Vol. 326 No. 8
`
`COMPARISON OF TREATMENTS FOR ISLET-CELL CARCINOMA — MOERTEL ET AL.
`
`519
`
`STREPTOZOCIN—DOXORUBICIN, STREPTOZOCIN—FLUOROURACIL, OR
`CHLOROZOTOCIN IN THE TREATMENT OF ADVANCED ISLET-CELL CARCINOMA
`
`CHARLES G. MOERTEL, M.D., IVIYRTO LEFKOPOULO, Sc.D., STUART LIPSITZ, Sc.D., RICHARD G. HAHN, M.D.,
`AND DAVID KLAASSEN, M.D.
`
`Abstract Background. The combination of streptozo-
`cin and fluorouracil has become the standard therapy
`for advanced islet-cell carcinoma. However, doxorubicin
`has also been shown to be active against this type
`of tumor, as has chlorozotocin, a drug that
`is struc-
`turally similar to streptozocin but less frequently causes
`vomiting.
`In this multicenter trial, we randomly as-
`Methods.
`signed 105 patients with advanced islet-cell carcinoma to
`receive one of three treatment regimens: streptozocin plus
`fluorouracil, streptozocin plus doxorubicin, or chlorozoto-
`cin alone. The 31 patients in whom the disease did not
`respond to treatment were crossed over to chlorozotocin
`alone or to one of the combination regimens.
`Results. Streptozocin plus doxorubicin was superior
`to streptozocin plus lluorouracil in terms of the rate of tu-
`mor regression, measured objectively (69 percent vs. 45
`percent, P = 0.05), and the length of time to tumor pro-
`gression (median, 20 vs. 6.9 months; P = 0.001). Strepto-
`zocin plus doxorubicin also had a significant advantage in
`terms of survival (median, 2.2 vs. 1.4 years; P = 0.004)
`
`DVANCED carcinoma of the islet cells of the pan-
`creas, although rare, presents a kaleidoscope of
`clinical challenges. In addition to the usual problems
`associated with primary and metastatic tumor bulk,
`patients with islet-cell carcinoma may have evidence
`of a variety of hormonal excesses — sometimes sub-
`clinical, sometimes life-threatening. A special feature
`of islet-cell carcinomas, which should be weighed in
`any treatment decision, is the frequently indolent pro-
`gression of disease even after metastasis has occurred.
`Treatment options should always include judicious
`observation. The choice in cases of advanced disease
`
`is strongly influenced by the distribution and bulk
`of tumor, the aggressiveness of the disease, and the
`
`From the Mayo Clinic, Rochester, Minn. (C.G.M. , R.G.H.); the Dana-Farber
`Cancer Institute, Boston (M.L., S.L.); and the Cancer Control Agency of British
`Columbia, Vancouver, Canada (UK). Address reprint requests to Dr. Moertel at
`the Mayo Clinic, Rochester, MN 55905,
`Performed for the Eastern Cooperative Oncology Group (D.C, Tonney, chair),
`Other participating institutions include Albany Medical College, Albany, N.Y.;
`Albert Einstein College of Medicine, Bronx, N.Y.; University of Califomia—
`Irvine, Orange; Case Western Reserve University, Cleveland: Chicago Medical
`School, Chicago; Fox Chase Cancer Center, Philadelphia; Hahnemann Medical
`College, Philadelphia; Johns Hopkins Oncology Center, Baltimore; Medical Col-
`lege of Ohio, Toledo; University of Minnesota, Minneapolis; Mount Sinai Medi-
`cal Center, New York; New York University Medical Center, New York; Newark
`Beth Israel Medical Center. Newark, N..l.; Northwestern University Medical
`Center, Chicago; Our Lady of Lourdes Hospital, Binghamton, N.Y.; Hospital of
`the University of Pennsylvania, Philadelphia; University of Pittsburgh, Pitts-
`burgh; University of Rochester Cancer Center, Rochester, N.Y.; Roswell Park
`Memorial Institute, Buffalo, N.Y.; Rush—Presbyterian—St. Luke’s Medical Cen-
`ter, Chicago; University of Pretoria, Pretoria. South Africa; the Swiss Group,
`Bern, Switzerland; Tufts—New England Medical Center Hospital. Boston; Nat-
`alie Warren Bryant Cancer Center, Tulsa, Okla.; and the University of Wisconsin
`Clinical Cancer Center, Madison.
`Supported in part by grants (CA 13650, CA 23318, CA 15947, CA 06594, CA
`14958, CA 14144, CA 18281, CA 13611, CA 16116, CA 20365, CA 17152.
`CA 16395, CA 17145. CA 15489, CA 11083, CA 12296, CA 25988, CA 21692,
`CA 07190. CA 21076, and CA 21115) from the National Cancer Institute.
`
`that was accentuated when we considered long-term sur-
`vival (>2 years). Chlorozotocin alone produced a 30 per-
`cent regression rate, with the length of time to tumor
`progression and the survival
`time equivalent to those
`observed with streptozocin plus lluorouracil. Crossover
`therapy after the failure of either chlorozotocin alone or
`one of the combination regimens produced an overall re-
`sponse rate of only 17 percent, and the responses were
`transient. Toxic reactions to all regimens included vomit-
`ing, which was least severe with chlorozotocin; hemato-
`logic depression; and, with long-term therapy, renal insuf-
`ficiency.
`Conclusions. The combination of streptozocin and
`doxorubicin is superior to the current standard regimen of
`streptozocin plus fluorouracil in the treatment of advanced
`islet-cell carcinoma. Chlorozotocin alone is similar in effi-
`cacy to streptozocin plus fluorouracil, but it produces lew-
`er gastrointestinal side effects than the regimens contain-
`ing streptozocin. It therefore merits study as a constituent
`of combination drug regimens.
`(N Engl J Med 1992;
`326:519-23.)
`
`nature and severity of the associated endocrine syn-
`dromes. The appropriate treatment may include sur-
`gical reduction of tumor bulk, hepatic-artery occlu-
`sion for disease that is predominantly in the liver,
`specific end-organ blockade for endocrine syndromes
`(e.g., omeprazole for gastrinoma), suppression of hor-
`mone production (e.g., octreotide for the vasoactive
`intestinal peptide syndrome), and usually last in line,
`systemic cytotoxic therapy.
`Streptozocin has been marketed specifically for the
`treatment of islet-cell carcinoma; it induces objective-
`ly measurable tumor regression in about one third of
`patients.‘ In an earlier study, our group found that a
`combination of fluorouracil with streptozocin pro-
`duced a significant improvement in response rate and
`a trend toward improved survival when compared
`with the use of streptozocin alone.’ We also found that
`doxorubicin was active in patients in whom previous
`chemotherapy had failed? These findings led to the
`consideration of a combination of doxorubicin and
`
`streptozocin as therapy for this type of cancer. A pilot
`study found that these agents could be combined safe-
`ly at essentially full doses of each (unpublished data).
`Chlorozotocin is a new drug that is structurally very
`similar to streptozocin; both contain a nitrosourea
`moiety. Its toxic effects include hematologic depres-
`sion, but with less nausea and vomiting than are asso-
`ciated with streptozocin.” It also has the practical
`advantage of being administered in a single intrave-
`nous dose during each course of treatment.
`The present study compared a combination of dox-
`orubicin and streptozocin with the more commonly
`used combination of fluorouracil and streptozocin in
`metastatic islet-cell cancer. We also compared the new
`
`The New England Journal of Medicine
`Downloaded Irom najm.org on June 21, 2016. For personal use only. No other uses without permission.
`Copyright © 1992 Massachusetts Medical Society. All rights reserved.
`
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`520
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`Feb. 20, 1992
`
`agent chlorozotocin with the two streptozocin combi-
`nations.
`
`METHODS
`
`The patients enrolled in this trial were cared for at a number of
`different centers; the study was conducted by the Eastern Coopera-
`tive Oncology Group (ECOG). All those enrolled in the study had
`histologic proof of unresectable or metastatic islet-cell carcinoma.
`Tissue diagnosis was confirmed by pathological review. It was re-
`quired that each patient have a measurable indicator of response to
`therapy, which could include evidence of tumor on physical exami-
`nation or chest films or well-defined metastatic lesions in the liver on
`radioisotope or CT scanning, provided these lesions measured at
`least 5 cm at their widest point. Malignant hepatomegaly could be
`used as an indicator if there was a clearly palpable liver edge at least
`5 cm below the xiphoid process or the costal margins during quiet
`respiration. For patients without measurable tumor, laboratory as-
`says demonstrating excessive hormone production could be accept-
`ed as the only indicators of response. This was the case for only
`seven patients. The criteria for exclusion were an ECOG perform-
`ance score of 4 (indicating total disability), severe nutritional im-
`pairment, recent major surgery (within three weeks), previous ther-
`apy with any of the study agents, any chemotherapy or radiation
`therapy within the previous month, active infection, a leukocyte
`count <4><l0” per liter or a platelet count <l50><|09 per liter,
`active heart disease, a serum creatinine level >l32.6 mmol per liter
`(1.5 mg per deciliter) or a blood urea nitrogen level >l0.7 mmol per
`liter (30 mg per deciliter), or any elevation of serum bilirubin.
`Patients were also excluded if they had any other concurrent or
`recent malignant disease except cutaneous epitheliomas or cervical
`carcinoma in situ.
`
`Randomization Procedures
`
`Patients were stratified according to ECOG performance score
`and according to whether their indicator of response was measur-
`able tumor or endocrine abnormalities on laboratory assays. They
`were then randomly assigned to therapy with chlorozotocin alone,
`fluorouracil plus streptozocin, or doxorubicin plus streptozocin.
`If the initially assigned treatment
`failed,
`the patients treated
`with chlorozotocin alone were randomly assigned to receive either
`lluorouracil plus streptozocin or doxorubicin plus streptozocin.
`Those originally assigned to a streptozocin regimen received chloro-
`zotocm.
`
`Treatment
`
`Chlorozotocin was given in a single intravenous injection (l50 mg
`per square meter of body—surface area), repeated every seven weeks.
`For the combination regimens, streptozocin was given by intrave-
`nous injection at a dose of 500 mg per square meter per day for live
`consecutive days, repeated every six weeks. Fluorouracil was given
`by intravenous injection at a dose of 4-00 mg per square meter per
`day for five days concurrently with streptozocin. Doxorubicin was
`given along with streptozocin by intravenous injection at a dose of
`50 mg per square meter on days I and 22 of each six-week treatment
`cycle, with a maximal total dose of 500 mg per square meter. Leuko-
`cyte and platelet counts were obtained weekly; serum creatinine
`measurements and urinalyses were performed before each cycle of
`therapy. Dosages were reduced if patients had severe nausea or
`vomiting, stomatitis, diarrhea, leukopenia, or thrombocytopenia. If
`the creatinine level became elevated or persistent proteinuria devel-
`oped, the dose of streptozocin or chlorozotocin was reduced. If
`these abnormalities persisted, treatment with these agents was dis-
`continued. Therapy was continued until disease progression was
`noted.
`
`Evaluation of Response
`
`Patients treated with the drug combinations were reevaluated
`every six weeks, and those treated with chlorozotocin were reevalu-
`ated every seven weeks. Measurable tumor masses were considered
`to have regressed if the product of perpendicular diameters was
`
`reduced by at least 50 percent. For malignant hepatomegaly, regres-
`sion was defined as a reduction of at least 30 percent in the sum of
`the measurements below the xiphoid process and the costal mar-
`gins. For hormonal assays, it was defined as a reduction of at least
`50 percent in pretreatment abnormalities. If both tumor size and
`endocrine abnormalities were used as indicators, the response to
`treatment was determined on the basis of measurable tumor. Dis-
`ease progression was defined as an increase of at least 25 percent in
`tumor measurements or the detection of new areas of malignant
`disease.
`
`Statistical Analysis
`
`Analysis of disease progression and survival was based on a pro-
`portional-hazards multivariate model, used to evaluate the rela-
`tion of differences among treatment groups to characteristics of
`the patients and the disease.” Analyses of differences in rates of re-
`gression were modeled by multivariate linear logistic regression.7
`Unadjusted medians for the lengths of time to various events
`were estimated from Kaplan—Meier life-table curves,” and differ-
`ences in time distributions that were not adjusted for patients’
`characteristics were evaluated with the log-rank test.“ For the com-
`parison of rates of toxicity and response to treatment, we used
`the Kruskal—Wallis exact test for ordered contingency tables.'""'
`For comparisons of patients‘ characteristics we used the RXC
`contingency—table exact
`test, which is similar to Fisher’s exact
`test.” Only P values of less than 0.10 are reported. All tests were
`two—sided.
`
`RESULTS
`
`Between November 1978 and June I985, 125 pa-
`tients were enrolled in this study. Eighteen patients
`were subsequently found to be ineligible (eight ran-
`domly assigned to receive chlorozotocin, seven to re-
`ceive fluorouracil plus streptozocin, and three to re-
`ceive doxorubicin plus streptozocin). An additional
`two patients withdrew from the study. Up-to-date fol-
`low-up information was availableron all the remaining
`105 patients, except 1 who was lost to follow-up after
`eight years. As Table 1 shows, the characteristics of
`the patients who could be evaluated were reasonably
`well balanced among the treatment groups.
`Results of Treatment
`
`Among the 105 eligible patients who underwent
`treatment, 3 did not have serial measurements ade-
`quate to determine their response. Results for the re-
`maining 102 are shown in Figure l. The overall differ-
`ences in rates of regression among treatment groups
`are highly significant (P = 0.005). The doxorubicin—
`streptozocin group had significantly higher rates of
`regression than either the fluorouracil—streptozocin
`group (P = 0.05) or the chlorozotocin group (P =
`0.002). The median durations of regression, measured
`from the start of therapy to the last observation
`of regression, were 17 months for chlorozotocin, 14
`months for fluorouracil plus streptozocin, and 18
`months for doxorubicin plus streptozocin. By an alter-
`native measurement, from the first observation of re-
`gression to relapse, the median durations of regression
`were 21 months, 13 months, and 22 months, respec-
`tively. There was a larger number of patients with
`very long regressions (lasting two or more years) in the
`doxorubicin—streptozocin group (ll patients, vs. 4-" in
`the chlorozotocin group and 2 in the fluorouracil-
`
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`
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`
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`

`Vol. 326 No. 8
`
`COMPARISON OF TREATMENTS FOR ISLET-CELL CARCINOMA — MOERTEL ET AL.
`
`streptozocin group). Six patients treated with doxoru-
`bicin plus streptozocin (17 percent) had regressions
`that persisted for more than four years, the longest of
`which lasted seven years and nine months.
`Table 2 shows the relation of tumor regression to
`patient characteristics. Regression rates were higher
`for middle-aged patients (40 to 60 years of age), but
`this difference was only of borderline significance.
`There was no strong evidence that any specific type of
`endocrine abnormality made a patient either more re-
`sponsive or more resistant to chemotherapy; the num-
`bers were small, however.
`Figure 2 shows the length of time to tumor pro-
`gression. Doxorubicin plus streptozocin had a strong
`
`Table 1. Characteristics of the Study Patients.
`DOXORUBICIN +
`FLUOROURACIL +
`STREPTOZOCIN
`STREPTOZOCIN
`
`CHLOROZOTOCIN
`
`CHARACTERISTIC
`
`Sex (M/F)
`Median age — yr (range)
`Time from diagnosis
`<3 mo
`3—<l2 mo
`>12 mo
`ECOG perfonnance score
`0-1
`2-3
`Endocrine abnormality‘l'
`Gastrin
`S—HIAA
`Hypercalcemia
`Insulin
`Corticotropin
`VIP
`Glucagon
`None recorded
`Indicator of response
`Tumor size
`Honnone assay
`Both
`
`13/20
`57 (25-80)
`
`20/14
`51 (18-78)
`
`22
`6
`6
`
`
`
`>—--—v—-IQ~n——-t>—-—-oc-
`
`18/20
`53 (16-75)
`19
`14
`5
`
`27
`11
`
`Btu-—-—-tow-—-:
`
`18
`2
`13
`
`no
`no16
`
`i3wG
`“The ECOG score is on a scale from 0 (fully active) to 4 (totally disabled).
`l'Nine patients had more than one endocrine-function abnonnality. 5-HIAA denotes
`5-ltydroxyindoleacetic acid. and VIP vasoactive intestinal peptide.
`
`advantage in these terms over the other regimens
`(P = 0.001 for both comparisons), and this advantage
`was sustained over six years of observation. The
`P values remained unchanged after multivariate Cox
`regression analysis.
`Survival times are compared in Figure 3. The chlor-
`ozotocin and fluorouracil—streptozocin groups had
`essentially the same survival times (median survival,
`1.5 and 1.4 years). The patients who received doxoru-
`bicin plus streptozocin, however, had decidedly longer
`survival
`(median, 2.2 years);
`this survival advan-
`tage was even more striking in the long-term follow-
`up data. Table 3 shows survival
`in relation to a
`number of patient characteristics. Statistically sig-
`nificant predictors of survival included the ECOG
`performance score and age. The age effect was quad-
`ratic — i.e., patients from 40 to 60 years of age
`had longer survival
`times than older or younger
`patients. Survival differences among the treatment
`groups remained significant after adjustment for im-
`
`Chlorozotocin
`(n = 33}
`
`Fluorouracil + Strep-
`tozocin (n = 33)
`
`Doxorubicin + Strep-
`tozocin (n = 38)
`
`0
`
`10
`
`20
`
`so
`
`40
`
`so
`
`60
`
`in 30
`
`Patients with Regression (96)
`
`Figure 1. Rates of Tumor Regression, Measured Objectively, Ac-
`cording to Treatment Group.
`
`balances in these prognostic factors by the Cox regres-
`sion analysis;
`that is,
`the doxorubicin—streptozocin
`regimen continued to be superior to the other two regi-
`mens in terms of survival (P<0.01 for both compari-
`sons).
`Thirty-one patients were crossed over to alternative
`therapy after their originally assigned treatment failed
`to induce regression. One of these did not have se-
`rial measurements adequate to determine response.
`Only 2 of 15 patients who could be evaluated had a
`regression with chlorozotocin after the previous fail-
`ure of a streptozocin regimen; the same was true for
`only 3 of 15 patients who received a streptozocin regi-
`men as secondary treatment. Regressions during sec-
`ondary treatment were transient, persisting for a
`median of less than six months. The median inter-
`
`to disease progression for all patients receiving
`val
`secondary therapy was 4- months, and the median
`>
`
`Table 2. Response to Therapy According to Pa-
`tienls’ Characteristics.*
`No. WITH
`OBJECTIVE
`No. or
`PATIENTS REGllESSION(%)
`
`PVALUE
`
`CHARACTERISTIC
`Sex
`Male
`Female
`Age (yr)
`$40
`>40—60
`>60
`Time from diagnosis
`<3 mo
`3—<l2 mo
`212 mo
`ECOG performance score
`0-1
`2-3
`Endocrine abnorrnalityi’
`Yes
`No
`Specific abnormality
`Gastrin
`13 (52)
`5-HIAA
`2 (25)
`5 (83)
`Hypercalcemia
`Insulin
`4 (67)
`2 (40)
`Corticotropin
`VIP
`2 (50)
`NS
`I (50)
`Glucagon
`*NS denotes not significant. 5-HIAA 5-hydroxyindoleaceiic acid, and
`VIP vasoactive intestinal peptide. Objective regression was defined as
`regression measured objectively by the methods described in the text.
`'l‘Nine patients had more than one endocrine-function abnormality.
`
`26 (52)
`24 (46)
`
`7 (37)
`29 (59)
`I4 (41)
`
`30 (48)
`14 (61)
`6 (38)
`
`38 (53)
`12 (40)
`
`23 (49)
`27 (49)
`
`50
`52
`
`19
`49
`34
`
`63
`23
`16
`
`72
`30
`
`47
`55
`
`2
`
`l\)J>LIIO\O\<WLII
`
`_
`
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`Exhibit 1
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`
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`

`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`Feb. 20, 1992
`
`"-- Doxorubiein + streptozocin (n = 38)
`-—- Fluorouracil + streptozocin (n = 34)
`— Chlorozotocin (n = 33)
`
`was distinctly more tolerable. This difference was
`more striking than Table 4 indicates, since nausea and
`vomiting associated with chlorozotocin generally oc-
`curred for only a few hours after the single-dose treat-
`ment. On the other hand, the two streptozocin regi-
`mens were usually associated with nausea or vomiting
`lasting through the entire five days of treatment. Sto-
`matitis and diarrhea were essentially nonexistent in
`patients given chlorozotocin alone. Alopecia (data not
`shown) was almost universal with the regimen of dox-
`orubicin plus streptozocin. The frequency of hemato-
`logic toxicity was roughly comparable among the
`three treatment groups. Thrombocytopenia was more
`frequent with chlorozotocin, and leukopenia was more
`severe with fluorouracil plus streptozocin. As is typical
`for agents containing nitrosourea, there was a definite
`tendency to increased hematologic toxicity with long-
`term chlorozotocin therapy. Heart failure developed
`in three patients, possibly as a consequence of doxoru-
`
`Table 3. Length of Survival According to Patients‘
`Characteristics.
`
`CHARACTEIUSTIC
`Sex
`Male
`Female
`Age (yr)
`$40
`>40—60
`>60
`Time from diagnosis
`<3 mo
`3—<l2 mo
`>12 mo
`ECOG performance score
`0-]
`2-3
`Endocrine abnonnality
`Yes
`No
`
`*NS denotes not significant.
`
`No. or
`PATIENTS
`
`MEDIAN SURVIVAL
`(vn)
`
`5 1
`54
`
`20
`50
`35
`
`65
`17
`23
`
`74
`31
`
`49
`56
`
`bicin toxicity; in the case of one of these patients, the
`maximal dose of 500 mg per square meter specified in
`the protocol was exceeded. There was one treatment-
`related death, of a patient treated with fluorouracil
`plus streptozocin who had severe leukopenia compli-
`cated by sepsis.
`Nephrotoxicity was in most cases limited to a mild
`increase in serum creatinine. Nine patients had severe
`chronic renal insufficiency, however. Seven of them
`had azotemia requiring dialysis;
`two, both treated
`with streptozocin regimens, had severe Fanconi’s syn-
`drome. Since in many patients in this study the disease
`did not respond to treatment and they therefore had
`only short exposures to chlorozotocin or streptozocin,
`the figures in Table 4- undoubtedly underestimate the
`potential of these agents for causing chronic renal
`damage. Among the patients who received chlorozoto-
`cin, there was a clear relation between the total dose
`and chronic nephrotoxicity. No patient who received a
`total dose of 750 mg of chlorozotocin per square meter
`
`
`
`
`
`
`
`PatientswithoutProgression(%)
`
`Years after Start of Treatment
`
`Figure 2. Length of Time to Disease Progression, According to
`Treatment Group.
`P<0.001 for the comparison between doxorubicin plus streptozo-
`cin and fluorouracil plus streptozocin; P<0.001 for the compari-
`son between doxorubicin plus streptozocin and chlorozotocin.
`
`survival 12 months — both figures less favorable
`than with primary therapy.
`Since the end results of this study depended on the
`evaluation of response, we studied the association of
`endocrine response and tumor-size response. Among
`45 sets of adequate serial measurements of both tumor
`mass and endocrine abnormalities during primary or
`secondary treatment, 21 were recorded as indicating
`objective tumor regressions; 19 of these also showed a
`reduction in abnormal endocrine levels, and in one
`patient the endocrine level was unchanged. The only
`truly discordant results were in a patient who had a
`transient partial regression of malignant hepatomega-
`ly (lasting four months) in association with a rising
`serum gastrin level.
`Toxic Reactions
`
`Toxic reactions to the first cycle of therapy are
`shown in Table 4, which is a composite of observa-
`tions from both primary and secondary treatment.
`With regard to vomiting, the chlorozotocin regimen
`
`"" Doxorubicin + streptozocin (n = 38)
`-—-- Fluorouracil + streptozocin (n = 34)
`— chlorozotocin (n = 33)
`
`100 ~,
`
`PatientsAlive(%)
`
`Years after Start of Treatment
`
`Figure 3. Survival, According to Treatment Group.
`P<0.004 tor the comparison between doxorubicin plus streptozo-
`cin and fluorouracil plus streptozocin; P<0.03 for the comparison
`between doxorubicin plus streptozocin and chlorozotocin.
`
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`Vol. 326 No. 8
`
`COMPARISON OF TREATMENTS FOR ISLET—CELL CARCINOMA — MOERTEL ET AL.
`
`523
`
`feet and more convenience in administration. This
`
`agent seems attractive as a possible replacement for
`streptozocin in combination regimens. Other agents
`with apparent activity in islet-cell carcinoma that
`have not yet been evaluated in randomized trials in-
`clude dacarbazine and interferon alfa.“’*'5
`
`In the past we have continued chemotherapy indefi-
`nitely in patients who have achieved an objective tu-
`mor regression, a practice that can be trying for pa-
`tients and that sometimes leads them to abandon
`
`therapy. In addition, such a policy can result in irre-
`versible chronic renal failure requiring dialysis. Fu-
`ture studies should examine the possibility of con-
`tinuing therapy only until the disease has stabilized,
`with maximal tumor regression. Considering the usual
`slow rate of growth of islet-cell tumors, such an ap-
`proach may allow patients more freedom from the
`stress of therapy before the malignant disease ad-
`vances to the point at which the resumption of therapy
`is justified.
`Clearly, islet-cell carcinoma is responsive to chemo-
`therapy, but the chance of long-term survival with
`current regimens remains small. There is strong justi-
`fication for continued clinical research into this rare
`disease.
`We are indebted to Ms. Helen Ranchuck for her assistance in
`data management.
`
`REFERENCES
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`West-Ward Pharm.
`Exhibit 1023
`Page 005
`
`Table 4. Toxic Reactions According to Treatment Group.
`FLUOROURACIL + Doxonuarcm +
`STREYTOZOCIN
`STREPTOZOCIN
`(N = 42)
`(N = 44)
`
`CHLOROZOTOCIN
`(N = 51)
`
`Toxic REACrroN*
`
`percent
`
`81
`41
`
`29
`
`77
`
`32
`I5
`7
`
`Vomiting
`Any
`Severe
`Stomatitis
`Any
`Severe
`Diarrhea
`Any
`Severe
`Leukopeniai
`<4>< I0’ cells/liter
`<2>< l0° cells/liter
`Thrombocytopenial’
`< IOOX I09 cells/liter
`<50X10° cells/liter
`Creatinine elevationi
`>0.03 mg/dl
`>1 .0 mg/dl
`Chronic renal insufficiency
`
`*For vomiting. stomatitis, diarrhea, leukopenia, and thrombocytopenia, the results are for
`the first course of therapy only. The values for creatinine elevation are for all courses. Only the
`patients who had adequate documentation of toxic reactions are included.
`T0nly patients for whom adequate serial measurements were available are included.
`iTo convert values for creatinine to millimoles per liter. multiply by 88.4.
`
`or less had this complication, whereas 20 percent of
`those who received 751 to 1000 mg per square meter
`and 56 percent of those who received more than 1000
`mg per square meter had chronic renal failure.
`DISCUSSION
`
`Advanced islet-cell carcinoma has proved to be sur-
`prisingly sensitive to a variety of cytotoxic drugs — a
`sensitivity not shared by other neuroendocrine can-
`cers.” Streptozocin seems to have a specificity for this
`neoplasm, and we have observed a progressive in-
`crease in therapeutic effectiveness as we have moved
`from streptozocin alone to streptozocin plus fluoroura-
`cil and then to streptozocin plus doxorubicin. This
`effectiveness seems to be substantial, resulting in pal-
`liation of endocrine syndromes and, most important,
`improved survival. The duration of tumor regression
`and of improvement in endocrine syndromes was in
`the main relatively long, with a median of 1.5 years
`and a maximum of almost 8 years.
`Although the combination of streptozocin and dox-
`orubicin was the most effective, streptozocin produced
`frequent and often severe nausea and vomiting, which
`compromised both the patients’ quality of life and
`their compliance. Chlorozotocin was found to have
`therapeutic activity comparable to that of streptozo-
`cin plus fluorouracil, with considerably less emetic ef-
`
`West-Ward Pharm.
`Exhibit 1023
`Page 005
`
`