Chemotherapy of Metastatic Carcinoid and Islet Cell Tumors
`
`A Review
`
`LARRY K. KVOLS, M.D.
`MARTIN BUCK, F.R.A.C.P.
`Rochester.
`Minnesota
`
`Depart-
`Oncology,
`of Medical
`the Division
`From
`Founda-
`and Mayo
`Mayo Clinic
`ment of Oncology,
`in
`this
`The material
`Minnesota.
`tion, Rochester,
`submitted
`to Seminars
`review was part of an article
`in Oncology,
`which
`is
`in press.
`Requests
`for
`re-
`prints
`should
`be addressed
`to Dr. Larry
`K. Kvols,
`Division
`of Medical
`Oncology,
`Mayo
`Clinic,
`200
`First
`Street
`Southwest,
`Rochester,
`Minnesota
`55905.
`
`The concept of a single unifying cell of origin for tumors of widely sepa-
`rate sites of origin but similar cytochemical and ultrastructural properties
`is recognized as that of the APUD (Amine Precursor Uptake and Decar-
`boxylation) cell theory [l]. These APUD cells are thought ta be the origin
`of tumors such as carcinoids, chemodectomas, ganglioneuroblastomas,
`islet cell carcinomas of the pancreas, medullary carcinomas of the thy-
`roid, melanomas, neuroblastomas, paraganglionomas, pheochronlocyto-
`mas, and small cell carcinomas of the lung [2]. This cytologic basis of cell
`similarity has enabled investigators to use similar treatment programs for
`tumors of great anatomic diversity.
`The different biologic behavior of metastatic endocrine tumors often
`requires a unique approach to therapy. For example, aggressive treat-
`ment should not be used in patients in the early stages of metastatic
`carcinoid if they have no tumor symptoms or only minor symptoms from
`the carcinoid syndrome. Symptoms that significantly interfere with daily
`activities and are not amenable to therapy with ordinary measures repre-
`sent one indication for chemotherapy. The development of one of the
`unfavorable prognostic signs, such as 5-hydroxyindoleacetic acid (5-
`HIAA) excretion of more than 150 mg per 24 hours or the presence of
`carcinoid heart disease, would be another indication [3]. Similarly, in
`many patients with endocrine hypersecretion syndromes from metastatic
`islet cell carcinoma, treatment with cytotoxic chemotherapy can be with-
`held until symptoms resistant to pharmacologic maneuvers develop, or if
`rapidly progressive disease supervenes. The distressingly low levels of
`antitumor activity with combination chemotherapy against some of these
`tumors make it necessary to carefully weigh the potential benefits of ther-
`apy against unwarranted toxicity resulting from therapy.
`Another unique problem associated with the treatment of these tumors
`with chemotherapy has been the lack of a consistent definition of re-
`sponse to therapy. The presence of a tumor product in serum or urine has
`enabled
`investigators to detect reductions in secretion of these sub-
`stances without necessarily observing objective regression of tumor
`masses. Often, these decreases in tumor products are associated with
`symptomatic improvement and therefore are important. In the past, many
`chemotherapeutic
`trials did not have rigid response criteria, and any
`tumor shrinkage or decline in tumor secretioh was interpreted as a re-
`sponse; consequently, overly enthusiastic therapeutic results sometimes
`appeared in the literature. We are now able to measure accurately serum
`levels of most gastroenterohepatic hormones, calcitonin, and neuropep-
`tides to determine the pattern of tumor secretion and to define a complete
`response to therapy. With the current emphasis on biochemical markers
`of disease activity, a 50 percent or greater drop in the serum or urine
`
`May
`
`29, 1987
`
`The American
`
`Journal
`
`of Medicine
`
`Volume
`
`92
`
`(suppl
`
`5B)
`
`77
`
`Ex. 1096-0001
`
`

`

`+
`
`+
`
`(weekly)
`
`Streptozotocin’
`5-fluorouracil
`+
`Streptozotocin
`cyclophosphamide
`Streptozotocin+
`5-fluorouracil
`+
`5-Fluorouracil
`+
`doxorubicin
`cyclophosphamide
`streptozotocin
`Streptozotocin
`doxorubicin
`l Streptozotocin
`%treptozotocin
`
`43
`
`47
`
`60
`
`20
`
`+
`
`+
`
`10
`courses
`courses
`
`repeated
`repeated
`
`in five-day
`in five-day
`
`[31
`
`[41
`
`1181
`
`WI
`PI
`
`14
`
`(33)
`
`12
`
`(26)
`
`18
`
`(23)
`
`7 (35)
`
`4 (40)
`every
`every
`
`six weeks.
`10 weeks.
`
`served using the same agent [7]. Nearly two decades ago,
`actinomycin D was reported to have caused improvement
`in three of five carcinoid patients [8]. The report of Van
`Hazel and co-workers was less encouraging, with only
`one of 17 patients showing a response to actinomycin D,
`but it is of interest that the patient with a response to acti-
`nomycin D has had remarkable clinical improvement last-
`ing more than eight years [7]. Fifteen patients with meta-
`static carcinoid tumor were treated with cisplatin at doses
`ranging from 45 to 90 mg/m* administered by rapid intra-
`venous infusion, and this treatment was repeated every
`three to four weeks [9]. Only one patient (7 percent)
`showed any evidence of tumor regression; regression
`was only partial and lasted only 3.5 months. It is unlikely
`that cispiatin given in this dose and schedule as a single
`agent has any therapeutic potential in carcinoid tumors.
`Single-agent chemotherapeutic experiences are summa-
`rized in Table I.
`The nitrosourea antibiotic streptozotocin was observed
`to induce diabetes mellitus in preclinical toxicologic stud-
`ies [lo]. This unique pattern of toxicity translated into sig-
`nificant activity against islet cell carcinomas and led to
`trials in patients with other neuroendocrine tumors. in six
`patients with carcinoid who
`received streptozotocin,
`Moertel [3] reported one objective regression and two
`mixed responses with regression of some lesions and
`progression of others. Two other reports also identified
`antitumor activity for this agent [11,12], but Schein et al
`[13] found no responses among eight patients.
`Mengel and Shaffer [14] reported responses in six of 11
`patients treated with the combination of cyclophospha-
`mide plus methotrexate. This treatment was one of the
`early reports of enhanced activity with combination drug
`therapy in carcinoids and was accepted as standard ther-
`apy for this disease for several years. Using more rigid
`response criteria, the Mayo group failed to observe a sin-
`gle response in 16 patients reported in 1984 [15].
`in 1975, Moertel [16] first reported responses in six of
`nine carcinoid patients using the combination of 5-fluor-
`ouracil plus streptozotocin. Later in that decade, Cher-
`nicoff et al [17j reported responses in four of 10 carcinoid
`patients treated with the same regimen. The combination
`of 5-fluorouracil plus streptozotocin was one of the treat-
`ment arms in a randomized multi-institutional
`trial per-
`formed by investigators in the ECOG [4]. That randomized
`trial compared 5-fluorouracil plus streptozotocin versus
`cyciophosphamide plus streptozotocin. The objective re-
`sponse rates were 33 and 26 percent, respectively (Table
`ii). Although a somewhat more favorable response rate
`was found with the 5-fluorouracil and streptozotocin com-
`bination, this difference was not statistically significant,
`nor were there differences in duration of response, inter-
`val to progression, or survival. Response rates were more
`favorable in patients with a documented carcinoid syn-
`drome and those with a better performance status. It was
`
`SYMPOSIUM ON GASTROINTESTINAL
`
`ENDOCRINE
`
`TUMORS-KVOLS
`
`and SUCK
`
`TABLE I
`
`Single-Agent Chemotherapy
`Tumors
`
`for Carcinoid
`
`Objective Response
`
`Agent
`
`Patients
`
`Number (percent)
`
`Reference
`
`Doxorubicin
`5-Fluorouracil
`Dacarbazine
`Actinomycin
`Cisolatin
`
`D
`
`33
`19
`15
`17
`15
`
`7 (21)
`5 (26)
`2 (13)
`1 ( ‘3
`1 ( 7)
`
`[31
`131
`[71
`[71
`Bl
`
`TABLE II
`
`Streptozotocin-Based Combination
`Chemotherapy Regimens for Carcinoid
`Tumors
`
`1.’
`
`Objective
`Response
`
`Regimen
`
`Patients Number (percent) Reference
`
`level is sometimes considered a re-
`marker hormone
`sponse, whether or not there has been a decrease in the
`size of measurable lesions.
`METASTATIC CARCINOID
`Initial reports by Moertel [3] on chemotherapy in carcinoid
`used 5fluorouracil at a dose of 500 mg/m*/day in five-day
`courses given every five weeks; objective responses were
`observed in five of 19 patients. Using the same dose and
`schedule, an identical response rate of 18 percent was
`observed in 11 patients in a multi-institutional trial done by
`the Eastern Cooperative Oncology Group (ECOG) [4].
`Two separate studies of an anthracycline antibiotic, doxo-
`rubicin, given at a dose of 60 mg/m* every three to four
`weeks, have reported objective responses in 21 percent
`of patients [3,5].
`Reports of other active single agents include the obser-
`vation by Kessinger’s group [6] of objective improvement
`lasting for a year in one patient and subjective improve-
`ment in another patient treated with dacarbazine.
`In a
`Mayo Clinic trial, two of 15 partial responses were ob-
`
`78
`
`May 29, 1987
`
`The American
`
`Journal
`
`of Medicine
`
`Volume
`
`82
`
`(suppl
`
`56)
`
`Ex. 1096-0002
`
`

`

`SYMPOSIUM ON GASTROINTESTINAL
`
`ENDOCRINE
`
`TUMORS-KVOLS
`
`and BUCK
`
`interesting that with both regimens, the response rate was
`significantly greater for small bowel carcinoids than for
`carcinoids of pulmonary or unknown origin.
`The next ECOG protocol used streptozotocin given
`every 10 weeks, rather than every five weeks, in an at-
`tempt
`to decrease anorexia, nausea, and vomiting;
`5fluorouracil was still given daily for five days every five
`weeks [18]. The second treatment arm in this randomized
`trial was single-agent doxorubicin, 80 mg/m’
`intrave-
`nously once each month. Unfortunately, nausea and vom-
`iting secondary to streptozotocin therapy were not attenu-
`ated, but the response rate seemed to be, with only 18 of
`80 patients (23 percent) fulfilling the criteria for response.
`The response rate for doxorubicin in this protocol was 17
`of 81 (23 percent). The median duration of response was
`26 weeks for doxorubicin and 31 weeks for the combina-
`tion. In contrast to the preceding ECOG study, the location
`of the primary tumor did not correlate with the likelihood of
`survival.
`A weekly schedule of streptozotocin given with doxoru-
`bicin in a single institution has been reported to cause
`regressions in four of 10 carcinoids [19]. A four-drug regi-
`men comprised of 5-fluorouracil, streptozotocin, doxorubi-
`tin, and cyclophosphamide does not appear to offer any
`clear-cut therapeutic advantage with seven of 20 (35 per-
`cent) patients showing a response [20].
`Other treatment approaches using non-chemothera-
`peutic agents such as cyproheptadine have been reported
`to produce tumor regression, but confirmation of these
`observations is still pending [21]. Tamoxifen was also re-
`ported to produce symptomatic control of the carcinoid
`syndrome and, subsequently, evidence of objective re-
`mission [22,23]. A collaborative trial to confirm this activity
`failed to note any tumor regression or improvements
`in
`5-HIAA levels [24]. A report by Oberg and associates [25]
`at the University of Upsala has sparked interest in using
`interferon for the carcinoid syndrome. Their six patients
`had significant symptomatic
`improvement and some re-
`duction in 5-HIAA excretion.
`Martin and colleagues [26] have described eight pa-
`tients with the carcinoid syndrome at our institution who
`underwent hepatic artery ligation at the time of laparot-
`omy. The advantage of the surgical approach is that it
`permits resection of the frequently obstructive ileal pri-
`mary lesions; this was necessary in five of the six patients
`with small-bowel primaries. Facial flushing ceased in all
`patients and diarrhea was uniformly reduced at the time of
`hospital discharge. All patients became febrile and had
`striking
`increases
`in the serum glutamic-oxaloacetic
`transaminase values during the first postoperative week,
`but showed quick recovery thereafter. The duration of re-
`sponse ranged from three to 10 months (median, five
`months). Other investigators have confirmed that hepatic
`artery occlusion alone is an effective means of inducing
`tumor debulking for this disease [27-291. Because vascu-
`
`lar occlusion-induced hepatic dysfunction is transient, the
`vascular occlusion does not preclude future chemother-
`apy.
`The early results of the Mayo Clinic trial of sequential
`hepatic artery occlusion and chemotherapy for metastatic
`carcinoid tumor have been reported previously [30]. Ten
`symptomatic patients with measurable hormonal and/or
`tumor parameters and proven hepatic dominant metasta-
`ses have been treated with hepatic artery occlusion either
`by surgical ligation or percutaneous embolization. Three
`weeks later, therapy was started with dacarbazine, 250
`mg/m* for five days, plus doxorubicin, 60 mg/m* intrave-
`nously, alternating every four weeks with 5-fluorouracil,
`400 mg/m* for five days, plus streptozotocin, 500 mg/m*
`for five days. Nine of the ten patients had striking or com-
`plete relief of the carcinoid syndrome, with urinary 5-HIAA
`elevations reduced from 63 to 100 percent. The remaining
`patient had minor improvement
`for 12 months. Hepatic
`artery occlusion had side effects as noted in the earlier
`study. Chemotherapy produced
`its anticipated side ef-
`fects, primarily vomiting and leukopenia. The early results
`with this program appear to show more frequent, more
`complete, and more lasting responses than in our prior
`experience with either hepatic artery occlusion or chemo-
`therapy used alone. This prospective trial remains in prog-
`ress.
`Somatostatin is a ubiquitous hormone that inhibits the
`release of numerous peptides such as growth hormone,
`insulin, glucagon, and gastrointestinal peptides [31]. Na-
`tive somatostatin has been reported to be effective in
`blocking the carcinoid flush induced by pentagastrin and
`in controlling other symptoms associated with the carci-
`noid syndrome [32,33]. These initial observations had lim-
`ited therapeutic application, because the short half-life of
`the native compound required continuous intravenous in-
`fusion. An analogue of somatostatin with eight amino
`acids rather than 14 was synthesized and reported to be
`more specific, potent, and longer acting in its inhibitory
`effects [34].
`Our initial experience with this longer-acting analogue
`of somatostatin
`(SMS 201-995) was very favorable
`in
`terms of ameliorating symptoms related to neuroendo-
`crine tumors (351. We have now studied the long-term
`administration of this analogue in 25 patients with histo-
`logically proven metastatic carcinoid tumor and the carci-
`noid syndrome. The drug was self-administered by subcu-
`taneous injections at a dose of 150 pg three times daily.
`Flushing and diarrhea associated with the syndrome were
`promptly relieved. All 25 patients had elevated 24-hour
`urine 5-HIAA excretions to serve as an objective indicator
`of disease activity (mean, 265 mg per 24 hours; range, 14
`to 1,079 mg per 24 hours). Eighteen of the 25 patients (72
`percent) have had a 50 percent or greater decrease in
`their 5HIAA level compared with their pretreatment level.
`The median duration of this biochemical response is 12+
`
`May
`
`29, 1997
`
`The American
`
`Journal
`
`of Medicine
`
`Volume
`
`92
`
`(suppl
`
`5B)
`
`79
`
`Ex. 1096-0003
`
`

`

`SYMPOSIUM ON GASTROINTESTINAL
`
`ENDOCRINE
`
`TUMORS-KVOLS
`
`and SUCK
`
`TABLE
`
`III
`
`Chemotherapeutic
`Carcinoma
`
`Experience
`
`in Islet Cell
`
`Objective
`Response
`
`Regimen
`
`’
`
`Patients
`
`Number (percent)
`
`Reference
`
`Streptozotocin
`Doxorubicin
`Chlorozotocin
`Streptozotocin
`5-fluorouracil
`*Previously
`+Patients
`
`+
`
`40
`patients.
`treated
`who had not previously
`
`17
`20*
`13+
`
`7 (41)
`4 (20)
`7 (53)
`
`25
`
`(63)
`
`WI
`(411
`1421
`
`[401
`
`received
`
`chemotherapy.
`
`TABLE
`
`IV
`
`Treatment
`Randomized
`Carcinoma
`
`for ECOG
`Schema
`Study of Islet Cell
`
`for this condition came
`effectiveness of streptozotocin
`from Murray-Lyon and colleagues [37] in 1968; following
`that report, many anecdotal reports appeared suggesting
`the efficacy of streptozotocin
`in this disease. Subse-
`quently, a large series compiled by Broder and Carter [38]
`from the National Cancer Institute confirmed the activity of
`streptozotocin in pancreatic islet cell cancer. In this series,
`37 percent of patients with measurable disease had an
`objective regression (greater than 50 percent reduction),
`and 54 percent of functional tumors had at least a 50 per-
`cent decline in biochemical parameters. At that time, there
`was no consensus on the dosage or schedule of adminis-
`tration of streptozotocin, and this series contained various
`methods of administration. Also, the toxicity of streptozo-
`tocin was often formidable, with frequent severe nausea
`and vomiting combined with less commonly encountered
`nephrotoxicity and hepatotoxicity.
`In 1971, investigators at the Mayo Clinic reported on the
`effectiveness of an
`intensive
`five-day administration
`schedule of streptozotocin, and this regimen was gener-
`ally accepted as the standard mode of therapy [39]. Be-
`cause of the lack of myelosuppression with this drug,
`combination with other agents appeared
`feasible, and
`early reports suggested an increased level of antitumor
`activity when combined with 5-fluorouracil [4]. A prospec-
`tive, randomized study by the ECOG published in 1980
`compared streptozotocin alone with the combination of
`streptozotocin and 5-fluorouracil [40]. The combination
`had advantages over streptozotocin alone in overall rates
`of response (63 versus 36 percent) and in the frequency
`of complete responses (37 versus 12 percent). The me-
`dian duration of response was 17 months for all patients,
`and there was no apparent difference in the response of
`the various hormone-producing
`tumors. Although not sta-
`tistically significant, those patients treated with the combi-
`nation survived a median of 26 months, compared with
`16.5 months for the single drug. Once again, toxicity was
`significant, with nausea and vomiting in more than 80 per-
`cent of patients, nephrotoxicity in 30 percent, and a single
`case of fatal hepatotoxicity. The drug combination was
`associated with more leukopenia (73 versus 5 percent),
`and there was one treatment-related death due to sepsis.
`This study confirmed the effectiveness of streptozotocin
`and 5-fluorouracil combinations but also indicated a need
`for ongoing studies to identify less toxic, equally active
`programs.
`Other combinations of streptozotocin have been used,
`and Kelsen et al [I91 have reported a program of weekly
`streptozotocin and doxorubicin therapy whereby one of
`five patients with pancreatic islet cell carcinoma had an
`objective remission. Since this treatment was associated
`with only minor myelosuppression, the hosage of doxoru-
`bicin was to be escalated in future trials to try to improve
`the response rate. Use of doxorubicin alone has also been
`
`Treatment Arm
`
`Group
`
`A
`
`Group
`
`6
`
`Group
`
`C
`
`their disease
`*If
`domly
`assigned
`
`Regimen
`
`on Days
`
`1 through
`
`5,
`
`on Days
`
`1 through
`
`5,
`
`(400 mg/m*
`5-Fluorouracil
`every
`6 weeks)
`Streptozotocin
`(500 mg/m2
`every
`6 weeks)
`3 weeks)
`on Day 1, every
`Doxorubicin
`(50 mg/m2
`Streptozotocin
`(500 mg/m2
`on Days
`1 through
`5,
`every
`6 weeks)
`Chlorozotocin
`(150 mg/m2
`7 weeks)’
`progresses,
`to either
`
`on Day
`
`1, every
`
`chlorozotocin-treated
`treatment
`arm A or B.
`
`patients
`
`are
`
`ran-
`
`months (range, one to 18+ months). There has been no
`evidence of renal, hepatic, neurologic, or hematologic tox-
`icity. We have previously reported one instance in which
`therapy with this somatostatin analogue promptly
`re-
`versed a potentially lethal carcinoid crisis occurring with
`the induction of anesthesia [38].
`At this point in time, combination chemotherapy for met-
`astatic carcinoid has not been clearly shown to have any
`major advantage compared with single-agent chemother-
`apy and continues to be a challenge to clinicians. Newer
`modalities such as hepatic artery occlusion, interferons,
`and’use of somatostatin analogues offer some promise,
`but all treatment of this nature should be considered an
`experimental endeavor.
`ISLET CELL CANCER OF THE PANCREAS
`in
`During early trials, the effectiveness of 5fluorouracil
`pancreatic islet cell cancer was found to be similar to that
`in other gastrointestinal malignancies [4]. It was not until
`the observation that streptozotocin induced selective pan-
`creatic beta-cell damage that a chemotherapeutic agent
`was identified that appeared to have specificity for meta-
`static pancreatic islet cell cancer. The first report of clinical
`
`80
`
`May 28, 1987
`
`The American Journal of Medicine
`
`Volume 82 (suppl 56)
`
`Ex. 1096-0004
`
`

`

`SYMPOSIUM ON GASTROINTESTINAL
`
`ENDOCRINE
`
`TUMORS-KVOLS
`
`and BUCK
`
`TABLE V
`
`Dacarbazine Regimens in Islet Cell Carcinomas
`
`Dacarbazlne
`Regimen
`
`Patients*
`
`Objective
`Response+
`
`Response Duration
`(months)
`
`Reference
`
`1
`1
`1
`2
`5
`5
`1
`
`1
`1
`1
`2
`4
`45
`1
`
`*All except
`‘Response
`?wo
`patients
`“Non-responder
`**Dosage
`was
`
`for 5 days
`250 mg/m2
`for 5 days
`250 mglm2
`for 5 days
`300 mg/m’
`for 5 days
`250 mg/m2
`for 5 days
`250 mg/m2
`for 5 days*
`250 mg/m2
`for 5 days”
`100 mg/m2
`glucagonomas.
`two patients
`had malignant
`or a reported
`levels
`hormonal
`drop
`in circulating
`required
`at
`least a 50 percent
`28 days.
`were
`treated
`with 850 mg/m2
`or 1 g intravenously
`every
`had a non-functional
`pancreatic
`islet cell
`tumor
`that
`remained
`later
`increased
`to 300 mg/m2
`for
`five days.
`
`22+
`30+
`3+
`22,24+
`3+,7+,7+,10+
`9+,14+,40+,46
`2+
`
`[431
`[441
`1451
`[4'51
`1471
`PI
`[481
`
`50 percent
`
`or greater
`
`decrease
`
`in measurable
`
`tumor.
`
`three
`
`years.
`
`stable
`
`for
`
`reported to have definite activity, with four of 20 responses
`in previously otherwise-treated patients [41]. Table Ill de-
`lineates these chemotherapeutic experiences in patients
`with pancreatic islet cell carcinoma.
`A current ECOG study (Table IV) is comparing the use
`of streptozotocin plus 5-fluorouracil with streptozotocin
`plus doxorubicin and with the new nitrosourea, chloro-
`zotocin. The latter agent is a drug structurally similar to
`streptototocin, with considerably less gastrointestinal tox-
`icity but increased myelosuppression. Chlorozotocin can
`be given at full doses on a single day every six to seven
`weeks, whereas streptozotocin needs to be given over
`five days; also, chlorozotocin appears to have less poten-
`tial for nephrotoxicity. This drug has been evaluated in a
`phase II trial by the Southwest Oncology Group. Among
`17 patients with pancreatic islet cell carcinoma receiving
`either 200 mg/m* or 100 mg/m* every six weeks, there
`were two complete and five partial responses [42]. No re-
`sponses were observed among the four previously treated
`patients, suggesting a similar mechanism of action and
`cross resistance to streptozotocin.
`If antitumor activity of
`equal degree as streptozotocin
`is confirmed with
`chlorozotocin, then improved tolerance may make the lat-
`ter drug the preferred nitrosourea in metastatic pancreatic
`islet cell carcinoma.
`In 1979, Kessinger and colleagues [43] identified dacar-
`bazine as an effective drug in the treatment of malignant
`glucagonoma resistant to streptozotocin. Their report was
`followed by several isolated reports confirming activity of
`dacarbazine
`in untreated and a few previously treated
`patients with metastatic malignant glucagonoma
`[44-481.
`In 1983, Kessinger et al [8] expanded their experience to
`include five additional patients with pancreatic islet cell
`carcinoma among a series of patients with APUD tumors
`treated with dacarbazine.
`In this group, there was one
`complete tumor regression, as well as one complete and
`two partial biochemical remissions. Almost all reported
`
`islet cell carcinoma
`responding cases of pancreatic
`treated with dacarbazine are malignant glucagonomas
`(Table V). This high level of response possibly represents
`some
`reporting bias. Nevertheless,
`this activity has
`prompted some authors to recommend dacarbazine as
`the drug of choice for malignant glucagonoma
`[6,46-481.
`A prospective trial of this agent in patients with pancreatic
`islet cell carcinoma is being done by the ECOG at this
`time.
`Anecdotal reports of other chemotherapeutic agents
`used in pancreatic islet cell carcinoma have been less
`encouraging. A single response to actinomycin D and ste-
`roids has been reported, whereas etoposide (VP-16) has
`been found to be ineffective in a report of two patients
`[49,50]. The combination of doxorubicin and cisplatin
`used in patients with APUD tumors resulted in two minor
`responses lasting 52 and 23 weeks in patients with pan-
`creatic islet cell carcinoma [51]. Experience with cisplatin
`alone is limited, and further studies are needed to identify
`its level of antitumor activity for islet cell carcinoma.
`Experience with hepatic artery occlusion in pancreatic
`islet cell carcinoma is much less than with carcinoid tu-
`mors but has shown early promise. Moertel and col-
`leagues [30] have treated three functioning pancreatic
`islet cell carcinomas with hepatic artery occlusion followed
`by chemotherapy. All patients have had dramatic hor-
`monal responses; two patients have had striking tumor
`regressions. Two patients with non-functional
`tumors
`have had only minor improvements [30].
`to have
`Somatostatin analogues have been shown
`some very exciting applications in the treatment of the
`plethora of endocrine manifestations of pancreatic
`islet
`cell carcinoma affecting the function of the gastrointestinal
`tract [52,53]. Long and colleagues [54] reported their initial
`experience with an analogue of somatostatin in the treat-
`ment of eight patients with a variety of islet cell tumors and
`found striking inhibition of insulin and glucagon secretion.
`
`May 29, 1987
`
`The American
`
`Journal
`
`of Medicine
`
`Volume
`
`82 (suppl 5B)
`
`81
`
`Ex. 1096-0005
`
`

`

`SYMPOSIUM ON GASTROINTESTINAL
`
`ENDOCRINE
`
`TUMORS-KVOLS
`
`and BUCK
`
`This therapy was not associated with any side effects and
`appeared ideally suited for the long-term control of symp-
`toms. Subsequently,
`there have been further reports of
`the effectiveness of somatostatin analogues in the treat-
`ment of functioning islet cell tumors [55,56]. Kraenzlin and
`co-workers
`[57] have described a case of malignant
`VlPoma that had excellent symptomatic control and an
`accompanying decline in VIP levels associated with re-
`gression of hepatic metastases after 14 months of treat-
`ment. Similarly, Clements and Elias [58] described a case
`of metastatic VlPoma that regressed after nine months of
`treatment with SMS 201-995, and Santangelo and col-
`leagues [59] reported a case with excellent symptomatic
`control without tumor regression for nine months. The
`exact role of somatostatin analogues in the overall man-
`agement of patients with functioning islet cell tumors re-
`mains to be determined, but it does appear that sympto-
`matic control can be remarkable.
`Considerable progress in the treatment of pancreatic
`islet cell carcinoma has been made, and multicenter co-
`operative studies have played a major role in the identifi-
`
`cation of new, effective, and less toxic drug combinations.
`Further research is still needed to determine the role of
`agents such as the somatostatin analogue in the overall
`management of this disease.
`
`COMMENTS
`
`tumors appear to
`Although all of these neuroendocrine
`have similar cells of origin, there appear to be considera-
`ble differences
`in the chemosensitivity of the various
`tumor types. Major progress in the treatment of some of
`these rare tumors has been made, while in others we are
`continuing
`to use therapies
`that have remained un-
`changed for many years. Exciting developments
`in the
`manipulation of the cellular regulation of endocrine secre-
`tion may enable us to retard the growth of the malignant
`cell without the toxicity of chemotherapy. Large-scale co-
`operative studies are urgently required to fully evaluate
`new therapeutic modalities. Patients with these rare neo-
`plasms should be entered into prospective clinical trials
`whenever possible.
`
`1.
`
`2.
`
`10.
`
`11.
`
`12.
`
`and ultrastructure
`AG: The cytochemistry
`Pearse
`hormone
`producing
`cells of the APUD
`series
`logic,
`physiologic
`and pathologic
`implications
`J Histochem
`Cytochem
`1969;
`17: 303-313.
`Gazdar
`AF, Carney
`DS, Guccion
`JC, Baylin SB: Small cell carci-
`nomas
`of
`the
`lung:
`cellular
`origin
`and
`relationship
`to other
`pulmonary
`tumors.
`In: Greco
`FA, Oldham
`RK, Bunn PA, eds.
`Small
`cell
`lung cancer.
`New York: Grune
`and Stratton,
`1981;
`145-175.
`the malignant
`and
`tumor
`of the carcinoid
`Moertel CG: Treatment
`1: 727-740.
`1983;
`J Clin Oncol
`carcinoid
`syndrome.
`in
`trials
`chemotherapy
`JA: Combination
`Moertel
`CG, Hanley
`tumor
`and
`the malignant
`carcinoid
`syn-
`metastatic
`carcinoid
`drome.
`Cancer
`Clin Trials
`1979;
`2: 327-334.
`Engstrom
`P, Lavin
`P, Folsch
`E, Moertel
`CG:
`+
`(STZ)
`fluorouracil
`(FU)
`vs. adriamycin
`(AD)
`carcinoid
`tumors.
`Proc
`Amer
`Assoc
`Cancer
`551.
`APUD
`of malignant
`JF, Lemon HM: Therapy
`A, Foley
`Kessinger
`cell
`tumors:
`effectiveness
`of DTIC.
`Cancer
`1983;
`51: 790-
`794.
`J, Moertel
`van Hazel GA, Rubin
`dactinomycin
`carcinoid
`tumor
`with
`Treat Rep 1983;
`67: 583-585.
`treatment
`in the
`D
`Dollinger
`M, Golbey
`R: Actinomycin
`carcinoid
`tumors
`(abstr).
`Clin Res 1967;
`15: 335.
`of cisplatin
`Moertel CG, Rubin
`J, O’Connell
`MJ: A phase
`II study
`therapy
`in patients
`with metastatic
`carcinoid
`tumor
`and
`the
`malignant
`carcinoid
`syndrome.
`Cancer
`Treat Rep 1986;
`70:
`1459-l
`460.
`MV: Studies
`ML, Nadkani
`Rakieten
`N, Rakieten
`genie action
`of streptozotocin
`(NSC-37917).
`ther Rep 1969;
`29: 91-98.
`Stolinsky
`DC, Sadoff
`L, Braunwald
`tocin
`in the
`treatment
`of cancer.
`30: 616-667.
`RE Jr, Muracek
`Feldman
`JM, Quickel
`treatment
`of metastatic
`carcinoid
`65: 1325-l
`327.
`
`Streptozotocin
`for metastatic
`Res
`1983;
`24:
`
`of metastatic
`CG: Treatment
`or dacarbazine.
`Cancer
`
`of
`
`the
`
`of the diabeto-
`Cancer
`Chemo-
`
`JR: Streptozo-
`J, Bateman
`Phase
`II study. Cancer
`1972;
`
`RL, et al: Streptozotocin
`tumors.
`South Med J 1972;
`
`REFERENCES
`of polypeptide
`13.
`and
`the embryo-
`of
`the concept.
`
`14.
`
`activ-
`antitumor
`MJ, Blom J, et al: Clinical
`PS, O’Connell
`Schein
`000.
`ity and
`toxicity
`of streptozotocin.
`Cancer
`1974; 34: 993-l
`Mengel
`CE, Shaffer
`RD: The
`carcinoid
`syndrome.
`In: Holland
`JF, Frei E, eds. Cancer medicine.
`Philadelphia:
`Lea and Febi-
`ger,
`1973;
`1584-1593.
`J: An evalua-
`RJ, Rubin
`MJ, Reitemeier
`Moertel CG, O’Connell
`and methotrexate
`ther-
`tion of combined
`cyclophosphamide
`and
`carcinoid
`tumor
`the
`apy
`in
`the
`treatment
`of metastatic
`malignant
`carcinoid
`syndrome.
`Cancer
`Treat
`Rep 1984;
`68:
`665-667.
`of advanced.gastrointestinal
`Moertel CG: Clinical management
`cancer.
`Cancer
`1975;
`36: 675-682.
`Chernicofl
`D, Bukowski
`RM, Groppe
`chemotherapy
`for
`islet cell
`carcinoma
`noid
`tumors
`with
`5-fluorouracil
`and
`Treat Rep 1979;
`63: 795-796.
`Engstrom
`PF, Lavin
`PT, Moertel
`Streptozotocin
`plus
`fluorouracil
`for metastatic
`carcinoid
`tumor.
`1259.
`N, Magill GB, Yagoda
`E, Kemeny
`Kelsen DP, Cheng
`zotocin
`and Adriamycin
`in the
`treatment
`of APUD
`cinoid,
`islet
`cell, and medullary
`carcinomas
`of
`Proc Amer
`Assoc
`Cancer
`Res
`1982;
`23: 433.
`Bukowski
`RM, Stephens
`R, Oishi N, Petersen
`R, Chen T: Phase
`II trial of 5-FU, Adriamycin,
`cyclophosphamide,
`and streptozo-
`tocin
`(FAC-S)
`in metastatic
`carcinoid.
`Proc Amer
`Sot Clin
`Oncol
`1983;
`2: 130.
`of carcinoid
`Harris
`AL, Smith
`IE: Regression
`285: 475.
`heptadine.
`Br Med J 1982;
`GG, Yiotis J: Tamoxifen
`Stathopoulous
`GP, Karvountzis
`noid syndrome.
`N Engl J Med 1981;
`305: 52.
`Myers
`CF, Ershler WB, Tannenbaum
`MA, et al: Tamoxifen
`carcinoid
`tumor.
`Ann
`Intern Med 1982;
`96: 383.
`Moertel
`CG, Engstrom
`PF, Schutt
`AJ: Tamoxifen
`metastatic
`carcinoid
`tumor:
`a negative
`study.
`Ann
`1984;
`100: 531-532.
`of
`Oberg
`K, Funa
`K, Alm GV: Effects
`clinical
`symptoms
`and hormone
`levels
`
`et al: Combination
`CW,
`and metastatic
`carci-
`streptozotocin.
`Cancer
`
`HO:
`E, Douglas
`CG, Folsch
`versus
`doxorubicin
`therapy
`J Clin Oncol
`1984;
`2: 1255-
`
`A: Strepto-
`tumors
`(car-
`the
`thyroid).
`
`tumor with
`
`cypro-
`
`in carci-
`
`and
`
`for
`therapy
`Intern Med
`
`leukocyte
`in patients
`
`on
`interferon
`with mid-gut
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
`
`21.
`
`22.
`
`23.
`
`24.
`
`25.
`
`82
`
`May
`
`29, 1987
`
`The American
`
`Journal
`
`of Medicine
`
`Volume
`
`82
`
`(suppl
`
`5B