Neuro
`-endocrinology
`
`
`
`Neuroendocrinology 2004;80(suppl 1):79-84
`DOI: 10.1159/000080747
`
`
`
`Chemotherapyfor Gastro-Enteropancreatic
`Endocrine Tumours
`
`Dermot O’Toole Olivia Hentic Olivier Corcos Philippe Ruszniewski
`
`Service de Gastroentérologie, Hépital Beaujon, Clichy, France
`
`Key Words
`Gastro-enteropancreatic endocrine tumours-
`Chemotherapy- Well-differentiated tumours - Poorly
`differentiated tumours
`
`Abstract
`
`Despite similar histological and morphological aspects,
`gastro-enteropancreatic (GEP) endocrine tumoursrepre-
`sent a heterogeneous group of tumours with varying
`clinical expression depending on tumour type (function-
`al or not), origin and extension, but also on histological
`differentiation and proliferative capacity. The natural his-
`tory of well-differentiated tumours is often favourable
`without treatment and GEP endocrine tumours may
`remain indolent for many years. Chemotherapy may
`however be indicated in the presence of symptomatic
`non-progressive disease (progression evaluated over 3—
`6 months). In contrast, poorly differentiated GEP endo-
`crine tumoursare frequently aggressive and early treat-
`ment is required. Accurate staging is mandatory and
`where surgery is possible (even in the event of limited
`metastatic disease), this option should be re-evaluated in
`a multidisciplinary approach. Approximately 2/3 of ma-
`lignant GEP tumoursare metastatic at discovery and sur-
`gery is possible in a minority of patients; therefore, che-
`motherapy, with/without other strategies (e.g. local abla-
`
`tion), is frequently indicated in patients with symptomat-
`ic, bulky or progressive disease. For well-differentiated
`pancreatic tumours, the reference association is Adria-
`mycin with streptozotocin yielding objective responses
`(OR) in 40-60% of patients. Prolonged treatmentis lim-
`ited due to potential cardiotoxicity of Adriamycin and
`standard 2nd-line regimens are notof proven efficacy;
`thus, other treatment modalities are usually additionally
`required (e.g. chemo-embolisation). A significant OR
`may render a small number of patients secondarily am-
`enable to surgery. Published series evaluating chemo-
`therapy for midgut endocrine tumours are outdated and
`disappointing. Objective response rates with combined
`associations (including either 5-fluorouracil and/or strep-
`tozotocin) rarely exceed 20% and where possible, che-
`mo-embolisation for hepatic metastases combined with
`somatostatin analogues (+ interferon) should be pre-
`ferred. Poorly differentiated GEP tumours are generally
`aggressive tumours with metastases at diagnosis and
`tend to progress rapidly. Surgery is rarely possible and
`ineffective even in locally advanced disease due to a high
`risk of recurrence. Chemotherapy, using cisplatin and
`etoposide,
`is the reference treatment and frequently
`yields OR rates >50%. However, despite being chemo-
`sensitive, disease control is limited (8-10 months). Over-
`all, advances in therapeutic chemotherapeutic options
`are required in the managementofall types of advanced
`
`KARG E R
`Fax + 41 61 306 12 34
`E-Mail karger@karger.ch
`www.karger.com
`
`© 2004 S. Karger AG,Basel
`0028-3835/04/0807-0079$21.00/0
`
`Accessible online at:
`www. karger.com/nen
`
`D. O'Toole
`Service de Gastroentérologie, Hépital Beaujon
`100, boulevard du Général Leclerc
`FR-92110 Clichy Cedex (France)
`Tel. +33 1 40 87 57 33, Fax +33 1 42 70 37 84, E-Mail dermot.otoole@bjn.ap-hop-paris.fr
`
`West-Ward Pharm.
`Exhibit 1063
`Page 001
`
`West-Ward Pharm.
`Exhibit 1063
`Page 001
`
`

`

`GEP endocrine tumours and evaluation of new drugs
`(e.g. irinotecan) and combination strategies (chemother-
`apy with local ablative therapies) are required in the
`future.
`
`Copyright © 2004 S. Karger AG,Basel
`
`Introduction
`
`Endocrine tumours of gastro-enteropancreatic (GEP)
`origin are a heterogeneous group of tumours of variable
`prognosis. The natural history varies from a frequently
`indolent course for tumours which are well differentiated
`to a much more aggressive form with poorly differen-
`tiated tumours. The principles of managementofpatients
`with GEP endocrine tumours depend on a numberoffac-
`tors requiring a multidisciplinary approach. Recent ad-
`vances in surgery imply that patients even with bilobar
`liver metastases may be deemed suitable to surgery using
`two-stage hepatectomies[1, 2] and therefore prior to con-
`sidering patients for chemotherapy, a surgical option
`should always be reconsidered. Nonetheless, surgery is
`rarely possible in patients with metastatic disease and oth-
`er approachesare therefore necessary.
`As opposed to treatment decisions for other solid
`tumours of the digestive tract, ‘wait-and-see’ strategies
`can often be adopted in patients with GEP tumours.
`The slow-growing nature of well-differentiated tumours
`means that chemotherapy and other treatment strategies
`should be reserved for patients with progressive disease.
`Indeed, to date interpretation of data on treatment of
`patients with GEP tumours has been hampered by the
`lack of evidence for progressive disease in a number of
`studies. Documented progression (on eithersolid clinical
`groundsora = 25%increasein targeted lesions or appear-
`ance of a new disease in patients with non-symptomatic
`disease) should be based on accurate and comparable
`evaluation ofclinical, biological and morphological data
`at least at 3-monthly intervals. Given that response to
`cytotoxic agents in patients with GEP tumours may be
`short-lived, determining the correct moment to com-
`mence treatmentis often difficult. Early treatment at the
`outset is, on the contrary, usually necessary for patients
`with aggressive well-differentiated tumours and for those
`with poorly differentiated lesions whose natural history
`mirrors that of small cell lung cancer. Another consider-
`ation in commencingtreatmentat the momentof diagno-
`sis is the presence ofbulky disease, especially the presence
`of extensive liver metastases (usually >70%).
`
`Until now, the type of chemotherapy has been largely
`based onthesite of origin of the primary tumour and on
`the histological differentiation. Endocrine tumoursof the
`duodenum or pancreas, whether functional or not, are
`considered for cytotoxic regimens, which greatly differ
`from those of midgut origin. In addition, given that
`tumour differentiation also dictates response to individu-
`al cytotoxic protocols, correct histological classification
`should be applied using strict WHOcriteria [3]. Accurate
`histological classification is not always easy as interob-
`server differences among pathologists are not uncommon
`and guidelines to increase uniformity are required. The
`importance of accurate histology cannot be underesti-
`mated and in cases where doubt exists, slides should be
`sent for an expert opinion. The recentuse ofthe prolifera-
`tion index Ki-67 has been helpful in distinguishing certain
`tumours and guiding treatment regimens; this markeris
`invariably high (>15%) in poorly differentiated lesions;
`however,cases with a histological architecture resembling
`well-differentiated tumours and moderately elevated Ki-
`67 (between 2 and 15% or‘borderline tumours’) [3] may
`be problematic when it comes to choosing chemotherapy.
`The appraisal of proliferation indices on treatment out-
`comesis requisite in future protocols.
`
`Chemotherapyfor Well-Differentiated GEP
`Tumours of the Pancreas or Duodenum
`
`Apart from insulinomas, other GEP tumours from the
`pancreas or duodenum are frequently associated with
`metastatic disease and curative surgical optionsare rarely
`possible (<25%) [4]. Thus, cytotoxic therapyis a frequent-
`ly posed question in these patients. Single-agent chemo-
`therapy with streptozotocin yielded tumour response
`rates of between 36 and 42% [5, 6]; however, these early
`studies can becriticized with respect to the crude methods
`ofinterpreting morphological responses. Other monother-
`apies including chlorozotocin, doxorubicin, 5-fluorouracil
`(5-FU)[7] or dacarbazine[5, 8] have been used butcriti-
`cised either due to the high toxicity rate or lack of objec-
`tive response. Such strategies have been universally re-
`placed by combination chemotherapy protocols. As seen
`in table 1, many associations have been used with strepto-
`zotocin, 5-FU and anthracyclines forming the cornerstone
`of the regimens tested. The results by Moertelet al. [9] in
`1992 using streptozotocin and doxorubicin have not been
`bettered to date, with a 69% objective response rate and a
`median survival of 26 months; this compared to a 45%
`objective response rate for 5-FU and streptozotocin. The
`
`80
`
`Neuroendocrinology 2004;80(suppl 1):79-84
`
`O’Toole/Hentic/Corcos/Ruszniewski
`
`West-Ward Pharm.
`Exhibit 1063
`Page 002
`
`West-Ward Pharm.
`Exhibit 1063
`Page 002
`
`

`

`Table 1. Combination chemotherapy for
`well-differentiated endocrine tumoursof
`the pancreas and duodenum
`
`Reference
`
`Phase Regimen
`
`Moertelet al. [10]
`
`Moertelet al. [9]
`
`Erikssonet al. [13]
`Bukowskiet al. [14]
`Rivera and Ajani[11]
`Cheng andSaltz [15]
`Bajetta et al. [37]
`
`III
`
`Ill
`
`II
`II
`II
`II
`II
`
`STZ
`STZ +5-FU
`DOX + STZ
`5-FU + STZ
`DOX + STZ
`CLZ +5-FU
`STZ +5-FU + DOX
`DOX + STZ
`5-FU+EPI+DTIC
`
`n
`
`42
`42
`36
`33
`25
`44
`12
`16
`15
`
`Objective Response Median
`response duration survival
`%
`months months
`
`36
`63
`69
`45
`36
`36
`55
`6
`27
`
`17
`17
`18
`14
`22
`11
`15
`18
`10
`
`17
`26
`26
`18
`-
`-
`21
`-
`-
`
`STZ = Streptozotocin; DOX = doxorubicin; CLZ = chlorozotocin; EPI = epirubicin;
`DTIC = dacarbazine.
`
`same group had previously obtained better results with
`5-FU/streptozotocin in a phase III trial comparison to
`monotherapywith streptozotocin [10]. While no group has
`managed to achieve the same response rates, objective
`response rates of between 36 and 55% have been estab-
`lished using streptozotocin/doxorubicin [11-14] with the
`exception of Chenget al. [15] who reported a 6% response
`rate in a group of 16 patients. Chenget al. [15] in their
`article questioned the reliability of the earlier studies by
`Moertel et al. [9] especially concerning methods of mea-
`suring responses. However,a recent report by Delaunoit et
`al. [12] in 45 patients found a 36% overall response rate
`using well-defined criteria for recruitment and evaluation;
`in addition, 2- and 3-year overall survival rates were 50
`and 24%, respectively. Such discrepancies are difficult to
`explain; however, while the 69% response rates by Moer-
`tel’s group have not been re-achieved, a combination of
`streptozotocin with either doxorubicin or 5-FU in the
`treatment of advanced GEP tumours of the pancreas or
`duodenum is supported by recent data [11-14]. Nonethe-
`less, despite being the standard treatment, newer agents
`needto be tested in appropriate phase II andIII trials.
`The cumulative cardiotoxicity of doxorubicin, quick-
`ly attained following the standard Moertel regimen (the
`prevalence of cardiomyopathy increases significantly
`when patients are given doses of doxorubicin >550 mg/
`m? [16]) meansthat strategies with 5-FU should be con-
`sidered either at the outset or following maximal treat-
`ment with anthracyclines. The use of agents with less car-
`diotoxicity may also be worthwhile (e.g. epiadriamycin
`and liposomal formulations [17, 18]); however, appraisal
`of both efficacy and toxicity is required prior to universal
`approval for this indication. Careful monitoring of renal
`
`function with 24-hour proteinuria prior to each cycle
`administration of streptozotocin is advised to avoid per-
`manent renal damage. Nausea and vomiting are usually
`not problematic provided adequate antiemetics are sys-
`tematically administered (we combine 5-HT;inhibitors
`with corticosteroids on a routine basis unless otherwise
`contra-indicated).
`
`Well-Differentiated GEP Tumours of Midgut
`Origin
`
`Similar to well-differentiated GEP tumoursof the pan-
`creas and duodenum, in GEP tumours of midgutorigin,
`single-agent regimens have been largely disappointing
`with objective response rates <25% and response dura-
`tions rarely exceeding 3 months[5]. In 1979, Moertel and
`Hanley [19] combined 5-FU with streptozotocin in mid-
`gut carcinoids yielding a response rate of 33%. Studies
`using the same combination since then have failed to
`reproducetheseresults (table 2) [20-23]. Therefore, other
`combinations have also been examined and apart from a
`40% objective response rate for patients with midgutcar-
`cinoids observed using doxorubicin andstreptozotocin in
`a phaseII study [24], no otherreliable cytotoxic regimen
`has been found for patients with advanced or metastatic
`disease of midgut origin. The association of cytotoxics
`with interferon has also been investigated with largely
`poor outcomesuccess apart from one study by Andreyev
`et al. [25] who demonstrated a 47% objective response
`using a combination of interferon with continuous infu-
`sion of 5-FU; response duration lasted 21 months. The
`excellent, and reproducible, results obtained with chemo-
`
`Chemotherapy for Gastro-Enteropancreatic
`Endocrine Tumours
`
`Neuroendocrinology 2004;80(suppl 1):79-84
`
`81
`
`West-Ward Pharm.
`Exhibit 1063
`Page 003
`
`West-Ward Pharm.
`Exhibit 1063
`Page 003
`
`

`

`Table 2. Combination chemotherapy for
`well-differentiated GEP tumours of midgut
`origin
`
`Reference
`
`Phase Regimen
`
`Moertel and Hanley[19]
`
`Engstrom etal. [20]
`
`Moerteletal. [21]
`
`Frameetal. [24]
`Moertelet al. [22]
`Di Bartolomeo etal. [23]
`
`Ill
`
`Ill
`
`Ill
`
`II
`II
`II
`
`5-FU + cyclophosphamide
`5-FU + STZ
`5-FU + STZ
`DOX
`MTX + cyclophospahmide
`STZ + cyclophosphamide
`DOX + STZ
`VP 16 + cisplatin
`5-FU + DOX + DTIC
`
`n
`
`47
`422
`80
`81
`16
`14
`33
`13
`20
`
`Objective Median
`response
`survival
`%
`months
`
`26
`33
`22
`21
`0
`0
`40
`0
`~=10
`
`-
`-
`15
`11
`-
`-
`11
`-
`5
`
`STZ = Streptozotocin; DOX = doxorubicin; DTIC = dacarbazine.
`
`Table 3. Combination chemotherapy for
`poorly differentiated GEP tumours
`
`Reference
`
`Regimen
`
`Moertelet al. [22]
`Seitz et al. [28]
`Mitry et al. [29]
`
`etoposide + cisplatin
`etoposide + cisplatin
`etoposide + cisplatin
`
`1
`
`65% survival at 1 year.
`
`n
`
`18
`11
`41
`
`Objective Duration Median
`response
`ofresponse
`survival
`%
`months
`months
`
`67
`54
`42
`
`8
`-
`9
`
`19
`-!
`15
`
`embolisation in patients with hepatic metastases and car-
`cinoid syndrome (tumourresponserates of approximate-
`ly 40-50% andexcellent control of symptoms) [26] argue
`for its use in such patients with liver metastases. In
`patients with extensive disease outside of the liver (e.g.
`carcinomatosis or bony metastases), current treatment
`strategies are wanting and novel approachesusing peptide
`receptor radionuclide therapy [27] have appeared more
`seductive to date than endlesstrials with largely ineffec-
`tive cytotoxics. Investigation of newer treatment options
`such as targeted molecular approaches mayalso prove of
`value in these patients.
`
`Chemotherapyof Poorly Differentiated GEP
`Tumours
`
`Standard treatment in patients with advanced poorly
`differentiated GEP tumours has largely been based on
`protocols containing etoposide and cisplatin (table 3).
`While tumour response rates are often good (42-65%),
`duration of response rarely exceeds 10 months and me-
`
`dian survival is in the order of 15 months [22, 28, 29].
`Newer options are required for the treatment of these
`patients.
`
`OtherIndications for Chemotherapy in GEP
`Tumours (Adjuvant or Neo-Adjuvant)
`
`To date, there have been no data to support the system-
`atic use of chemotherapy in an adjuvant setting. Some
`units have adoptedpolicies of 4 cycles of adjuvant chemo-
`therapy following resection of hepatic metastases (includ-
`ing some unpublished personal observations); however,
`evaluation of such treatment requires a randomized study
`comparing adjuvant treatmentto surgery alone. Adjuvant
`chemotherapy is frequently employed following hepatic
`transplantation for metastases of digestive GEP tumours
`[2, 30]; however,its indication has not been evaluated and
`such a study would provevery difficult given the rarity of
`transplantation in this setting. While chemotherapy in a
`neo-adjuvant setting has not been formally evaluated in
`patients with digestive GEP tumours, we and others have
`
`82
`
`Neuroendocrinology 2004;80(suppl 1):79-84
`
`O’Toole/Hentic/Corcos/Ruszniewski
`
`West-Ward Pharm.
`Exhibit 1063
`Page 004
`
`West-Ward Pharm.
`Exhibit 1063
`Page 004
`
`

`

`performed resection of both primary tumours andliver
`metastases following excellent chemotherapy-induced ob-
`jective responses (personal experience). A surgical ap-
`proach should be discussed where chemotherapy or other
`strategies render patients (event with metastatic disease)
`operable.
`
`Perspectives
`
`Agents showing promisingresults in the setting of oth-
`er solid gastro-intestinal tumours have been applied to
`patients with GEP tumours. Irinotecan, in a single-agent
`form, has recently been found to be inactive in patients
`with carcinoid syndrome [31]. Paclitaxel in high dose
`(250 mg/m) was also found to be disappointing with an
`8% response rate and significant haematological toxicity
`[32]. A search for expression of tyrosine kinase receptors,
`namely c-kit, has also been performed in GEP tumours.
`Fyallskog etal. [33] found 35 of 38 tissue specimens (92%)
`from GEP tumoursto express c-kit on tumourcells. How-
`ever, a phaseII trial using the PDGF-Rinhibitor imatinib
`(found to be revolutionary in gastro-intestinal stromal
`
`tumours) in 21 patients with advanced GEP tumours
`demonstrated only weak biological activity with a partial
`responsein only 1 patient; 8 patients with progressive dis-
`ease at study entry were progression-free at 3 months[34].
`This might be explained by the mixed results for c-kit
`staining found in GEP tumoursas highlighted by Theo-
`dossiouetal. [35] who found only 9% positive weak stain-
`ing in 21 patients with metastatic GEP tumours. Interest-
`ingly,
`inhibitors of epidermal growth factor receptors
`have shown antiproliferative activity in in vitro GEP
`tumour models. Hopfneret al. [36] demonstrated a time-
`and dose-dependantgrowth inhibition of the insulinoma
`cell line as well as in pancreatic BON cells and in gut
`SCT-1 cells. Discerning antiproliferative mechanisms
`should provide more efficacious chemotherapeutics and
`molecular arsenals for the targeting of these tumours. One
`such approach which should work stems from the vascu-
`larity of such tumoursallowing the intriguing prospect of
`developing anti-angiogenic agents(e.g. anti-VEGFfactors
`and inhibitors of EGF-R) and while industry-driven re-
`search is mainly focused on otherdigestive solid tumours,
`advances in the latter area will no doubt aid in our
`approach to GEP tumours.
`
`References
`
`13 Eriksson B, Skogseid B, Lundqvist G, Wide L,
`7 Moertel CG, Lavin PT, Hahn RG: Phase II
`1 Kianmanesh R, Farges O, Abdalla EK, Sauva-
`Wilander E, Oberg K: Medical treatment and
`trial of doxorubicin therapy for advancedislet
`net A, Ruszniewski P, Belghiti J: Right portal
`long-term survival in a prospective study of 84
`cell carcinoma. Cancer Treat Rep 1982;66:
`vein ligation: A new planned two-step all-surgi-
`patients with endocrine pancreatic tumors.
`1567-1569.
`cal approach for complete resection of primary
`Cancer 1990;65:1883-1890.
`8 Altimari AF, Badrinath K, Reisel HJ, Prinz
`gastrointestinal tumors with multiple bilateral
`14 Bukowski RM, Tangen C, Lee R, Macdonald
`RA: DTICtherapy in patients with malignant
`liver metastases. J Am Coll Surg 2003;197:
`JS, Einstein AB Jr, Peterson R, Fleming TR:
`intra-abdominal neuroendocrine tumors. Sur-
`164-170.
`PhaseII trial of chlorozotocin and fluorouracil
`gery 1987;102:1009-1017.
`2 O’Toole D, Kianmanesh R, Farges O, Rusz-
`in islet cell carcinoma: A Southwest Oncology
`9 Moertel CG, Lefkopoulo M, Lipsitz S, Hahn
`niewski P: Treatment of pancreatic-duodenal
`Group study. J Clin Oncol 1992;10:1914—
`RG, Klaassen D: Streptozocin-doxorubicin,
`endocrine tumors. Rev Prat 2002;52:1546—
`1918.
`streptozocin-fluorouracil or chlorozotocin in
`1553.
`15 Cheng PN,Saltz LB: Failure to confirm major
`the treatment of advanced islet-cell carcinoma.
`3 Solcia E, Kléppel G, Sobin LH: Histological
`objective antitumor activity for streptozocin
`N Engl J Med 1992;326:519-523.
`typing ofendocrine tumours; in Solcia E, Klép-
`
`pel G, Sobin LH (eds): Histological Typing of|10 Moertel CG, Hanley JA, Johnson LA:Strepto- and doxorubicin in the treatment of patients
`Endocrine Tumours(International Classifica-
`zocin alone compared with streptozocin plus
`with advanced islet cell carcinoma. Cancer
`tion of Tumours), ed 2. New York, Springer,
`fluorouracil in the treatment of advancedislet-
`1999;86:944-948,
`2000.
`cell carcinoma. N Engl J Med 1980;303:1189-
`16 Yeh ET, Tong AT, Lenihan DJ, Yusuf SW,
`4 McEntee GP, Nagorney DM, Kvols LK, Moer-
`1194.
`Swafford J, Champion C, Durand JB, Gibbs H,
`tel CG, Grant CS: Cytoreductive hepatic sur-
`11 Rivera E, Ajani JA: Doxorubicin, streptozocin,
`Zafarmand AA, Ewer MS: Cardiovascular
`gery for neuroendocrine tumors. Surgery 1990;
`and 5-fluorouracil chemotherapy for patients
`complications of cancer therapy: Diagnosis,
`108:1091-1096.
`with metastatic islet-cell carcinoma. Am J Clin
`pathogenesis, and management. Circulation
`5 Moertel CG: Karnofsky memorial lecture. An
`Oncol 1998;21:36-38.
`2004; 109:3122-3131.
`odyssey in the land of small tumors. J Clin
`12 Delaunoit T, Ducreux M, Boige V,DromainC,
`17 Gill PS, Espina BM, Muggia F, Cabriales S,
`Oncol 1987;5:1502-1522.
`Sabourin JC, Duvillard P, Schlumberger M,de
`Tulpule A, Esplin JA, Liebman HA,Forssen E,
`6 Broder LE, Carter SK: Pancreatic islet cell car-
`Baere T, Rougier P, Ruffie P,et al: The doxoru-
`Ross ME, Levine AM: Phase I/II clinical and
`cinoma. 2, Results of therapy with streptozoto-
`bicin-streptozotocin combination for the treat-
`pharmacokinetic evaluation of liposomal dau-
`cin in 52 patients. Ann Intern Med 1973;79:
`mentof advanced well-differentiated pancreat-
`norubicin. J Clin Oncol 1995;13:996-1003.
`108-118.
`ic endocrine carcinoma; a judicious option?
`Eur J Cancer 2004;40:515-520,
`
`Chemotherapy for Gastro-Enteropancreatic
`Endocrine Tumours
`
`Neuroendocrinology 2004;80(suppl 1):79-84
`
`83
`
`West-Ward Pharm.
`Exhibit 1063
`Page 005
`
`West-Ward Pharm.
`Exhibit 1063
`Page 005
`
`

`

`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`Levine AM, Tulpule A, Espina B, Sherrod A,
`Boswell WD, Lieberman RD, Nathwani BN,
`Welles L: Liposome-encapsulated doxorubicin
`in combination with standard agents (cyclo-
`phosphamide, vincristine, prednisone) in pa-
`tients with newly diagnosed AIDS-related non-
`Hodgkin’s lymphoma:Results of therapy and
`correlates of response. J Clin Oncol 2004;22:
`2662-2670.
`Moertel CG, Hanley JA: Combination chemo-
`therapy trials in metastatic carcinoid tumor
`and the malignant carcinoid syndrome. Cancer
`Clin Trials 1979;2:327-334.
`Engstrom PF, Lavin PT, Moertel CG,Folsch E,
`Douglass HO Jr: Streptozocin plus fluorouracil
`versus doxorubicin therapy for metastatic car-
`cinoid tumor, J Clin Oncol 1984;2:1255-
`1259.
`Moertel CG, O’Connell MJ, Reitemeier RJ,
`Rubin J: Evaluation of combined cyclophos-
`phamide and methotrexate therapy in the treat-
`ment of metastatic carcinoid tumor and the
`malignant carcinoid syndrome. Cancer Treat
`Rep 1984;68:665-667.
`Moertel CG, Kvols LK, O’Connell MJ, Rubin
`J: Treatment of neuroendocrine carcinomas
`with combined etoposide and cisplatin. Evi-
`dence of major therapeutic activity in the ana-
`plastic variants of these neoplasms. Cancer
`1991;68:227-232.
`Di Bartolomeo M, Bajetta E, Bochicchio AM,
`Carnaghi C, Somma L, Mazzaferro V, Visini
`M, Gebbia V, Tumolo §, Ballatore P: A phase
`II trial of dacarbazine, fluorouracil and epiru-
`bicin in patients with neuroendocrine tumours.
`A study bythe Italian Trials in Medical Onco-
`logy (ITMO) Group. Ann Oncol 1995;6:77-
`79.
`
`24
`
`25
`
`26
`
`27
`
`28
`
`29
`
`30
`
`Frame J, Kelsen D, Kemeny N, Cheng E,
`Niedzwiecki D, Heelan R, Lippermann R: A
`phaseII trial of streptozotocin and adriamycin
`in advanced APUD tumors. Am J Clin Oncol
`1988;11:490-495,
`Andreyev HJ, Scott-Mackie P, Cunningham D,
`Nicolson V, Norman AR, BadveSS, Iveson A,
`Nicolson MC: Phase II study of continuous
`infusion fluorouracil and interferon alfa-2b in
`the palliation of malignant neuroendocrinetu-
`mors. J Clin Oncol 1995;13:1486-1492.
`O’Toole D, Maire F, Ruszniewski P: Ablative
`therapies for liver metastases ofdigestive endo-
`crine tumours. Endocr Relat Cancer 2003;10:
`463-468.
`Krenning EP, Kwekkeboom DJ, Valkema R,
`Pauwels S, Kvols LK, De Jong M: Peptide
`receptor radionuclide therapy. Ann N Y Acad
`Sci 2004; 1014:234-245.
`Seitz J, Perrier H, Giovannini M, Monges G,
`Fourdan O, Barrriére N Viens P: Cancers neu-
`roendocrines anaplasiques avancés: intérét de
`Passociation VP16-CDDP.Bull Cancer 1995;
`82:433-434.
`Mitry E, Baudin E, Ducreux M, Sabourin JC,
`Rufie P, Aparicio T, Lasser P, Elias D, Duvil-
`lard P, Schlumberger M,et al: Treatment of
`poorly differentiated neuroendocrine tumours
`with etoposide and cisplatin. Br J Cancer 1999;
`81:1351-1355.
`Fernandez JA, Robles R, Marin C, Hernandez
`Q, Sanchez Bueno F, Ramirez P, Rodriguez
`JM, Lujan JA, Navalon JC, Parrilla P: Role of
`liver transplantation in the management of
`metastatic neuroendocrine tumors. Transplant
`Proc 2003;35:1832-1833.
`
`31
`
`32
`
`33
`
`34
`
`35
`
`36
`
`37
`
`Baker J, Schnirer II, Yao JC, Carr K, Ho L,
`Ajani JA: PhaseIItrial of irinotecan in patients
`with advancedcarcinoid tumour. Proc Am Soc
`Clin Oncol 2002;21:662.
`Ansell SM, Pitot HC, Burch PA, Kvols LK,
`Mahoney MR, Rubin J: A phase II study of
`high-dose paclitaxel in patients with advanced
`neuroendocrine
`tumors. Cancer
`2001;91:
`1543-1548.
`Carr K, Yao JC, Rashid A, Yeung S-C, Skela-
`ruk J, Baker J, Vaugthey JN, Curley S, Ellis L,
`Ajani JA: A phaseII trial of imatinib in pa-
`tients with advanced carcinoid tumour. Proc
`AmSoc Clin Oncol 2003;22:4124.
`Fjallskog ML, Lejonklou MH, Oberg KE,
`Eriksson BK, Janson ET: Expression of molec-
`ular targets for tyrosine kinase receptor antago-
`nists in malignant endocrine pancreatic tu-
`mors. Clin Cancer Res 2003;9:1469-1473.
`Theodossiou C, Fayard N, Anthony L, Sartin
`B: CD-117 expression in carcinoid tumors.
`Proc Am Soc Clin Oncol 2003;22:378.
`Hopfhner M,Sutter AP, Gerst B, Zeitz M, Sche-
`rubl H: A novel approach in the treatment of
`neuroendocrine gastrointestinal tumours. Tar-
`geting the epidermal growth factor receptor by
`gefitinib (ZD1839). Br J Cancer 2003;89:
`1766-1775.
`Bajetta E, Rimassa L, Carnaghi C, SeregniE,
`Ferrari L, Di Bartolomeo M,Regalia E, Cassa-
`ta A, Procopio G, Mariani L; 5-Fluorouracil,
`dacarbazine, and epirubicin in the treatment of
`patients with neuroendocrine tumors. Cancer
`1998;83:372-378.
`
`84
`
`Neuroendocrinology 2004;80(suppl 1):79-84
`
`O’Toole/Hentic/Corcos/Ruszniewski
`
`West-Ward Pharm.
`Exhibit 1063
`Page 006
`
`West-Ward Pharm.
`Exhibit 1063
`Page 006
`
`