Neuro
`endocrinology
`
`Neuroendocrinology 2004;80(supp| 1):79—84
`DOI: 10.1159/000080747
`
`Chemotherapy for Gastro-Enteropancreatic
`Endocrine Tumours
`
`Dermot O'Toole Olivia Hentic Olivier Corcos Philippe Ruszniewski
`
`Service de Gastroentérologie, Hopital Beaujon, Clichy, France
`
`Key Words
`Gastro-enteropancreatic endocrine tumours -
`Chemotherapy - We||—differentiated tumours - Poorly
`differentiated tumours
`
`Abstract
`
`Despite similar histological and morphological aspects,
`gastro-enteropancreatic (GEP) endocrine tumours repre-
`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 we||—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 tumours are 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 tumours are 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 treatment is lim-
`ited due to potential cardiotoxicity of Adriamycin and
`standard 2nd—|ine regimens are not of proven efficacy;
`thus, other treatment modalities are usually additionally
`required (e.g. chemo—embo|isation). 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`therapy for midgut endocrine tumours are outdated and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 (i 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 management of all types of advanced
`
`E R
`Fax +41 61 306 12 34
`E-Mail k1uger@ka.tger. ch
`www.karger.com
`
`© 2004 S. Karger AG, Basel
`0028-3835/04/0807—0079$21.00/0
`
`Accessible online at:
`www.karger.comlnen
`
`D. O’Toole
`Service de Gastroentérologie, Hépital Beaujon
`100, boulevard du Général Leclerc
`FR—921 10 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
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`

`

`GEP endocrine tumours and evaluation of new drugs
`(e.g. irinotecan) and combination strategies (chemother-
`apy with local ablative therapies) are required in the
`futu re.
`
`Copyright© 2004 S. KargerAG, 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 management of patients
`with GEP endocrine tumours depend on a number of fac-
`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 approaches are 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 either solid clinical
`grounds or a 2 25 °/o increase in targeted lesions or appear-
`ance of a new disease in patients with non-symptomatic
`disease) should be based on accurate and comparable
`evaluation of clinical, 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 treatment is 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 commencing treatment at the moment of diagno-
`sis is the presence of bulky disease, especially the presence
`of extensive liver metastases (usually >70%).
`
`Until now, the type of chemotherapy has been largely
`based on the site of origin of the primary tumour and on
`the histological differentiation. Endocrine tumours of 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 WHO criteria [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 recent use of the prolifera-
`tion index Ki-67 has been helpful in distinguishing certain
`tumours and guiding treatment regimens; this marker is
`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-
`comes is requisite in future protocols.
`
`Chemotherapy for 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 options are rarely
`possible (<25 %) [4]. Thus, cytotoxic therapy is 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 be criticized with respect to the crude methods
`of interpreting morphological responses. Other monother-
`apies including chlorozotocin, doxorubicin, 5-fluorouracil
`(5-FU) [7] or dacarbazine [5, 8] have been used but criti-
`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 Moertel et 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
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`Neuroendocrinology 2004;80(suppl 1):79—84
`
`O’Toole/Hentic/Corcos/Ruszniewski
`
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`Table 1 . Combination chemotherapy for
`well-differentiated endocrine tumours of
`the pancreas and duodenum
`
`
`
`Moertel et a1. [10]
`
`Moertel et al. [9]
`
`Eriksson et al. [13]
`Bukowski et al. [14]
`Rivera and Ajani [1 1]
`Cheng and Saltz [15]
`Bajetta et al. [37]
`
`III
`
`III
`
`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
`
`42
`42
`36
`33
`25
`44
`12
`16
`15
`
`36
`6 3
`69
`45
`36
`36
`55
`6
`27
`
`17
`17
`18
`14
`22
`1 1
`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
`monotherapy with 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 [1 1-14] with the
`exception of Cheng et al. [15] who reported a 6% response
`rate in a group of 16 patients. Cheng et 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 [1 1-14]. Nonethe-
`less, despite being the standard treatment, newer agents
`need to be tested in appropriate phase II and III 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/
`m2 [l6]) means that 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-HT3 inhibitors
`with corticosteroids on a routine basis unless otherwise
`
`contra-indicated).
`
`Well-Differentiated GEP Tumours of Midgut
`Origin
`
`Similar to well-differentiated GEP tumours of the pan-
`creas and duodenum, in GEP tumours of midgut origin,
`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
`reproduce these results (table 2) [20—23]. Therefore, other
`combinations have also been examined and apart from a
`40% objective response rate for patients with midgut car-
`cinoids observed using doxorubicin and streptozotocin in
`a phase II study [24], no other reliable 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 outcome success 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
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`Table 2. Combination chemotherapy for
`well-differentiated GEP tumours of midgut
`origin
`
`
`
`Moertel and Hanley [19]
`
`Engstrom et al. [20]
`
`Moertel et al. [21]
`
`Frame et al. [24]
`Moertel et al. [22]
`Di Bartolomeo et al. [23]
`
`III
`
`III
`
`III
`
`II
`II
`II
`
`5-FU + cyclophosphamide
`5-FU + STZ
`5-FU + STZ
`DOX
`MTX + cyclophospahmide
`STZ + cyclophosphamide
`DOX + STZ
`VP 1 6 + cisplatin
`5-FU + DOX + DTIC
`
`47
`422
`80
`81
`16
`14
`33
`13
`20
`
`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
`
`Moertel et al. [22]
`Seitz et al. [28]
`Mitry et al. [29]
`
`etoposide + cisplatin
`etoposide + cisplatin
`etoposide + cisplatin
`
`18
`11
`41
`
`67
`54
`42
`
`8
`—
`9
`
`19
`-1
`15
`
`1
`
`65% survival at 1 year.
`
`embolisation in patients with hepatic metastases and car-
`cinoid syndrome (tumour response rates of approximate-
`ly 40-50% and excellent 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 approaches using peptide
`receptor radionuclide therapy [27] have appeared more
`seductive to date than endless trials with largely ineffec-
`tive cytotoxics. Investigation of newer treatment options
`such as targeted molecular approaches may also prove of
`value in these patients.
`
`Chemotherapy of 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.
`
`Other Indications 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 adopted policies 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 treatment to 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 prove very 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
`
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`performed resection of both primary tumours and liver
`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 promising results 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/m2) 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.
`Fjéillskog et al. [33] found 35 of 38 tissue specimens (92%)
`from GEP tumours to express c-kit on tumour cells. How-
`ever, a phase II trial using the PDGF-R inhibitor 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
`response in 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 tumours as highlighted by Theo-
`dossiou et al. [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. Hopfner et al. [36] demonstrated a time-
`and dose-dependant growth 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 tumours allowing the intriguing prospect of
`developing anti-angiogenic agents (e.g. anti-VEGF factors
`and inhibitors of EGF-R) and while industry-driven re-
`search is mainly focused on other digestive solid tumours,
`advances in the latter area will no doubt aid in our
`
`approach to GEP tumours.
`
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