
`effective with a monthly dose of 20 – 30 mg octreotide or 60 –
`120 mg somatuline. In clinical practice the patient is treated
`subcutaneously with immediate release octreotide 100 mg 2 – 3
`times/day for at least 3 – 4 days to see whether the patient can
`tolerate somatostatin analogue treatment. Thereafter, a long-
`acting formulation of octreotide 20 mg or somatuline 90 mg is
`given intramuscularly every 4 weeks. The immediate release
`formulation of octreotide is continued during the first 2 weeks
`to prevent symptoms until the long-acting formulation of the
`drug reaches a steady state concentration. If symptoms return
`before the next administration, the interval can be shortened
`to 2 or 3 weeks. The patient should also have a supply of
`immediate release octreotide for particular situations.
`When a patient develops resistance to a somatostatin ana-
`logue, which may occur after 9 – 12 months of treatment, dose
`escalation may be tried with doses up to 60 mg for octreotide
`or 150 mg of somatuline.
`
`Table 3. NE tumours: somatostatin analogue therapy (summary of several trials)
`
`Response
`
`Symptomatic
`
`Biochemical
`
`Standard dose
`(100 – 1500 mg/day) (%)
`
`High dose
`(>3000 mg/day) (%)
`
`Slow release
`(20 – 30 mg/day every 2 – 4 weeks) (%)
`
`64 (146/228)
`
`42 (11/26)
`
`63 (76/119)
`
`Complete response
`
`11 (6/54)
`
`Partial response
`
`55 (116/211)
`
`Stable disease
`
`34 (72/211)
`
`Progressive disease
`
`11 (23/211)
`
`Tumour
`
`Complete response
`
`–
`
`Partial response
`
`5 (7/131)
`
`Stable disease
`
`38 (50/131)
`
`Progressive disease
`
`56 (74/131)
`
`3 (1/33)
`
`72 (24/83)
`
`21 (7/33)
`
`3 (1/33)
`
`2 (1/53)
`
`11 (6/53)
`
`47 (25/53)
`
`39 (21/51)
`
`3 (3/119)
`
`64 (76/119)
`
`18 (21/119)
`
`15 (19/119)
`
`–
`
`3 (4/119)
`
`79 (94/119)
`
`18 (21/119)
`
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`to somatostatin analogue
`If a patient becomes resistant
`treatment, IFN-a might be an alternative to up-regulate the
`number of somatostatin receptors type 2 or to give a period of
`rest to somatostatin receptors. Somatostatin analogue therapy
`can be re-instituted after 2 – 3 months, by using either the
`immediate release or the long-acting formulation.
`SOM230 is a new somatostatin analogue that has a
`prolonged half-life, ( 24 h) and exerts a more potent inhibi-
`tory effect than the compounds currently available, as it binds
`with much higher affinity to somatostatin receptors 1, 2, 3 and
`5. The introduction of SOM230 into clinical practice will
`address a long-standing question as to whether somatostatin
`receptor subtypes 1 and 3, which mediate antitumour effects
`(cell cycle inhibition and induction of apoptosis) will be clini-
`cally beneficial in NE tumours [28 – 31]. Results of trials with
`somatostatin analogues are given in Table 3.
`
`Interferons
`
`Interferons are compounds known to exert a combination of
`effects directed to several groups of tumours and are con-
`sidered as biological response modifiers as they interact with
`other soluble or cell-associated regulatory factors. The rec-
`ommended dose of IFN-a is 3 – 9 MU subcutaneously every
`other day, or slow release formulation pegylated IFN-a 80 –
`100 mg subcutaneously once a week. The dose should be
`titrated individually and the leucocyte count may be used
`as guidance: a leucocyte count of <3.0 109/l indicates an
`optimal IFN-a dose.
`Several studies in patients with carcinoid tumours have
`reported a median symptomatic and biochemical response rate
`of 40 – 70%, biochemical responses in 40 – 60% and significant
`tumour reduction in 10 – 12% (Table 4). Disease stabilization
`is noted in a further 35% of the patients. Flu-like symptoms
`are almost universal with interferon treatment but are usually
`short
`lasting. Chronic fatigue and mild depression may
`develop in  50% of patients. Autoimmune reactions appear
`in  15% of patients [27, 32, 33].
`
`Table 4. Therapy with IFN-a in patients with midgut carcinoids
`
`Number of
`patients
`
`Biochemical
`response (%)
`
`Subjective
`response (%)
`
`Tumour value
`response (%)
`
`PR 53 (13/25)
`
`72 (32/29)
`
`PR 10 (3/29)
`
`SD 36 (9/25)
`
`PR 39 (9/23)
`
`65
`
`PR 16 (1/6)
`
`SD 86 (25/29)
`
`PR 20 (4/20)
`
`PR 0 (0/16)
`
`SD 50 (3/6)
`
`80 (4/5)
`
`SD 66 (10/15)
`
`29a
`
`27b
`
`16
`
`14
`
`13
`
`PR 44 (4/9)
`
`55
`
`PR 8 (1/13)
`
`PR 0 (0/16)
`
`PR 8 (1/13)
`
`SD 77 (10/13)
`
`SD 31 (4/13)
`50
`aNatural leucocyte IFN-a, 6 MU subcutaneously 8 weeks.
`bHigh-dose IFN-a2a 24 MU/m2 subcutaneously 8 weeks.
`PR, partial response; SD, stable disease.
`
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`
`Figure 1. Algorithm of NE tumours.
`
`Combination of IFN and somatostatin analogue
`
`The value of combining IFN-a with somatostatin analogues
`has been discussed during the past few years. Early non-
`randomized studies indicated a beneficial effect of the combi-
`nation, with significant antitumour and biochemical responses
`in patients
`resistant
`to either
`IFN or
`a
`somatostatin
`analogue alone [34, 35].
`Recent randomized trials have not supported this early
`observation, but these studies have several flaws. One of these
`studies included a low number of patients and the statistical
`analyses were not performed correctly [36]. The combination
`of IFN-a and a somatostatin analogue showed a non-signi-
`ficant trend to improved survival. The other study included
`different types of NE tumours with different tumour biology
`and it was not easy to evaluate the combination therapy [37].
`The tolerance of IFN-a is improved by use of a concomi-
`tant somatostatin analogue and experimental data indicate an
`up-regulation of the somatostatin receptor type 2 by IFN-a.
`IFN-a with a somatostatin
`Therefore the combination of
`analogue should be evaluated in randomized studies
`in
`pre-defined patient populations. Current concepts in therapy
`are summarized in Figure 1.
`
`New compounds
`
`transduction by tyrosine
`intracellular signal
`Inhibition of
`kinase receptors may be a new target in the treatment of NE
`tumours. Many NE tumours express platelet-derived growth
`factor-a and -b receptor subtypes and ligands, and also
`vascular endothelial growth factor and epidermal growth
`factor receptors.
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`Another interesting new compound is rapamycin, which
`may block signal transduction through the mTOR pathway.
`Clinical trials with this compound as a single agent or in
`combination with cytotoxic agents are planned.
`Over the next 5 years the precise role of tumour-targeted
`radioactive treatment with somatostatin analogue-based com-
`pounds will be defined. New somatostatin analogues, such as
`SOM230 and somatostatin receptor subtype-specific analogues
`will also be developed. The tumour biology for different sub-
`types of NE tumour will be defined and thus new treatments
`including tyrosine kinase inhibitors, anti-angiogenic com-
`pounds as well as combinations of these, will be applied in
`clinical trials.
`
`References
`
`1. Kimura W, Kuroda A, Morioka Y. Clinical pathology of endocrine
`tumors of the pancreas. Dig Dis Sci 1991; 36: 933– 942.
`2. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carci-
`noid tumors. Cancer 2003; 97: 934 – 959.
`3. Solcia E, Kloppel G, Sobin L (eds). Histological Typing of Endocrine
`Tumours. New York, USA: Springer 2000; 38 – 74.
`4. Rindi G, Villanacci V, Ubiali A. Biological and molecular aspects
`of gastroenteropancreatic neuroendocrine tumors. Digestion 2000; 62
`(Suppl 1): 19 – 26.
`5. Oberg K. Carcinoid tumors: molecular genetics, tumor biology, and
`update of diagnosis and treatment. Curr Opin Oncol 2002; 14:
`38 – 45.
`6. Oberg K. Neuroendocrine gastrointestinal tumors—a condensed over-
`view of diagnosis and treatment. Ann Oncol 1999; 10 (Suppl 2):
`S3– S8.
`7. Thompson GB, van Heerden JA, Grant CS et al. Islet cell carcinomas
`of
`the pancreas: a twenty-year experience. Surgery 1988; 104:
`1011– 1017.
`8. Bieligk S, Jaffe BM. Islet cell tumors of the pancreas. Surg Clin
`North Am 1995; 75: 1025 – 1040.
`9. Caplin ME, Buscombe JR, Hilson AJ et al. Carcinoid tumour. Lancet
`1998; 352: 799– 805.
`10. Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med 1999; 340:
`858 – 868.
`11. Granberg D, Wilander E, Stridsberg M et al. Clinical symptoms,
`hormone profiles, treatment, and prognosis in patients with gastric
`carcinoids. Gut 1998; 43: 223– 228.
`12. Feldman JM, O’Dorisio TM. Role of neuropeptides and serotonin in
`the diagnosis of carcinoid tumors. Am J Med 1986; 81: 41 – 48.
`13. Lamberts SW, Hofland LJ, Nobels FR. Neuroendocrine tumor mar-
`kers. Front Neuroendocrinol 2001; 22: 309– 339.
`14. Stridsberg M, Eriksson B, Oberg K, Janson ET. A comparison
`between three commercial kits for chromogranin A measurements.
`J Endocrinol 2003; 177: 337 – 341.
`15. Ricke J, Klose KJ, Mignon M et al. Standardisation of imaging in
`neuroendocrine tumours: results of a European delphi process. Eur
`J Radiol 2001; 37: 8 – 17.
`16. Kwekkeboom D, Krenning EP, de Jong M. Peptide receptor imaging
`and therapy. J Nucl Med 2000; 41: 1704– 1713.
`17. Krenning EP, de Jong M, Kooij PP et al. Radiolabelled somatostatin
`analogue(s)
`for peptide receptor
`scintigraphy and radionuclide
`therapy. Ann Oncol 1999; 10 (Suppl 2): S23– S29.
`
`18. Orlefors H, Sundin A, Ahlstrom H et al. Positron emission tomo-
`graphy with 5-hydroxytryprophan in neuroendocrine tumors. J Clin
`Oncol 1998; 16: 2534– 2541.
`19. Hellman P, Lundstrom T, Ohrvall U et al. Effect of surgery on the
`outcome of midgut carcinoid disease with lymph node and liver
`metastases. World J Surg 2002; 26: 991– 997.
`20. Le Treut YP, Delpero JR, Dousset B et al. Results of liver trans-
`plantation in the treatment of metastatic neuroendocrine tumors.
`A 31-case French multicentric report. Ann Surg 1997; 225: 355– 364.
`21. Ruszniewski P, Malka D. Hepatic arterial chemoembolization in the
`management of advanced digestive endocrine tumors. Digestion 2000;
`62 (Suppl 1): 79 – 83.
`22. Ajani JA, Carrasco CH, Wallace S. Neuroendocrine tumors metastatic
`to the liver. Vascular occlusion therapy. Ann NY Acad Sci 1994; 733:
`479– 487.
`23. Anthony LB, Woltering EA, Espenan GD et al. Indium-111-pentetreo-
`tide prolongs survival in gastroenteropancreatic malignancies. Semin
`Nucl Med 2002; 32: 123– 132.
`24. De Jong MBW, Bernard HF et al. Response to radionuclide therapy
`using 90Y and 111In-labeled somatostatin analogs is dependent on
`tumor size. J Nucl Med 2000; 41: 147.
`25. Kwekkeboom DJ, Bakker WH, Kooij PP et al. [177Lu-DOTAOTyr3]-
`octreotate: comparison with [111In-DTPAo]octreotide in patients. Eur
`J Nucl Med 2001; 28: 1319 – 1325.
`26. Oberg K. Advances in chemotherapy and biotherapy of endocrine
`tumors. Curr Opin Oncol 1998; 10: 58 – 65.
`27. Oberg K. Chemotherapy and biotherapy in the treatment of neuro-
`endocrine tumours. Ann Oncol 2001; 12 (Suppl 2): S111 – S114.
`28. Eriksson B, Oberg K. Summing up 15 years of somatostatin analog
`therapy in neuroendocrine tumors: future outlook. Ann Oncol 1999;
`10 (Suppl 2): S31– S38.
`29. Oberg K. Established clinical use of octreotide and lanreotide in
`oncology. Chemotherapy 2001; 47 (Suppl 2): 40 – 53.
`30. Oberg K, Kvols L, Caplin M et al. Consensus report on the use
`of somatostatin analogs for
`the management of neuroendocrine
`tumors of the gastroenteropancreatic system. Ann Oncol 2004; 15:
`966– 973.
`31. Bruns C, Lewis I, Briner U et al. SOM230: a novel somatostatin pep-
`tidomimetic with broad somatotropin release inhibiting factor (SRIF)
`receptor binding and a unique antisecretory profile. Eur J Endocrinol
`2002; 146: 707– 716.
`32. Oberg K, Eriksson B. The role of interferons in the management of
`carcinoid tumors. Acta Oncol 1991; 30: 519 – 522.
`33. Jakobsen M, Hansen LE, Kolmannskog F, Schrumpf E, Vatn MH,
`Bergan A. Interferon-a 2b, with or without prior hepatic artery embo-
`lization: clinical response and survival in midgut carcinoid patients.
`Scand J Gastroenterol 1995; 30: 789 – 796.
`34. Fjallskog ML, Sundin A, Westlin JE et al. Treatment of malignant
`endocrine pancreatic tumors with a combination of alpha-interferon
`and somatostatin analogs. Med Oncol 2002; 19: 35 – 42.
`35. Frank M, Klose KJ, Wied M et al. Combination therapy with octreo-
`tide and alpha-interferon: effect on tumor growth in metastatic endo-
`crine gastroenteropancreatic tumors. Am J Gastroenterol 1999; 94:
`1381– 1387.
`36. Kolby L, Persson G, Franzen S, Ahren B. Randomized clinical trial of
`the effect of interferon alpha on survival in patients with disseminated
`midgut carcinoid tumours. Br J Surg 2003; 90: 687– 693.
`randomized,
`37. Faiss S, Pape UF, Bohmig M et al. Prospective,
`multicenter trial on the antiproliferative effect of lanreotide, interferon
`alfa, and their combination for therapy of metastatic neuroendocrine
`gastroenteropancreatic
`tumors—the
`International Lanreotide
`and
`Interferon Alfa Study Group. J Clin Oncol 2003; 21: 2689 – 2696.
`
`West-Ward Pharm.
`Exhibit 1026
`Page 006
`
`

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