Basic Science and Clinical Management
`
`With 82 Figures
`
`C.D. Johnson and C.W. Imrie
`
`Pancreatic Disease
`
`Springer
`
`NOVARTIS EXHIBIT 2053
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`Page 1 of 16
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`

`

`
`
`C.D, Johnson, M'Chir, FRCS
`University Surgical Unit
`Southampton General Hospital
`Southampton, UK
`
`C.W. Imrle, BSC, MB, FRCS
`Royal Infirmary
`Glasgow, UK
`
`British Library Cataloguing in Publication Data
`Pancreatic disease: basic science and clinical management
`1. Pancreas — Diseases 2. Pancreas - Cancer 3. Pancreatitis
`I. )ohnson, C.D. (Colin David), 1952' II. Imrie, C.W.
`(Clement William)
`616.3’7
`lSBN 1852337117
`
`2003054423
`
`Apart from any fair dealing for the purposes of research or private study, or criticism or
`review, as permitted under the Copyright, Designs and Patents Act 1988, this publication
`may only be reproduced, stored or transmitted, in any form or by any means, with the
`prior permission in writing of the publishers, or in the case of reprographic reproduc-
`tion in accordance with the terms of licences issued by the Copyright Licensing Agency.
`Enquiries concerning reproduction outside those terms should be sent to the publishers.
`
`lSBN 1-85233—711-7 Springer-Verlag London Berlin Heidelberg
`Springer-Verlag is a part of Springer Science+Business Media
`springeronline.com
`
`© Springer—Verlag London Limited 2004
`Printed in Singapore
`
`The use of registered names, trademarks, etc. in this publication does not imply, even in
`the absence of a specific statement, that such names are exempt from the relevant laws
`and regulations and therefore free for general use.
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`liability: The publisher can give no guarantee for information about drug
`Product
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`respective user must check its accuracy by consulting other pharmaceutical literature.
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`Typeset by EXPO Holdings, Malaysia
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`283830643210 Printed on acid-free paper SPIN 10900925
`
`Library of Congress Cataloging-in-Publicaiion Data
`Pancreatic disease: basic science and clinical management] C.D. )ohnSOn and
`CW. lmrie (eds).
`p. ; cm.
`Includes bibliographical references.
`lSBN 1-85233-711-7 (alk. paper)
`1. Pancreas—Diseases. I. Title: Pancreatic disease in the twenty-first century, ll.
`Johnson. C. D. (Colin David), 1952- III. Imrie, C. W.
`[DNLMz l. Pancreatic Diseasesvdiagnosis. z. Pancreatic Diseases~etiology. 3. Pancreatic
`Diseases—therapy 4. Therapies, lnvestigational.Wl 800 P1892 2004]
`RC857iP3225 2004
`616.'3’7—dc21
`
`
`
`
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`
`----_-.-__-,.:;-:magma-:-
`
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`

`Neuroendocrine Tumours
`
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`l Epidemiology of Pancreatic Neuroendocrine Tumours
`Helen Doran. John‘P. Neoptolemos, Evelyn M.l.Wi||iams and Robert SuttonW
`
`Pancreatic neuroendocrine tumours are rare neoplastic growths of endocrine
`pancreatic tissue with both neural and endocrine features, frequently causing clin~
`ical syndromes from uncontrolled hormone secretion.” Those tumours that cause
`such syndromes have been classified as ‘functional’ whilst those without obvious
`hypersecretion have been classified as ‘non-functional’.“3 However, ‘non~
`functional’ tumours secrete various peptides and, proteins, including chromo-
`granins, plasma levels of which can be used as tumour markers.‘-"4 There are a
`number of well recognised syndromic tumours, the commonest being insuli'noma
`and gastrinoma, although many gastrinomas arise in the duodenum (see
`Table 1.1). A minority of patients presenting with pancreatic neuroendocrine
`tumours have one of four inherited disorders producing tumours at many sites:
`multiple endocrine neoplasia type 1 (MEN-U5, von Hippel-Lindau disease6 (see
`Ch. 12), neurofibromatosis7 and tuberous sclerosis.3
`
`ical features.
`
`Pancreatic neuroendocrine tumours have been found in 0.1—1.60/0 of autopsies in
`unselected series.10 This wide variation is likely to be attributable to varying
`methods of identification; systematic sectioning of the pancreas in transverse
`blocks 0.3A0.S cm thick, with subsequent thorough examination of all slides made
`from each block, will give higher figures. In one autopsy series using meticulous
`identification the percentage with pancreatic neuroendocrine tumours was 10%.16
`However, as in other endocrine glands, many tumours are smailadenomas that are
`slow growing and without significant hormonal effects, and so do not present
`during life. In a 25 year study of 11 472 autopsies conducted in Hong Kong, pancre-
`atic neuroendocrine tumours were identified in only 10 cases, only one of which
`had presented during life.m Another study suggests that tumours not presenting in
`life are more likely to occur in the body and tail of the gland, and contain more
`pancreatic polypeptide than any other hormone.18 Such studies have helped to
`develop our understanding of natural history, but provide limited insight into clin—
`
`Incidence and Prevalence
`
`Autopsy Series
`
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`""-
`
`TIMI 1.1, Principal clinical features of less rarc types of pancreatic neurocndocrine tumours Tumour
`Survival
`Diagnosis
`Malignancy
`Symptoms
`lnxulinnma
`Complete resection cures most
`Confusion, sweating. dizziness,
`[0% of patients develop
`Inappropriate insulin secretion
`metastases
`patients
`weakness, unconsciousness,
`during hypogiycacmia from up
`‘to 72 h fasting
`relief with eating
`Complete resection results in
`Elevated serum gastrin when
`_Zollinger- Ellison syndrome of
`10 year survival of 90%; less likely
`patient oil all acid suppression
`severe peptic ulceration and
`treatment
`diarrhoea
`if large primary
`More, favourable with complete
`Elevated serum glncagon. Other
`Necrolytic migratory erythema,
`hormones can be elevated
`resection: prolonged even with
`weight loss. diabetes mellitus.
`liver metastases
`stmnatitis, diarrhoea
`Complete resection: five year
`Verna—Morrison syndrome of
`survival of 95%;
`profuse watery diarrhoea with
`with metastases: 60%
`marked hypnkalacmia
`Complete resection associated
`Symptomatic chnlclithinsis;
`with five year survival of 95%;
`weight loss; diarrhoea and
`with metastases, 60%
`steatorrhoea
`Complete resection associated
`Symptoms from pancreatic
`mass and/or liver metastases
`with five year survival of at
`least 50%
`
`Metastases develop in 50%
`of patients; likelihood
`correlated with size of primary
`Metastases develop in 60% or
`more patients
`
`Metastases develop in up to
`70% of patients; majority found
`at presentation.
`Metastases likely in about 50%
`of patients
`
`Hypochlorhydria, +
`hypercalcaemia; elevated
`serum VIP
`Elevated serum somatostatin
`
`.n...n.1'...m.
`
`
`.,.,.Fur...-
`
`m'"'flaw...-:.n-u'Jun..an.—---
`
`
`m‘'m'
`
`(inst ri unma
`
`Glumgnnnnm
`
`Vipmna
`
`Sumatostutinoma
`
`Nnn it'ndrmnlc pancreatic
`ltt‘tln‘olttll‘ct mo tumour
`
`A variety of hormones may be
`clevatcd. including
`clrmmogranins
`
`Metastases develop in up
`to 50% ct patients
`
`
`
`smotunlatlzuauvd
`
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`

`Epidemiology of Pancreatic Neuroendocrine Tumours
`
`Clinical and Surgical Series
`
`Clinical series have been compiled from collections of cases that include tumours
`identified incidentally on radiological imaging or pathological examination of a
`pancreatic specimen performed for another reason. In surgical series functioning
`tumours have more often been reported.“19 Without assessment of the population
`base from which each series was drawn, no proper epidemiological picture can be
`drawn.
`
`Prevalence
`
`For indolent neoplastic lesions such as pancreatic neuroendocrine tumours,
`prevalence is an important measure of population disease burden. Prevalence esti-
`mates are reported at 1.0 per 100 000,10'21 but these estimates were made over three
`decades ago using older histological techniques. More recent data from the SEER
`project
`identified 401 islet cell tumours amongst 22 747 pancreatic cancers
`(< 2%).21 However, these data are also limited, because only malignant tumours
`were included, and more importantly-,most pancreaticcancers are associated with
`a survival of less than six months, quite different from most pancreatic neuro-
`endocrine tumours.
`
`incidence
`
`All Pancreatic Neuroendocrine Tumours
`
`Insulinoma
`
`Estimates for this tumour have ranged from 0.67—40 cases per million per year,
`varying widely despite the use of reference populations.""“"'23'24
`
`Gastrinoma
`
`The reported incidence of this tumour has ranged from 0.14.0 cases per million
`per year,”25 with that for the defined Northern Ireland population the incidence
`reported by Watson and colleagues was 0.5 per million per year}2 Historically,
`
`wan
`
`i
`
`if
`
`
`
`
`
`u.-9-::n.._..-..n.-..I.,.-...,.3{-
`
`Mfisfi-fi‘fimfi1-—-1-r--—«-—-u«par-n
`
`-.-.—qr.—.—-..-.—....
`
`There are two population-based studies that have assessed the overall incidence of
`pancreatic neuroendocrine tumours identified during life,“7 but in neither was the
`autopsy rate reported. Watson and co-workers used cases identified in Northern
`Ireland that had been entered into a neuroendocrine tumour database compiled in
`conjunction with a specialist reference laboratory conducting hormone assays.22
`From these data they estimated the incidence to be 2.0 per million per year.
`Eriksson and co—workers took all cases treated in Uppsala over a 20 year period
`and assumed a local population base, despite an international referral practice;
`they calculated 4.0 cases per million per year.23
`
`
`
`
`
`
`
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`

`v—immrramnw"!
`
`Marked differences in the reported incidence of pancreatic polypeptide producing
`tumours (PPoma) have arisen because historically, many non—syndromic tumours
`were not tested for pancreatic polypeptide. The principal documented physiolo~
`gical action of pancreatic polypeptide is inhibition of biliary and pancreatic
`exocrine secretion.‘7 The incidence of pancreatic polypeptide hypersecretion is
`variable depending on the type of endocrine cell tumour; all pure PPomas present
`with elevated pancreatic polypeptide levels”-38 Thus, although 50—75% of patients
`with non—syndromic tumours have increased basal levels of pancreatic polypep—
`tide,” and cells producing pancreatic polypeptide are found in 28—74% of other
`syndromic tumours, pure or dominant PPoma have been estimated to comprise
`only l—2%,of all pancreatic neuroendocrine tumours.”
`
`Vipoma
`
`VIPomas, which are usually located in the pancreas, produce the Verner—Morrison
`or WDHA (watery diarrhoea, hypokalaemia and achlorhydria) syndrome from an
`excess of vasoactive intestinal polypeptide.""” Their incidence has been estimated
`at 01240 per million per year,“23 comprising 3—5% of all pancreatic neuroen-
`docrine tumours.32
`
`Ppoma
`
`Rarer Syndromic Tumours
`
`The more infrequent pancreatic neuroendocrine tumours are reported primarily
`as case series; incidence is difficult to estimate. Somatostatinomas, like gastrino—
`
`_*I__---emf-stF,.fgfifie’E-"fflfi‘fl'fl'fi'f52"???""."E"-tL'-L'=!=-'-W"':fl?.--...Eva-ma'fiffltfiflfiF-W.“wen” mafia me. It}
`
`8
`
`Pancreatic Tumours
`
`insulinoma was considered the most common pancreatic neuroendocrine tumour
`but more recent reports suggest that gastrinoma is more common?” However,
`the terms Zollinger—Ellison syndrome and gastrinoma have been used inter-
`changeably, without specification as to tumour location, and most studies have
`given combined pancreatic and extra-pancreatic gastrinoma rates. Earlier studies
`cited the pancreas as the organ most frequently harbouring a gastrinoma
`(40—53%).27'2” However these reports contained a significant number of cases
`where tumour was not detected (27—34%). Small, occult duodenal gastrinomas
`account for a significant number of such cases.LS
`
`Glucagonoma
`
`The Northern Ireland study of Watson and colleagues estimated the annual incid-
`ence of glucagonoma at 0.05 per million (1 per 20 000 000) per year}2 accounting
`for 2.5% of all their pancreatic neuroendocrine tumours. Other estimates suggest
`that glucagonoma accounts for 8% of all syndromic pancreatic neuroendocrine
`tumours and for 5% of all pancreatic endocrine tumours presenting during lifem"
`A more recent report suggests that glucagonoma is an underdiagnosed condition,
`because it is asymptomatic for long periods, and produces non-specific symptoms;
`this report suggests that the true incidence may approach that of insulinoma and
`gastrinoma,31 although this has not been confirmed.
`
`
`
`~7_7_.--..-.-.-._....1.
`
`l g
`
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`

`Epidemiology of Pancreatic Neuroendocrine Tumours
`
`9
`
`mas, occur in both pancreatic and extra-pancreatic sites, although the distinction
`between sites has rarely been made.“°‘41 Somatostatinomas have been estimated to
`account for about 1% of all active neuroendocrine tumours of the gut and
`pancreas.‘2 Other very occasional tumours include those producing growth factor
`releasing hormone or growth hormone, parathyroid hormone or parathyroid
`related hormone, or adrenocorticotrophic hormone."3 Some of these tumours
`may be misclassified as non-syndromic if a full screen of potential ectopic
`hormones is not performed.
`
`Carcinoid
`
`Carcinoid tumours of the pancreas are rare, and reports must include at least
`immunohistochemical analysis or appropriate hormone assays to avoid confusion
`from vague terminology. A detailed report is that of thirty cases collected up to
`1995,“3 which found the most frequent symptom to be pain, followed by diarrhoea
`and weight 1053. An atypical carcinoid syndrome characterised by skin flushing
`was found in to cases (33%). Elevated urinary S-hydroxyindole acetic acid levels
`were found in 25 (83%).
`
`I7;,nflv.‘
`
`In the past 20 years more accurate identification of pancreatic neuroendocrine
`tumours has resulted from heightened awareness. supported by improved diag—
`nostic technology as well as development of specialist tertiary referral units.
`Specific reports detailing changes in the incidence of these tumours over time
`suggest that the percentage of non—syndromic tumours has increased during the
`last two to three decades.”32 A study from the Mayo Clinic examining insulinomas
`diagnosed in Olmstead County between 1927—1986 demonstrated a significant
`increase in incidence over time, with no detectable change in age or gender distri-
`bution,26 However, clinical practica has changed so dramatically it is not possible
`to conclude whether such an increase is real or artefactual.
`
`Small Cell Carcinoma
`
`Small cell carcinoma is a poorly differentiated pancreatic tumour composed of
`small to intermediate sized cells with neuroendocrine features. It is extremely rare
`and estimated to account for less than 1% of all (exocrine and endocrine) pancre—
`atic malignancy.“4
`
`Non~syndromic Pancreatic Neuroendocrine Tumours
`
`The reported incidence of non—syndromic tumours has varied from 15—40%,‘3-33'“
`depending on assay and classification procedures.36 Earlier reports included
`glucagonoma and somatostatinoma as non-syndromic tumours, as these do not
`produce obvious hormone-specific symptoms when serum hormone levels are
`low.” However, more recent reports suggest higher numbers of non-syndromic
`tumours, because of increased accuracy in their detection”""~22 (see Table 1.2).
`
`Incidence Trends Over Time
`
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`

`Pancreatic Tumours
`
`Table 1.2. Location, association with MEN-l and incidence of less rare types of pancreatic
`neuroendocrine tumours
`y
`
`humor
`Insulinoma
`Gastrinoma
`Glucagonoma
`Vipoma
`Somatostatinoma
`Non-syndromic tumour
`
`Location
`Pancreas
`50% pancreas
`Pancreas
`Pancreas
`50% pancreas
`Pancreas
`
`Metastases
`10%
`60%
`50—80%
`40-70%
`70%
`60%
`
`% MEN-l
`5%
`25-40%
`10%
`5%
`45%
`20%
`
`Incidence
`1—2 per million
`1—2 per million
`0.1 per million
`0.1 per million
`< 0.1 per million
`14. per million
`
`Sex Distribution
`
`The overall sex distribution for all pancreatic neuroendocrine tumours appears to be
`approximately equal, with variations between syndromic types. For inSulinoma 'most
`series have reported a higher incidence in women;“'1“'3‘*‘5“6 for gastrinoma the male
`to female ratio has been reported at 3:2;W’3 whilst for glucagonoma it
`is 1:2.31
`Somatostatinoma has been reported to be commoner in women“‘” as has
`VlPoma,”'5° whereas small cell carcinoma has been found predominantly in men.“51
`
`
`
`formant-H(henna-gm(1‘
`
`N
`
`H-Hmfixfi‘H-)
`
`_|- and! .—..qmn-m.uanmummamfiw-H—IHWMWWIFJwW-rd MWESSH'W'mmflJf El"
`
`The crude median age for all pancreatic neuroendocrine tumours has been report-
`ed to be 52 years, with children below 15 years of age rarely affected.”"*‘4
`Insulinoma has a Very wide age range but the crude peak incidence occurs between
`40—50 yearsl3’29'45'46 Gastrinomas can occur at any age and in one series children
`formed almost one in 10 of those affected.“7 The peak incidence of sporadic gastri-
`noma occurs between 40—60 years, whereasin association with multiple endocrine
`neoplasia, the peak age is between 20—40 years.25 The reported median age for
`glucagonoma is between 40—70 years,"52 fOr somatostatinoma between 30—
`60 years“"9 and small cell carcinoma between 40—75;“51 as the numbers are few,
`the ranges are wide.
`
`Age Distribution
`
`Geographical and Ethnic Variation
`
`There are no studies examining geographical variation in a meaningful way,
`although there are reported series from both east and west“)
`
`Risk Factors for Pancreatic Neuroendocrine Tumours
`
`Inherited Diseases
`
`Multiple Endocrine Neoplasia Type 1(MEN—1)
`
`This syndrome is characterised by pituitary, parathyroid and pancreatic islet cell
`tumours, produced by mutation of the MEN—i gene encoding menin?‘55 a nuclear
`protein that suppresses cell proliferation.56 Numerous microscopic neuroen-
`
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`

`Epidemiology of Pancreatic Neuroendocrine Tumours
`
`l]
`
`Von Hippel—Lindau Disease (VHL)
`
`This disease is inherited as an autosomal dominant disorder with high penetrande,
`this produces brain and spinal cord haemangioblastomas, retinal angiomas, renal
`cell carcinomas, pancreatic neuroendocrine tumours, phaeochromocytomas,
`endolymphatic sac tumours and‘also papillary cystadenomas of the epididymis
`and broad ligament.6 It results from mutation of the tumour suppressor VHL gene,
`and may rise de novo through somatic mutation}? (See Ch, 12.)
`
`Neurofibromatosis
`
`Type 1 neurofibromatosis (NF 1) affects about 1 in 4000 individuals, and is inheri‘
`ted as an autosomal dominant condition with variable penetrance of mutations in
`the tumour suppressor NFl gene encoding the protein neurofibromin; 50% of
`affected individuals have new mutations.7 It is characterised by multiple pigment—
`ed and thickened patches of skin, neurofibromata of nerves and occasionally,
`phaeochromocytomas. Pancreatic neuroendocrine tumours occur in a small
`minority of affected individuals."3
`
`docrine tumours (0.3—5 mm in diameter) occur throughout the pancreas, occas-
`sionally associated with one or more larger tumours. In individuals with an estab-
`lished diagnosis of MEN-l, between 30—85% have clinical evidence of pancreatic
`neuroendocrine tumours.”58 Autopsies of patients with MEN—1 have shown
`pancreatic neuroendocrine tumours to be invariably present,53 but most are non-
`syndromic and clinically silent. Thus in one surgical series of 132 patients with
`pancreatic neuroendocrine tumours, non-syndromic tumours were identified in
`only eight of 36 (22%) patients with MEN-1, the other 28 having syndromic
`tumours.” Of these, gastrinoma is the commonest; up to 50% of MEN-1 patients
`display typical symptoms.“ Of all patients with gastrinomas, MEN-1 is present in
`one of every four.’1
`
`monfn'63 Somatic mutations of VHL have been found occasionally. It appears that
`
`Tubero us Sclerosis
`
`This rare disorder arises from mutation in the tumour suppressor TSCI or TSC2
`genes, producing focal hyperplasia of neuroglia and neuronal tissue of the brain,
`astrocytoma, rhabdomyoma of the heart, adenoma sebaceum, and uncommonly,
`pancreatic neuroendocrine tumours.8
`
`Sporadic Pancreatic Neuroendocrine Tumours:
`
`Allelic loss of chromosome 11Q, which includes the MEN-l gene, is the most
`frequent chromosomal alteration in these tumours.“ Somatic mutations of the
`MEN-1 gene have been found in 25—50% of sporadic pancreatic neuroendocrine
`tumours, excepting insulinoma, in which somatic MEN-1 mutations are uncom-
`
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`

`He.
`_
`‘m‘llr.--..-....-+-.-r “nun-ru-.—.—:-.m"Wee-mmwtueg-wqaman:.H.z!r-fi't'fldru'l'wm-anI’MII
`
`u --
`
`.-
`
`:-
`
`'- "
`
`12
`
`Pancreatic Tumours
`
`many of the commoner oncogenes and tumour suppressor genes (p53,
`DPC4/SMAD4, PTEN, K-ras, c-myc, c-erb2, c-fos) are of little importance in
`pancreatic neuroendocrine tumour development, although p16/MTSI may have a
`role in gastrinomafhé“
`
`Risk of Malignancy
`
`Traditional histopathological criteria of malignancy have limited application in the
`assessment of primary pancreatic neuroendocrine tumours. Thus uniformity of
`tumour cell appearance can be deceptively reassuring, whilst vascular and/or
`perineural invasion are unusual. Only the presence of local invasion and/or meta~
`stases are definitive in determining malignancy.3"53'5‘ Metastases are most
`commonly found in the liver (up to 80% of cases), less frequently in regional lymph
`nodes, whilst dissemination to other distant sites is unusual.65 Generally, tumours
`composed of cells producing eutopic hormones (that are normally produced by
`pancreatic islets) have a much lower malignancy risk that tumours producing
`ectopic hormones (gastrin,VIP, neurotensin, ACTH), which is useful in prognostic
`evaluation.“1 Overt malignancy has been found in 4—16% of patients with insu-
`linoma,33""""6"’4"7 with a large series of 951 patients reporting overt metastatases in
`5%.46 in contrast, malignant features have been reported in 23—90% of patients
`with gastrinomas,with a consensus of around 60%.3”‘7-"“"““'70 Over 60% of patients
`with glucagonoma have invasive or metastatic disease,33 as do 50—75% of those
`with somatostatinomas”49 and 50—90% of those with VIPomas.33'5° Between
`45—90% of patients with non-syndromic tumours have been reported to have
`invasive or metastatic disease, a wide range that is probably a reflection of selecv
`tion factors such as referral patterns, as well as methods of classification and
`management.7'”*’5 The vast majority of tumours secreting hormones such as
`ACTH, PTH and vasopressin are malignant.M
`
`tumours; 80% of those with benign tumours were alive at 10 years.“3 Most malig—
`
`Management and Prognosis
`
`Staging
`
`Until recently (see Table 1.3“), there has been no relevant staging system, and only
`now are randomised controlled trials underway to test alternative strategies in
`therapy. Furthermore, gastrointestinal carcinoids and pancreatic neuroendocrine
`tumours have often been considered together as gastroenteropancreatic endocrine
`tumours, so that figures for survival are imprecise.
`
`Survival
`
`Overall Survival
`
`The Uppsala group reported a median survival from diagnosis of 8.7 years for all
`pancreatic neuroendocrine tumours, reduced to 6.7 years for those with malignant
`
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`

`Epidemiology of Pancreatic Neuroendocrine Tumours
`
`Tabla 1.3. Consensus classification of pancreatic neuroendocrine tumours developed under the
`auspices of the World Health Organisation 7‘
`Well differentiated:
`Confined to pancreas:
`Benign behaviour:
`Nonangioinvasive
`< 2 cm in size
`Ki-67 proliferationindex < 2%
`< 2 mitoses peril) high power fields
`Uncertain behaviour:
`Angioinvasion
`> 2 cm in size
`Ki~67 proliferation index >2%
`Gross local invasion or metastasis:
`Low grade malignant:
`Often have angioinvasion and/or perineural invasion
`Metastases
`
`Poorly differentiated:
`High grade malignant:
`Highly atypical cells
`Metastases
`
`Comparison ofSyndromic and Non-syndromic Tumours
`
`The overall survival for syndromic tumours, especially those producing eutopic
`hormones, has been consistently longer than for non-syndromic tumours. These
`latter tend to present at a later stage; the rate of liver metastasis amongst patients
`with non~syndrornic tumours has been estimated at 60—90% of cases.“ Eriksson
`and coworkers reported a 5 year survival rate of 42% for non-syndromic tumours
`compared to 80% for syndromic tumoursfl7 Most series confirm non—syndromic
`tumours to have a poorer survival7‘” but some authors contradict this.35'6"'3°
`
`nant pancreatic neuroendocrine tumours grow slowly and are generally associated
`with far longer survivals than other solid tumours. For patients with regional
`and/0r distant metastases, overall 5-year survivals of between 30 and 40% have
`been reported.19'°"73'7‘ In patients with untreated or unresponsive metastatic
`disease, a median survival of 3—4 years has been observed from the time of diag-
`nosis,73 approximately 8 years from the onset of symptoms.” Whilst curative resec—
`tions are rarely possible for metastatic disease, combinations of therapies includ-
`ing surgical debulking andvhormonal inhibition can achieve effective palliation for
`prolonged periods.76 Now that the effects of 1ife~threatening hypersecretion can
`usually be controlled, the commonest cause of death. is liver failure from slow
`tumour progression.”‘-5“-76 However, pharmacological suppression of hormonal
`hypersecretion is not always effective, and the debilitating effects of liVer meta-
`stases may still warrant hepatic resection or other ablative therapies.77
`
`cidence of benign disease, and surgical excision is Curative for most patients.” In
`
`Insulinoma
`
`All series report insulinoma to have an excellent prognosis because of the high in~
`
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`

`-_--=-r:--n_-..--:.r-~:=.-.nast-. 7.Asset:
`
`use fifit‘fli’:
`
`l4
`
`Pancreatic Tumours
`
`earlier reports, peri-operative mortality was attributed to pancreatic fistulas,
`pseudocysts and pancreatitis; more often after enucleation than after distal pancre-
`atectomyfgi“ but with increasing specialisation the complications of pancreatic
`surgery have fallen. Even limited metastatic disease can be cured by surgery: Svyear
`survival rates for metastatic insulinoma have been reported at 30~46%.8‘“
`
`Gastrinoma
`
`
`
`n--. .0."- NIH-1|- H-I'l'l-r'umm -xW¢WM--er.wfiw-W-mhm?wswhyehmmw'w’W-Wmfiwfl- '
`
`Pancreatic neuroendocrine tumours are a rare group of neoplasms with complex
`patterns of behaviour requiring detailed specialist management. Interpretation of
`the current literature is limited by difficulties in classification, diagnosis and
`staging, with no randomised controlled trials that compare alternative treatments
`Descriptive epidemiological studies are based on clinical or autopsy series with
`poorly defined reference populations. Only two population-based studies provide
`estimates of the incidence in life, one at 2.0 per million per year, the other at 4.0 per
`million per year, whilst autopsy series suggest a more frequent occurrence. The
`course of these tumours is often indolent, and although ectopic hormone produc-
`tion can be life threatening, crude survival rates of 50% or more at 5 years have
`been recorded, even for more malignant forms. There is a need for further popu-
`lation-based studies with accurate ascertainment to evaluate the epidemiology of
`these tumours.
`
`Zollinger reported an overall survival of 50% at 10 years for malignant gastri—
`noma.68 Even with liver metastasis the overall 5—year survival has been reported at
`20—33%.fié’68 Gastrinoma is associated with lymph node involvement in 60—80% of
`cases.23 interestingly, lymph node involvement without hepatic or distant metasta—
`sis does not appear to exert a major influence on survival from gastrinoma.48 This
`finding suggests that the presence of lymph node metastases should not necessar-
`ily discourage an aggressive surgical approach.
`
`Other Syndromic Tumours
`
`The majority of patients with glucagonoma have metastatic disease at the time of
`presentation. However, this tumour tends to progress slowly and patients may
`survive for years without treatment.66 VIPomas, often metastatic at the time of
`diagnosis. may be associated with extended survivals, with a median of 3.6 years.27
`Patients with pancreatic carcinoids have fared less well, the median survival being
`7 months in a series of 30 patients, 21 of whom had metastases.79
`
`Summary
`
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`_'H.',_...,.._-,_.__..__..__.._,_wt.
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`._.'.’.'_'__'_:r
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