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`Original article
`
`Annuls of Oncology 12: 1139-1143. 2001.
`© 2001 Kluwer Academic Publishers. Printed in the Netherlands.
`
`Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell
`carcinoma. Study of the Eastern Cooperative Oncology Group-E6282
`
`R. K. Ramanathan,1 A. Cnaan/ R. G. Hahn/ P. P. Carbone4 & D. G. Hailed
`1 University of Pittsburgh Cancer Institute. Pittsburgh. Pennsylvania. 2 University of Pennsylvania. Philadelphia. Pennsylvania; 3 Mayo Clinic.
`Rochester, Minnesota; A University of Wisconsin, Madison. Wisconsin. USA
`* See Appendix on page 1142 for participating institutions
`
`Summary
`
`Background: A phase II study of dacarbazine (DTIC), was
`conducted to determine the response rate, duration of re-
`sponse, toxicity and overall survival of patients with advanced
`pancreatic islet cell tumors.
`Patients and methods: Fifty patients with advanced pancre-
`atic islet cell tumors, having progressive symptoms or evidence
`of rapidly advancing disease were entered on this study. DTIC
`was given by IV infusion at a dose of 850 mg/m2, over 60-90
`minutes, repeated every four weeks.
`Results: The response rate was 33% in 42 patients who had
`measurable tumor, and 34% in the 50 patients (90% confidence
`
`interval (90% CI): 23%-47%). The majority of the responses
`were seen in patients without prior chemotherapy. Median
`overall survival was 19.3 months. There were two lethal
`toxicities on the study, one septic shock and one myocardial
`infarction. Grade 4 toxicities were, hematological (5 patients),
`sepsis, neurological (depression and paranoid behavior) and
`bleeding (1 patient each). The most common toxicity was
`vomiting, grade 3 in 13% of patients.
`Conclusions: DTIC has activity in advanced previously
`untreated pancreatic islet cell tumors.
`
`Key words: dacarbazine, islet cell tumors, pancreas, phase II
`
`Introduction
`
`Pancreatic islet cell tumors are a rare group of neo-
`plasms. These tumors have a neuroendocrine origin,
`and have the ability to synthesize various peptide hor-
`mones by amine precursor uptake and decarboxylation
`(APUD) [1]. Aggressive surgical resection is the treat-
`ment of choice in resectable tumors. The clinical course
`of advanced tumors is variable, with most patients
`initially having an indolent course not requiring phar-
`macologic therapy. After a period of slow growth, many
`of these tumors show an aggressive behavior requiring
`intervention. In patients with bulky liver metastasis, sur-
`gical debulking of liver metastasis or chemoembolisation
`may result in palliation. In patients with hormone hyper-
`function syndromes, octreotide, a synthetic octapeptide,
`is effective in control of symptoms [2]. Chemotherapy is
`frequently used for symptomatic patients with advanced
`tumors who have progressive disease. Agents with activ-
`ity in this disease are 5-flourouracil (5-FU), streptozo-
`cin, chlorozotocin and doxorubicin [3-5]. Combination
`chemotherapy with streptozocin and doxorubicin results
`in higher response rates and improved survival com-
`pared to single agent therapy, but at the expense of
`increased toxicity [6]. Dacabazine (DTIC, NSC-45388)
`is a non-classic synthetic alkylating agent [7]. It has
`single agent activity in metastatic malignant melanoma,
`Hodgkin's disease, sarcomas, childhood neuroblasto-
`
`mas and primary brain tumors. The common side effects
`of this drug are myleosuppresion and vomiting [8]. We
`evaluated the activity of DTIC in pancreatic islet cell
`tumors, as preliminary reports indicated this to be an
`active agent. [9, 10]. In one report, therapy with DTIC
`resulted in 3 of 5 patients having a biochemical or
`objective response [9], and in the other study 5 of 10
`patients had an objective response [10].
`
`Patients and methods
`
`Study schema
`
`The Eastern Cooperative Oncology Group (ECOG) opened a two-
`armed crossover study of DTIC and cisplatin in patients with advanced,
`unresectable islet cell carcinoma Because of early toxicities on the
`cisplatin arm, it was subsequently terminated and the cross over design
`eliminated By that point in time only two patients received cisplatin as
`induction treatment and another four received cisplalin on crossover.
`This report is an analysis of DTIC treatment for patients with islet cell
`carcinoma, which was the primary focus of the study.
`
`Patients
`
`To be eligible for this protocol, patients had to have histologically
`confirmed unresectable islet cell carcinoma with measurable malignant
`disease to serve as an objective indicator of response to therapy. For
`patients without clearly measurable tumor, measurements of endocrine
`hyperfunction served as objective indicators of response. Patients had
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`progressive symptoms resulting from their malignant disease or evi-
`dence of rapidly advancing disease. Laboratory measurements had
`to be adequate (White cell count (WBQ > 4000/mm3 and platelet
`> 130,000/mm3), and ECOG performance status was 0-3 Patients
`could not enter the study within three weeks after a major surgical
`procedure, or within two weeks of an exploration or biopsy. Prior
`radiotherapy to the primary area of measurable disease, and chemo-
`therapy or radiotherapy one month prior to study entry were not
`allowed. Patients with active infectious process and severe malnutri-
`tion were ineligible. No other concomitant cancers were allowed The
`protocol was approved by the human investigations committee at each
`site and informed consent was obtained from all patients to participate
`in the study.
`
`Treatment plan
`
`The DTIC treatment was given at the dose of 850 mg/m2 by I.V.
`infusion over 60-90 minutes on day one, repeated every four weeks.
`Antiemtetic treatment with phenothiazines were allowed.
`
`Dose modifications
`
`Dose modifications for hematologic toxicities were based on nadir
`counts. If the WBC decreased to below 2000/mm3 and/or the platelet
`count decreased to below 75,000/mm'1, there was a 25% reduction in
`dose. If the WBC decreased to below lOOO/mm3, and/or the platelets
`decreased to below 25,000/mnr\ there was a reduction of 50% in dose.
`Treatment was to be given for at least two courses, if possible, and to be
`continued until progression occurred.
`
`Measurement of effect
`
`The principal endpoints of the study were 1) tumor response, 2)
`toxicity, 3) survival, and 4) duration of response. Complete response
`was defined as absence of any clinically detectable tumor mass and
`absence of any laboratory detectable evidence of endocrine hyper-
`function. Partial response was defined as a reduction of at least 50%
`of the product of the longest perpendicular diameters of the most
`clearly measurable mass lesion. If hepatomegaly was the prime indica-
`tor, then there had to be a reduction of the sum of liver measurements
`below costal margins of at least 30% In addition there could be no
`increase in any other indicator lesion and no new areas of malignant
`disease. Performance status could not decrease by more than one level
`(or to performance status 4) and weight loss could not be more than
`10% in order for the response to be still considered partial response.
`Objectively stable disease was defined as regression not large enough
`to meet the criteria of partial response, and less than 25% increase in
`any measurable lesion, no new areas of malignant disease, and no
`significant deterioration in weight symptoms or performance status.
`Objective progression was defined as an increase in any measurable
`lesion of more than 25% or significant deterioration in symptoms or
`decrease in weight or performance status.
`
`If endocrine hyperfunction was employed as the indicator of re-
`sponse, improvement in at least one of the following criteria had to be
`met: 1) Zollinger-Elhson syndrome, ACTH production, Urine 5HIAA
`and Glucagonoma: a reduction of hormonal levels by at least 50%
`compared to pretreatment levels. 2) Insulinoma a reduction of elevated
`blood insulin levels to normal range and freedom from hypoglycemia
`symptoms without glucose supplementation. 3) Pancreatic cholera: a
`reduction of fecal volume and/or weight by at least 75% with a return
`to normal of all associated electrolyte abnormalities
`
`Statistical considerations
`
`The study was designed so that if the true response rate was 30%. then
`with 90% probability (or greater) the observed response rates were to
`be between 15% and 45% Kaplan-Meier curves were calculated for
`
`overall survival, and for survival by baseline characteristics. Log-rank
`tests were done to compare survival between groups based on patient
`characteristics. Predefined risk factors for progression were examined
`whether they predicted response, using a Fisher's exact test. These
`risk factors were: 1) creatinine level: < 1.5 mg/dl or > 1.5 mg/dl; 2)
`performance status. ECOG 0/1 or ECOG 2/3; 3) functional status:
`functioning or non-functioning, 4) objective indicator: measurable
`tumor or non-measurable tumor/endocrine hyperfunction; 5) pre-
`viously treated, no or yes.
`
`Results
`
`Patient accrual
`
`A total of 54 patients entered this study between April
`1983 and September 1989. Two patients were excluded
`from the analysis since they were initially randomized
`to the cisplatin arm and another two patients were
`excluded on pathologic review. Sixteen ECOG institu-
`tions contributed patients to this study (see Appendix).
`Table 1 summarizes the characteristics of the 50 ana-
`lyzable patients. All but three patients were white, and
`distribution was about equal between males and females.
`Forty-two patients (84%) had measurable tumor, 8 (16%)
`patients had creatinine level > 1.5 mg/dl, 8 (16%) pa-
`
`Table I Patient characteristics.
`
`Characteristic
`
`Patients
`n = 50 (%)
`
`Creatinine
`< 1.5 mg/dl
`2*1.5 mg/dl
`Performance status
`0-1
`2-3
`Functional Status
`Functioning
`Non functioning
`Objective indicator
`Measurable tumor
`Endocrine function only
`Sex
`Male
`Female
`Age
`Mean
`Range (years)
`Race
`White
`Black
`Previous surgery
`No
`Yes
`Previous chemotherapy
`No
`Yes
`
`42 (84)
`8(16)
`
`42 (84)
`8(16)
`
`24 (48)
`26 (52)
`
`42 (84)
`8(16)
`
`24 (48)
`26 (52)
`
`53.8
`23-75
`
`47 (94)
`3(6)
`
`12(24)
`38 (76)
`
`28 (56)
`22 (44)
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`/»
`
`100
`3.8
`80
`26
`34
`
`Total
`
`52
`
`2 4
`
`13
`-
`
`Cases analyzed
`Unevaluable
`Complete response
`Partial response
`Response rate
`
`tients had performance status 2 or 3, 24 (48%) had
`endocrine hyperfunction and 22 (44%) had previous
`chemotherapy.
`
`Table 2. Objective response.
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`Table 3. Treatment related toxicities (ECOG toxicity criteria).
`
`4 0 0 0 1 1 0 1 0 0 5 0 0
`
`3 0 7 0 1 0 1 1 1 0 4 0 2
`
`0
`26
`
`4 3 0 2 6 0 4 8 2 7
`
`Grade
`
`1
`
`6
`11
`
`7 3 1 7
`
`11
`3
`II
`II
`1
`17
`
`Toxcity
`
`Gastrointestinal
`Vomiting
`Diarrhea
`Infection
`Bleeding
`Skin/Mucosa
`Neurologic
`Respiratory
`Genitourinary
`Hematologic
`Liver
`Other"
`
`° Other included fever, chills, alopecia, cardiac, edema, anorexia,
`sweats, fatigue, ascites, gastric ulcer, abdominal disc, headache and
`weight gain There were two grade 5 (lethal) toxicity's on study. One
`patient had a myocardial infarction and another sepsis.
`
`Discussion
`
`This phase II study, is the largest experience of DTIC in
`pancreatic islet cell tumors. The main toxicities observed
`were hematological and vomiting. Most patients had
`some degree of vomiting, and a severe degree was ob-
`served in 13%. Phenothiazines were used for control of
`nausea and vomiting in this study, serotonin type 3
`(5HT3) antagonists such as ondansetron, granisetron
`and dolasteron were not available at that time. As
`DTIC is classified as a highly emetogenic agent, patients
`receiving treatment in the present time would be given a
`5HT3 antagonist combined with steroids, which should
`result in better control of emesis.
`The combination of streptozocin and doxorubicin
`reported by Moertel et al. [6], can still be considered the
`best regimen in terms of response and overall survival
`for previously untreated patients with islet cell tumors.
`This study randomized 105 patients with advanced islet
`cell carcinomas to streptozocin plus flurouracil, strepto-
`zocin plus doxorubicin or chlorozotocin alone. The
`response rate (63%) and median survival (26.4 months)
`for the combination of streptozocin plus doxorubicin
`was significantly superior to the other two regimens.
`
`Antitumor activity
`
`The response rate in 50 evaluable patients according
`to study criteria was 34% (90% Cl: 23%-47%). In 42
`patients with measurable tumor, the response rate was
`33%. In the 50 patients there were 4 complete responses
`and 13 partial responses (Table 2). Onset of response was
`between one month after treatment was started and 17
`months. Median response duration was 10 months
`(range 4-28 months). Time from randomization to re-
`lapse was 7-39 months. There were only 3 responders,
`response rate 13.6%, (90% CI: 4%-32%) in 22 patients
`with previous chemotherapy. In untreated patients the
`response rate was 50% (90% CI: 33%-67%) with 14
`responders in 28 patients (P - 0.008, Fishers exact test).
`No other difference in baseline patient characteristics
`between the group of patients who responded and did
`not respond was significant.
`
`Survival
`
`Median survival overall was 19.3 months. Median sur-
`vival among the responders was 42 months (range 12-81
`months). Median survival for males was higher than
`females (P - 0.016, log-rank test), for patients with
`creatinine levels less than 1.5 mg % (P = 0.03, log-rank
`test), for patients with a better performance status (P =
`0.012, log-rank test), and for patients with no previous
`chemotherapy (P - 0.0045, log-rank test). No other
`significant differences in survival by baseline character-
`istics groups were observed. The median survival of
`patients with performance status ECOG 2 or 3 was only
`1.7 months.
`
`Toxicity
`
`Since DTIC was administered to 54 patients, toxicity
`data is provided for all 54 patients, including the two
`patients who crossed over from cisplatin and received
`DTIC and the two ineligible patients. A summary of the
`toxicities (ECOG toxicity criteria) is given in Table 3.
`A total of 16 patients (30%) had grade 3-4 toxicities.
`Apart from 5 grade 4, hematological toxicities, the most
`common toxicity was vomiting, with 7 grade 3 and 26
`grade 2 cases. There were two lethal toxicities on the
`study. One patient had septic shock on day 15, cycle 1,
`and another patient had a myocardial infarction. The
`patient who had sepsis also had a grade 4 hematologic
`toxicity (platelet 17,000/mm3 and WBC 1,200/mm3 on
`day 15, cycle 1). There were three grade 4 non-hemato-
`logical toxicities, one case of sepsis, one case of depres-
`sion and paranoid behavior with an unclear cause, and
`one case of bleeding without thrombocytopenia.
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`However, the regimen of streptozocin and doxorubicin
`resulted in severe degree of vomiting in 20% of patients.
`This regimen was also nephrotoxic with chronic renal
`insufficiency developing in 9% of patients. No new
`developments have taken place since the publication of
`this study by Moertel et al. in 1992, and even now
`streptozocin and doxorubicin are commonly used to
`treat pancreatic islet cell tumors.
`Both carcinoid and pancreatic islet cell tumors share
`a common origin from neuroendodermal cells and may
`be expected to respond similarly to chemotherapeutic
`agents. However, DTIC appears to have a lower response
`rate in carcinoid tumors. The Southwest Oncology Group
`(SWOG) conducted a study of DTIC in 56 evaluable
`patients with previously untreated carcinoid
`tumors
`[11]. The response rate was 16% (95% CI: 8%-28%),
`median survival 20 months, and the SWOG concluded
`that DTIC had minimal activity. The toxicity seen was
`similar to our study with severe vomiting in 18%.
`It is unfortunate that progress has not been made
`over the last decade. Studies with carboplatin, mitoxan-
`trone, and modulation of 5-flurouracil by interferon
`have shown disappointing results [12-15]. There is a
`need to develop and evaluate new treatments, however
`it is surprising that newer drugs such as the taxanes
`(paclitaxel, docetaxel), topoisomerase inhibitors (irino-
`tecan, topotecan), platinum compounds (oxaliplatin)
`and gemcitabine have not been tested in this group of
`cancers.
`Even though DTIC appears to have activity, its role
`in the treatment of pancreatic islet cell tumors is un-
`clear. The combination of streptozocin and doxorubicin
`remains the best regimen for patients with a good per-
`formance status. It is doubtful that patients who have a
`performance status of EGOG 2 or more, receive any
`benefit from chemotherapy. In our study the median
`survival was a dismal 1.7 months and consideration
`should be given to exclude these patients from future
`studies. Our study, which was designed in 1982, similar
`to most other published trials in neuroendocrine tumors
`had outmoded entry and assessment criteria. Future
`studies should assess response in those only with meas-
`urable tumor and restrict eligibility to those with normal
`organ function and a good performance status. No
`agent appears to be active as second line therapy of
`pancreatic islet cell tumors, and these patients should
`be treated on clinical protocols. As carcinoid and pan-
`creatic islet cell tumors are relatively uncommon, large
`multi
`institutional or cooperative group efforts are
`needed to improve the survival of these patients. By
`publication of this manuscript the authors hope to
`stimulate discussion in the clinical research community
`for newer therapies.
`
`Acknowledgements
`
`This study was conducted by the Eastern Cooperative
`Oncology Group (Robert L. Comis, MD, Chair) and
`
`supported in part by Public Health Service Grants
`CA23318, CA66636, CA2111, CA15488, CA21076,
`CA39229 and CA13650 from the National Cancer In-
`stitute, National Institutes of Heath and the Department
`of Health and Human Services. Its contents are solely
`the responsibility of the authors and do not necessarily
`represent the official views of the National Cancer In-
`stitute.
`The authors wish to thank Alicia Depastino for
`secretarial assistance and the manuscript and protocol
`writing group at the University of Pittsburgh Cancer
`Institute for critique of this manuscript.
`
`'Appendix: Participating institutions
`
`Albany Medical College; Case Western Metro, Health Medical Center,
`Fox Chase Cancer Center; Hospitals of the University of Pennsylvania;
`Mayo Clinic; New England Medical Center; New York University
`Medical Center; Northwestern Medical Center; Rochester School of
`Medicine; Roswell Park Memorial Institute; Rush Presbyterian, St.
`Lukes; Twin Tiers CCOP - Lourdes Hospital; Tulsa CCOP; University
`of Minnesota, VA Hospital; University of Pittsburgh, University of
`Wisconsin.
`
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`Received 5 March 2001; accepted 22 March 2001.
`
`Correspondence to •
`R. K. Ramanathan. MD
`University of Pittsburgh Cancer Institute
`200 Lothrop St, N 7.55-MUH
`Pittsburgh, PA 15213
`USA
`E-mail: ramanathanrk@msx upmc.edu
`
`1143
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