`
`K. Öberg
`
`Introduction
`
`Neuroendocrine tumours (NE) 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 neuroendocrine cell-system1. The largest
`group of NE tumours are the so called carcinoids, with an in-
`cidence of about 2.5/100.0002, which by tradition have be-
`en divided into foregut, midgut and hindgut tumours. Endo-
`crine pancreatic tumours has an incidence of 0.4-
`0.8/100.000. This old classification is based on the embryo-
`nic origin of the different tumours, where the foregut carci-
`noid primaries has been located in the lung, thymus, gastric
`mucosa and the midgut carcinoids with primary tumours in
`the ileum, caecum and proximal colon and the hindgut carci-
`noids with the primaries in the distal colon and rectum. This
`old classification is now about to be abandoned, and more
`tumour-biology-based classification has emerged. The new
`WHO-classification is now indicating five subtypes3.
`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 tumours,
`not only for carcinoids. A classical midgut carcinoid will be
`called with the new terminology A well-differentiated endocri-
`ne carcinomas of the ileum, whereas a benign insulin produ-
`cing tumour of the pancreas will be A well-differentiated en-
`docrine tumour of the pancreas. The differentiation between
`different tumours types is based on histomorphology, tumour-
`size and presence or absence of local invasion and/or metas-
`
`Dept. of Endocrine Oncology
`University Hospital
`Uppsala (Sweden)
`
`tases. This new classification of NE tumours is a step forward,
`although the former classification of carcinoid tumours into fo-
`regut, midgut and hindgut, remains clinically available and is
`still used in many clinical studies. It will take some time for the
`new classification to receive general acceptance.
`NE tumours exhibit substantial differences in terms of ge-
`notype and phenotype. Foregut carcinoids mainly pulmo-
`nary, but also endocrine pancreatic tumours, frequently show
`losses of 11q, which represent a characteristic genetic altera-
`tion in these tumours. Both typical and atypical carcinoids of
`the lung show loss of heterozygosity at 11q13, harboring the
`multiple endocrine neoplasia Type 1 (MEN-1) gene. Atypical
`carcinoids also show loss of heterozygosity at 3p14-p21.3.
`Recent studies have shown that carcinoid tumours of the lung
`and the GI tract may develop via different molecular path-
`ways. Inactivation of one of several tumours suppressor ge-
`nes on chromosome 18 may be important for the biological
`behaviour of GI tumours. Familiar midgut carcinoids are rare
`but bronchial carcinoids as well as endocrine pancreatic tu-
`mours and gastric carcinoids may be part of a MEN-1 syn-
`drome4, 5.
`Such differences in molecular genetics and tumour biology
`play a role for the diagnosis and treatment of neuroendocri-
`ne gastrointestinal tumours.
`
`Treatment of NE tumours
`
`Surgery
`
`The clinical management of metastatic NE tumours requi-
`res a multimodal approach including surgery and other me-
`ans of cytoreductive treatment, radiotherapy and medical tre-
`atment. 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 survival in certain groups of patients, as well as to redu-
`ce tumours bulk and prevent further local and systemic ef-
`fects. Surgical resection of primary tumours as well as lymph
`nodes and liver involvement can improve survival. In addi-
`tion, surgery can also be employed after medical treatment to
`achieve substantial tumour reduction in an attempt to maxi-
`ARGENTUM
`Exhibit 1027
`
`57
`
`000001
`
`
`
`K. Öberg
`
`TABLE IA
`
`Cytotoxic therapy for carcinoid tumours
`
`Drug
`
`Regimen
`
`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 x 5 every 5 weeks
`500-1500 mg/m2/day x 5 every 3-5 weeks
`250 mg/m2/day x 5 every 4-5 weeks
`45-90 mg/m2 every 3-4 weeks
`
`500 mg/m2/day x 5 every 3-6 weeks
`400 mg/m2/day x 5 every 3-6 weeks
`1000 mg/m2/week x 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 x 3
`45 mg/m2/day on day 2 and 3,
`repeat cycle every 4 weeks
`
`mize the disease-free interval6, 7. Surgery and thermal abla-
`tion (radiofrequency treatment) are new promising methods
`for treatment of liver metastases. Significant clinical improve-
`ment and reduction in tumour size has been reported8, 9.
`Liver transplantation has been suggested in selected pa-
`tients without residual extrahepatic manifestations. However,
`long-term results are not that encouraging at the moment and
`the liver transplantation should only be reserved for a very
`few patients, where other means of therapy cannot control
`the disease9.
`
`Enbolization/chemoenbolization
`
`A significant number of patients carry liver metastases at
`diagnosis, therefore treatment aimed at reducing the tumour
`bulk in the liver may significantly improve quality of life and
`survival. Such procedures include embolization of liver me-
`tastasis with or without concomitant cytotoxic agents (chemo-
`embolization). Objective symptomatic and hormonal respon-
`ses are ranging from 65% to 80%, but the method must be
`repeated to achieve long-lasting responses.
`
`Radiotherapy
`
`External radiotherapy has demonstrated limited value. To-
`day this kind of therapy is mainly reserved for treatment of
`brain metastases and pain related to bone metastases. Tu-
`mour-targeted radioactive treatment using radiolabeled so-
`matostatin analogues have been applied during the last ye-
`ars with some encouraging results. The different compounds
`have been 111Indium-DTPA-octreotide, 90Y-DOTA-octreoti-
`de, 90Y-DOTATOC and MAURITIUS giving about the same
`results with symptomatic improvement in 40% of the patients,
`biochemical responses in 24% to 30% and significant tumour
`reduction in a small number, 5% to 10%. In order to overco-
`me the limitation of administrating doses of radiotherapy to
`non octreotide avid lesions and the lack of uptake due to tu-
`mour heterogeneity in addition to Ytrium 90 several other
`
`58
`
`81
`30
`14
`15
`16
`
`175
`
`10
`
`24
`
`13
`
`21
`17-26
`0-17
`13
`6
`
`7-33
`
`40
`
`39
`
`0
`
`6
`3
`2
`4.5
`4.5
`
`3-7
`
`5
`
`6.5
`
`-
`
`TABLE IB
`
`Cytotoxic Therapy - Endocrine pancreatic tumours
`
`Regimen
`
`No of patients
`
`Streptozotocin
`Streptozotocin
`+5-FU
`Streptozotocin
`+ Doxorubicin
`Streptozotocin
`+ Doxorubicin
`+5-FU
`
`52
`
`106
`
`36
`
`11
`
`Over all
`response
`rate (%)
`
`Median
`duration
`
`42
`
`NA
`
`31-63
`
`14-23 mo
`
`69
`
`54,5
`
`18 mo
`
`15 mo
`
`isotopes such as Lutetium 177 and Rhenium-186 are being
`considered. 177Lu-DOTA-octreotate shows high tumours up-
`take with a very good ratio of tumour to kidney uptake and is
`suggested to be an ideal compound for radionuclear treat-
`ment. Radiotherapy with this compound has recently been
`administered to 80 patients with a variety of progressive NE
`tumours and 49% showed partial remission10, 11.
`
`Medical treatment
`
`Medical treatment of NE tumours includes treatment with
`both chemotherapy and biological agents, such as somatos-
`tatin analogues and interferon-alfa.
`
`Chemotherapy (Table Ia, Ib)
`
`Chemotherapy has been considered the gold standard for
`treatment of most NE tumours, however, it is usually reported
`for only a limited number of patients and with variable crite-
`
`000002
`
`
`
`Oncología, 2004; 27 (4):185-189
`
`Response
`
`Symptomatic (%)
`Biochemical (%)
`-complete response
`-partial response
`-stable disease
`-progressive disease
`Tumour (%)
`-complete response
`-partial response
`-stable disease
`-progressive disease
`
`TABLE II
`
`Neuroendocrine tumours: somatostatin analogue therapy (summary of several trials)
`
`Standard dose
`(100-1500 µµg/day)
`
`High dose
`(>3000 µµg/day)
`
`Slow release
`(20-30 mg/day every 2-4 weeks)
`
`64 (146/228)
`
`11 (6/54)
`55 (116/211)
`34 (72/211)
`11 (23/211)
`
`-
`5 (7/131)
`38 (50/131)
`56 (74/131)
`
`42 (11/26)
`
`3 (1/33)
`72 (24/83)
`21 (7/33)
`3 (1/33)
`
`2 (1/53)
`11 (6/53)
`47 (25/53)
`39 (21/51)
`
`63 (76/119)
`
`3 (3/119)
`64 (76/119)
`18 (21/119)
`15 (19/119)
`
`-
`3 (4/119)
`79 (94/119)
`18 (21/119)
`
`TABLE III
`Therapy with interferon-αα in patients with midgut carcinoids
`
`Number of patients
`
`Biochemical response (%)
`
`Subjective response (%)
`
`Tumour value response (%)
`
`29§
`
`27§§
`16
`
`PR 53 (13/25)
`SD 36 (9/25)
`PR 39 (9/23)
`PR 16 (1/6)
`SD 50 (3/6)
`PR 44 (4/9)
`PR 8 (1/13)
`SD 31 (4/13)
`§ Natural leukocyte interferon-α, 6 MU subcutaneously x 8 weeks
`§§ High-dose interferon-α,2a 24 MU/m2 subcutaneously x 8 weeks
`PR: Partial response; SD: Stable disease
`
`14
`13
`
`72 (32/29)
`
`65
`
`80 (4/5)
`55
`
`50
`
`PR 10 (3/29)
`SD 86 (25/29)
`PR 20 (4/20)
`PR 0 (0/16)
`SD 66 (10/15)
`PR 0 (0/16)
`PR 8 (1/13)
`SD 77 (10/13)
`
`ria for assessing antitumour responses. Cytotoxic treatment is
`predominantly used in patients with tumours that show high
`proliferative capacity and large tumour burden; a prolifera-
`tion index analyzed by the antibody Ki67 should be above
`10% to 15%. Classical midgut carcinoids with low prolifera-
`ting capacity (Ki67) usually <2%) have not benefited from re-
`gular cytotoxic treatment. The most common chemotherapy in
`endocrine pancreatic tumour is a combination of Streptozo-
`tocin plus 5-fluorouracil or doxorubicin. Reported objective
`response-rates has been between 40% and 70%, whereas in
`classical midgut carcinoids the same combination has only
`generated responses of <10% with short duration. For ana-
`plastic tumours and high proliferative capacity (Ki67 above
`15%) combination with cisplatinum and etoposide has been
`particularly useful with a response-rate up to 67% with a ten-
`dency to more prolonged survival12.
`
`Somatostatin analogues (Table II)
`
`The rationale for the clinical use of somatostatin analo-
`gues is based on the identification of high-affinity somatos-
`
`tatin receptors in 80% to 90% of NE tumours. Regular octre-
`otide at a subcutaneous daily dose of 200-450 _g is asso-
`ciated with a median 60% symptomatic, 70% biochemical
`and 8% tumour response. A limited number of patients have
`been reported with partial tumour regression during treat-
`ment with somatostatin analogues, and very few cases have
`shown complete tumour regression. However, a high num-
`ber of patients reached disease stabilization. Today slow-re-
`lease formulations of octreotide Sandostatin LAR® and So-
`matuline Autogel® have been effective with a monthly dosa-
`ge of 20-30 mg Sandostatin LAR® or 60-120 mg Somatuli-
`ne Autogel®. SOM230 is a new somatostatin analogue
`which has a prolonged half-live, (approximately 24h) and
`exerts a more potent inhibitory effect than currently availa-
`ble compounds as it binds with much higher affinity to so-
`matostatin 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 clinically beneficial in NE tu-
`mours13, 14.
`
`59
`
`000003
`
`
`
`K. Öberg
`
`Low prolif.
`(ki-67 < 2%)
`
`Biological Therapy
`(SMS, IFN, comb)
`
`NE-tumor
`
`Surgery
`RF, embol
`
`Failure
`
`Y90-DOTA-octreotide
`LU177-DOTA-octreotate alt.
`Experimental therapy
`(Gleevec, Herceptin, Rapamycin)
`
`High prolif.
`(ki-67 > 10%)
`
`Cytotoxic Therapy
`(STZ+5-FU, Cislp. + etop)
`
`Failure
`
`Fig. 1. Algorithm for the therapy of Neuroendocrine Tumours.
`
`Interferons (Table III)
`
`Interferons are compounds known to exert a combination
`of effects directed to several groups of tumours and are consi-
`dered as biological response modifiers as they interact with
`other soluble or cell-associated regulatory factors. The recom-
`mended dose of interferon-alfa is 3-9 MU every other day,
`subcutaneously or slow release formulation pegylated interfe-
`ron alfa 80-100 µg once a week, subcutaneously. Data deri-
`ved from several studies of carcinoid tumours have reported a
`median symptomatic and biochemical response rate of 40%
`to 70% and biochemical response in 40% to 60% and a signi-
`ficant tumour reduction in 10% to 12% of patients. 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 approximately 50% of patients. Autoimmune
`reactions appear in approximately 15% of patients15, 16.
`Combination therapy with IFNαα and somatostatin analogue
`
`Patients for whom mono-therapy with interferon alone or
`octreotide alone could not control the disease have received
`the combination. Both hormone levels and clinical symptoms
`were controlled in 40%-70% of the patients but also tumour
`growth in one third16.
`The therapy of Neuroendocrine Tumours is summarized in
`an algorithm (Fig. 1).
`
`New compounds
`
`Inhibition of the intracellular signal transduction from tyrosi-
`ne kinase receptors may be new targets in the treatment of NE
`tumours. Many NE tumours express platelet-derived growth
`factor alfa- and beta-receptor subtypes and ligands and also
`
`60
`
`EGF-receptor. Another interesting new compound is Rapamy-
`cin, which may block signal transduction through the m-TOR
`pathway. Clinical trials with this compound as a single agent
`or in combination with cytotoxic agents are planned. Over the
`next five years the precise role of tumour-targeted radioactive
`treatment with somatostatin analogue-based compounds will
`be defined. New somatostatin analogues, such as SOM230
`and somatostatin receptor subtype-specific analogues will also
`be developed. The tumour biology for different subtypes of NE
`tumours will be defined and thus new treatments including ty-
`rosine kinase inhibitors, antiangiogenic compounds as well as
`combinations of these, will be applied in clinical trials.
`
`References
`
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`ne Tumours. In: New York USA: Springer 2000; 38-74.
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`OTyr3)octreotate: comparison with (111In-DTPAo)octreotide in
`patients. Eur J Nucl Med 2001; 28: 1319-25.
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`neuroendocrine tumours. Ann Oncol 2001; 12 Suppl
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`13. Eriksson B, Oberg K. Summing up 15 years of somatostatin
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`Oncol 1999; 10 Suppl 2:S31-8.
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