Prospective study of chemotherapy in patients with metastatic gastrinoma

GASTROENTEROLOGY

1988;94:1326-34

Prospective Study of Chemotherapy in Patients With Metastatic Gastrinoma T. VON SCHRENCK, J. M. HOWARD, J. L. DOPPMAN, J. A. NORTON, P. N. MATON, F. P. SMITH, R. VINAYEK, H. FRUCHT, S. A. WANK, J. D. GARDNER, and R. T. JENSEN Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases; Surgery Branch, National Cancer Institute; Department of Radiology, Clinical Center, National Institutes of Health, Bethesda, Maryland; and V. T. Lombardi Cancer Research Center. Washington, D.C.

Ten consecutive patients with metastatic gastrinoma that increased in size over time were studied prospectively during treatment with monthly cycles of streptozotocin (3 g/mZ), 5-fluorouracil (1.2g/mZ), and adriamycin (40 mg/m’) to determine the response rate and time-courses of changes during chemotherapy and to assess various methods of evaluating the effect of chemotherapy. Forty percent of patients demonstrated an initial objective response (225% decrease in tumor size with no new lesions) and 60% failed chemotherapy (225% increase in tumor size or appearance of new lesions). The mean dose of streptozotocin was 27 g/m2 with objective responses occurring at 3.7 f 0.7 mo and failures at 4.5 + 0.7 mo. Responses lasted 9.7 + 2.8 cycles and no complete responses occurred. Survival was not significantly different in responders versus nonresponders (26 -C 11 vs.15 + 4.8 mo, p > 0.1). Changes in serum gastrin concentration, basal acid output, or sensitivity to a given dose of histamine Hz-receptor antagonist did not reflect changes in tumor size. Computed tomography and angiography were the best methods to assess changes in tumor size during chemotherapy, whereas liverspleen scan and ultrasound were relatively insensitive. All patients developed side effects with chemotherapy: 100% had vomiting, 80% alopecia, 40% transient proteinuria, and 20% leukopenia. The present results indicate that chemotherapy with streptozotocin, 5-fluorouracil, and adriamycin is much less effective in patients with extensive metastatic gastrinoma than previously reported. Computed tomography scanning is the method of choice to assess changes in tumor size. Changes in serum gastrin concentration, acid secretion, or tumor size assessed by liver-spleen scan or ultrasound are not

sensitive indicators chemotherapy.

of the tumor

response

during

M

of paetastatic disease occurs in 25%-40% tients with Zollinger-Ellison syndrome (1). In early studies it was reported that patients with Zollinger-Ellison syndrome and metastatic gastrinoma had an excellent long-term prognosis, with 5-yr survival rates of 40% (1,2). However, recently it has been shown that patients with Zollinger-Ellison syndrome with extensive metastatic disease documented by detailed imaging studies have a 5-yr survival rate of only 20% (3), and that only 20% of patients with Zollinger-Ellison syndrome and metastatic gastrinoma are candidates for possible surgical resection of the metastatic gastrinoma (3-5). After total gastrectomy, 50% of patients with gastrinoma die of tumor progression (1,6). With the ability to control gastric acid hypersecretion with potent antisecretory drugs (7-lo), the number of patients with metastatic disease will increase and, in all patients with metastatic spread, the growth of the gastrinoma will become an increasingly important determinant of long-term survival. It is important, therefore, to establish effective treatment of tumor growth in patients with metastatic gastrinoma. Various chemotherapeutic regimes such as streptozotocin, 5-fluorouracil (5-FU), and adriamycin have been reported to offer effective treatment in patients with metastatic gastrinoma (7,11-16). However, the majority of the studies included fewer than 3 patients, used different protocols, and differed in the extent of the gastrinoma from one study to Abbreviations used in this paper: CT, computed 5-FU, 5-fluorouracil. 0016-5085/88/$3.50

tomography;

lune 1988

CHEMOTHERAPY IN METASTATICGASTRINOMA 1327

another. Moreover, gastrinomas sometimes were grouped with other islet cell tumors (17,181, even though it has not been established that different islet cell tumors respond equally to chemotherapy. Furthermore, several studies used changes in serum gastrin concentration (11,12,14,17-20) or changes in gastric acid secretion (11,12) as criteria for the efficacy of chemotherapy, even though neither changes in serum gasirin concentrations nor changes in gastric acid secretion have been shown to reflect changes in tumor size. In addition, it has been reported that chemotherapy could reduce or even normalize gastric acid hypersecretion (11,12,15), but this effect has been reported only for individual cases. When tumor size was assessed during chemotherapy, differen+ imaging modalities have been used (1,6,11,13-15,17,19,21-24). However, the best imaging technique to reliably determine changes in tumor size during chemotherapy has not been established. The purpose of the present study was to evaluate the efficacy of chemotherapy with a combination of streptozotocin, 5-FU, and adriamycin in a prospective study. Ten patients with metastatic gastrinoma were studied and various modalities were evaluated to determine changes in tumor size during chemotherapy. The various imaging techniques were compared with respect to their abilities to detect changes in tumor size and the results of various imaging studies were compared with the changes in gastric acid secretion and serum gastrin concentration.

Materials and Methods Patients Ten consecutive patients with metastatic gastrinoma were studied. Each patient met the following criteria for entry into the study: (a) proven Zollinger-Ellison syndrome on the basis of a basal acid output >15 mEq/h and an elevated fasting serum gastrin concentration 3100 pg/ml; (b) histologically proven unresectable metastatic gastrinoma; (c) unequivocal growth of the tumor documented during the 6 mo immediately before the start of chemotherapy; (d) absence of major renal, cardiac, or pulmonary impairment; and (e) no previous chemotherapy. Each patient entering the study gave written informed consent. The protocol was approved by the Human Experimentation Committee of the National Institute of Diabetes and Digestive and Kidney Diseases. Chemotherapy

Protocol

The chemotherapeutic agents used in this study were streptozotocin (Upjohn Company, Kalamazoo, Mich.), 5-FU (Efudex; Hoffman La Roche, Nutley, N.J.), and adriamycin (Adriamycin, Adria, Dublin, Ohio). The agents were administered in cycles consisting of 28 days. On day 1 of each cycle the patient received 1.5 g/m2

streptozotocin diluted in 150 ml of 5% dextrose/water intravenously over 15 min, 40 mg/m’ adriamycin intravenously over 5 min, and 0.6 g/m” 5-FU diluted in 100 ml of 5% dextrose/water intravenously over 10 min. On day 8 of each cycle, the patient received the same dose of streptozotocin and 5-FU as given on day 1 without adriamycin. Before chemotherapy was given, a complete blood count was performed and renal function was evaluated. Chemotherapy was not given if there was evidence of heart failure, if the white blood cell count was ~2000 cells/mm3, if platelet count was <100,000/mm3, or if the hemoglobin was <9 g/dl. Before chemotherapy was given, urinalysis was performed and if proteinuria was present by dipstick, 24-h urinary protein excretion and creatinine clearance was determined. Streptozotocin was not given if proteinuria was ~500 mg/24 h or if creatinine clearance was <30 ml/min. If proteinuria was 300-500 mg/24 h, 75% of the dose of streptozotocin was given and if creatinine clearance decreased 260% from the pretreatment value, the streptozotocin dose was reduced by at least 50%.

Study Protocol Before entering the study, all patients underwent the following evaluation: a complete history and physical examination; measurement of serum gastrin concentration in the fasting state using Walsh antibody 1611 lot 4B, which recognizes gastrin 17 and gastrin 34 equally (25); secretin and calcium provocative tests as described previously (26); a complete blood count; urinalysis including 24-h urinary protein excretion and creatinine clearance and biochemicai studies including measurement of serum glutamic oxaloacetic transaminase, serum glutamic trahsaminase, electrolytes, and determination of basal and pentagastrin-stimulated gastric acid secretion (27,28). To asseas changes in the sensitivity of gastric acid secretion to histamine Hz-receptor antagonists, all antisecretory medication was stopped for 24 h, basal acid output was determined, and then the response to a fixed dose of histamine Hz-receptor antagonist was determined as previously described (3,26). The extent of tumor was evaluated by computed tomography (CT) scah, angiography, liverspleen scan, bone scan, and abdominal ultrasound as previously described (3,26). After three and six cycles, all of the above tests were repeated for patients l-4 (Table 2). For patients 5-10, reassessments were done after six cycles of chemotherapy by determination of serum gastrin concentration, CT scan, and angiography. After the 6-mo evaluation, all patients underwent assessments in 3-mo intervals by determination of serum gastrin concentration, CT scan, and angiography. An objective regression was defined as a 225% reduction in -diameter of the most clearly measurable tumor lesion and no appearance of new lesions. In most studies a 25096 reduction in tuinor size is used; however, in the present study because multiple imaging studies were performed at different times, a 225% change in size could be reliably detected. A complete remission was defined as the disappearance of all tumor when assessed by imaging studies and normalization of fasting gastrin concentration.

GASTROENTEROLOGY

1328 VON SCHRENCK ET AL.

Table 1. Clinical Characteristics Chemotherapy

Vol. 94, No. 6

and Tumor Extent in Patients With Metastatic Gastrinoma Treated With Patient No.

Characteristics Age (~4 sex

Fasting serum gastrin (pg/mJ] Basal acid output (mEq/h) Maximal acid output (mEq/h)

Tumor extent0

1

2

3

4

5

6

7

8

9

10

42

36

42

50

50

35

55

76

46

46

F

M

F

M

M

M

F

M

F

M

2,760

4,600

13,000

9,200

300

1,200 22

12,000

19,100

26,300

3,100

48

61

85

69

38

54

77

38

53

54

85

86

88

47

62

77

42

61

p, K, L

p, L

p, L

p, L

p, L,

BONE

L, BONE

P, AG, IVG

p, L

p, L

50

p, L

adrenal gland; IVC, inferior vena cava; K, kidney; L, liver; P, pancreas.’Tumor extent was determined by imaging studies before chemotherapyas outlined in Materials and Methods.

AG,

Chemotherapy was continued until complete remission occurred or was stopped when the most clearly measurable tumor lesion increased in diameter by 225% compared with the previous study or when new lesions occurred. Failure of chemotherapy was defined as a 225% increase in the diameter of the most clearly measurable tumor lesion or occurrence of new lesions.

Results Ten patients with histologically proven metastatic gastrinoma entered this study from June 1977 to June 1986. The clinical and laboratory characteristics of the 10 patients are listed in Table 1. The mean age was 48 + 3.5 yr (mean ? SEM, range 35-76 yr); the mean fasting serum gastrin concentration was 9156 * 2861 pg/ml (range 300-26,300 pg/ml); mean basal acid output was 54 + 5.9 mEq/h (range 22-85 mEq/h), and the mean maximal acid output was 65 + 5.3 mEq/h (range 42-88 mEq/h). In 9 patients the gastrinoma was metastatic to the liver and in 1 patient (patient 4, Table 1) the gastrinoma was invading the left adrenal gland and the inferior vena cava. In all 10 patients, a pancreatic tumor was found either by surgery or at autopsy; the tumor was identified by imaging studies before chemotherapy in 9 of the 10 patients. The effect of chemotherapy on tumor size assessed by CT scanning in the 10 patients is shown in Figure 1. Four patients (patients 1, 2,4, and 8, Figure 1) had a 225% decrease in tumor diameter with an onset of the response by 3.7 + 0.7 mo (range 3-6 mo). Two patients (patients 1 and 4, Figure 1) had a ~50% decrease in tumor diameter. In 6 patients (patients 3, 5, 6, 7! 9, and 10, Figure 1) no decrease in tumor diameter occurred with chemotherapy and the tumor diameter increased 225% in all patients after 4.5 f 0.7 mo (range 3-6 mo). In all patients who experienced an objective regression during chemotherapy, chemotherapy subsequently failed. In 3 patients there was a 225% increase in tumor diameter after a mean of 11 mo (range 618 mo) and in 1 patient (patient 8, Table 1) the appearance of meta-

static bone lesions occurred after 9 mo of chemotherapy. The mean duration of the remission in the 4 patients who demonstrated an objective response was 10 mo [range 6-18 mo). In 3 patients (patients 1, 2, and 3, Table 1) no significant changes in tumor diameter were detected after three cycles of therapy, whereas measurements after six cycles detected significant changes in tumor diameter in all patients. In the 4 patients with objective regression, the mean decrease was 50% (range 25%-95%). The response to chemotherapy of the patient showing the greatest decrease is shown in Figure 2. This patient (patient 4, Figure 1) was also the only patient in whom the gastrinoma was not metastatic to the liver. To investigate whether changes in serum gastrin concentration reflect changes in tumor size during chemotherapy, we compared changes in serum gas160

0

0

6

12

18

TIME Icycles)

Figure 1. Effect of chemotherapyon tumor diameterevaluatedby CT scan. The largest diameter of the most clearly measurabletumor lesion was measured before chemotherapy and at each of the indicated times after starting chemotherapy.Tumor diameter at times after starting chemotherapywas expressed as the percentage of the tumor diameter before chemotherapy. The numbers refer to the patient numbers in Table 1.

June 1988

CHEMOTHERAPY

IN METASTATIC

GASTRINOMA

1329

-Al 3

6

9

12

15

16

21

3

9

12

TIME (cycles)

TIME (cycles)

Figure

6

3. Changes in tumor size in relation to changes in serum gastrin concentration during chemotherapy. Arrows indicate changes in tumor size and the direction of the arrows indicates an increase or decrease in tumor size. The patient numbers refer to the patient numbers listed in Table 1.

decreased in size with no change in serum gastrin concentration and in 1 patient (patient 1, Figure 3), while the tumor size remained unchanged, serum

t :igure

2. Computed tomography scan of patient 4 (see Table 11 before chemotherapy (top] and after six cycles of chemotherapy (bottom). The pretreatment CT scan shows tumor (T) in the inferior vena cava (WC) and the left suprarenal area continuous with the tail of the pancreas Liver (L) and spleen (S) show no tumor. After six cycles of therapy, the tumor in the inferior vena cava and in the left suprarenal area has disappeared. Calcifications in the tail of the pancreas are suggestive of residual tumor (T).

trin concentrations with changes in tumor size assessed by imaging studies in each patient (Figure 3). Changes in serum gastrin concentration were compared with changes in tumor size assessed by imaging studies after the respective cycles of chemotherapy at 18 time points. In 10 of the 18 (55%) comparisons, the changes in serum gastrin concentration reflected actual changes in tumor size assessed by imaging studies. Specifically, at some time during chemotherapy in 6 patients [patients 1, 3, 4, 6, 7, and 10, Figure 3), the tumor size increased while serum gastrin concentration increased and in 4 patients (patients 1, 2, 4, and 8, Figure 3), tumor size decreased while serum gas&in concentration decreased. In 5 of the 10 patients (patients 2, 3, 5, 8, and 9, Figure 3), tumor size increased while there was no increase or a decrease in serum gastrin concentration. At some time during chemotherapy in 2 patients (patients 2 and 4, Figure 3), the tumor

gastrin concentration increased. To explore the relationship between changes in tumor size and changes in gastric acid secretion, changes in basal and maximal acid output were compared with changes in tumor size during chemotherapy in the first 4 patients (Figure 4). Two patients (patients 2 and 4, Figure 4) showed a decrease in tumor size during chemotherapy and also a decrease in basal and maximal acid output. One patient (patient 3) demonstrated tumor growth while basal and maximal acid output decreased, whereas the other patient (patient 1) showed a slight increase in

MAXIMAL

Figure

ouwu:

t

II Pretreatment

Aclo

After 6 CphS

Pretreatment

After 6 CvClW

4. Changes in tumor size in relation to changes in basal acid output and maximal acid output during chemotherapy in 4 patients (patients l-4). The patient numbers refer to the patients listed in Table I.

1330

VON SCHRENCK

ET AL.

GASTROENTEROLOGY

basal and maximal acid output while the tumor decreased in size. To evaluate changes in the requirements for antisecretory medication during chemotherapy, the sensitivity to a given dose of histamine Hz-receptor antagonist was assessed by determining the ability of a fixed dose of histamine HZ-receptor antagonist to inhibit basal gastric acid secretion measured before starting chemotherapy and after six cycles of chemotherapy in the first 4 patients (patients l-4, Table 1). Figure 5 shows the results for patient 1 and demonstrates the variable response to fixed doses of cimetidine during the course of chemotherapy. Before starting chemotherapy gastric acid secretion was inhibited by 62% at 3 h and by 20% at 6 h after 600 mg of cimetidine. After 6, 12, 18, and 21 cycles of chemotherapy a significant reduction in tumor size was observed, whereas basal acid output and acid output at 3 and 6 h after cimetidine were similar to that before starting chemotherapy [time “0”). After 21 cycles of chemotherapy an increase in tumor size was observed and gastric acid secretion was not reduced by 600 mg of cimetidine to the same degree as at 12 or 18 cycles of chemotherapy or before starting chemotherapy. Similar studies in patients 2-4 (Table 1) demonstrated no significant changes in the amount of suppression caused by a fixed dose of cimetidine despite significant changes in tumor size (data not shown). Moreover, in 2 patients (patients 1 and 4, Table 1) in whom chemotherapy resulted in a decrease in tumor size, an increase in the dose of HZ-receptor antagonists that controlled acid hypersecretion was required (data not shown). To determine which imaging modality best reflects changes in tumor size during chemotherapy, changes in tumor size were assessed by CT scan, angiography, liver-spleen scan, and ultrasound in patients 1-4 [Table 2). Computed tomography scanning detected objective responses or failure of chemotherapy as defined in the study protocol in all patients, angiography detected changes in 3 of 4 patients, and the changes in tumor size seen with CT Table

Patient No. 1 2 3 4

2.

Comparison Chemotherapy

of the Ability

change)

Imaging Selective

CT scan (%

of Various

a.b

Response (25% 1) Response (25% 1) Failure (25% f ) Response (70% i )

(%

Vol. 94, No. 6

0 0

6

12

16

21

1

TIME (Cycles)

Figure

5. Effect of a given dose of cimetidine on gastric acid hypersecretion compared with changes in tumor size in patient 1. The top panel shows the change in tumor diameter of the most clearly measurable tumor lesion as documented by CT after the indicated cycle of chemotherapy. Tumor diameter is expressed as the percentage of the diameter before chemotherapy. The bottom panel shows gastric acid secretion 3 and 6 h after 600 mg of cimetidine at the same time tumor size was assessed. Gastric acid secretion is expressed as the percentage of the basal acid output before taking cimetidine. Basal acid output was determined 24 h after discontinuing all antisecretory medication and was 48 mEq/h initially, 58 mEq/h at six cycles, 42 mEq/h at 12 cycles, 32 mEq/h at 18 cycles, and 50 mEq/h after 21 cycles of chemotherapy.

and angiography were of similar magnitude. Computed tomography and angiography were both more sensitive than ultrasound or liver-spleen scan as ultrasound detected objective responses or failure only in 1 of 4 cases and liver-spleen scan did not detect changes in the 3 patients studied. The clinical course of the 10 patients studied is summarized in Table 3. The average time of treat-

Techniques angiography change)

a.b

Response (30% c ] No change Failure (25% t ] Response (90% 1)

to Assess

Response

After

6 Months

of

Ultrasound (% change)a,b

Liver-spleen scan (% change)

No change No change No change Response (90% 4

No change No change No change ND

)

ND, Not determined. ’ Response was defined as a ~25% decrease in tumor diameter compared with the pretreatment value. Failure was defined as a 225% increase in tumor diameter compared with the pretreatment value. No change was defined as any change <25% in tumor diameter compared with the pretreatment value. b Percentage values and arrows refer to the percentage of change and direction of change in the diameter of the largest lesion 6 mo after chemotherapy compared with the pretreatment value.

rune

CHEMOTHERAPY

1988

Table

Patient No.

3. Length of Treatment and Response, Duration of treatment0

Side Effects, and Poststudy

Length of objective response”

Clinical

21

18

2

8

6

3

7

0

Vomiting, alopecia, leucopenia, proteinuria Vomiting, alopecia, proteinuria Vomiting, leukopenia

4

12

8

Vomiting,

leukopenia

5

6

0

Vomiting,

alopecia

6

6

Vomiting,

alopecia

7

8

Alopecia

8

8

9

a

Vomiting, alopecia, proteinuria Vomiting, alopecia

10

6

Vomiting,

alopecia

GASTRINOMA

1331

Course

Poststudy clinical course

Side effects

1

IN METASTATIC

Initial response to DTIC, later tumor progression: died 60 mo after beginning STZ, 5-FU, ADR Failed chemotherpy with DTIC; died 12 mo after beginning STZ, 5-FU, ADR Failed chemotherapy with DTIC; died 24 mo after beginning STZ, 5-FU, ADR Failed chemotherapy with DTIC; died 21 mo after beginning STZ, 5-FU, ADR Failed chemotherapy with VP-16, cisplatin, and DTIC; alive 36 mo after beginning STZ, 5-FU, ADR; tumor progressing Died during chemotherapy with STZ, 5-FU, ADR (6 mo after start of chemotherapy) Failed chemotherapy with DTIC; alive 14 mo after beginning STZ, 5-FU, ADR; tumor progressing Failed LAK and IL-2 therapy; died 13 mo after beginning STZ, 5-FU, ADR Failed chemotherapy with DTIC; alive 18 mo after beginning STZ, 5-FU, ADR; tumor progressing Failed chemotherapy with chlorozotocin; died 7 mo after beginning STZ, 5-FU, ADR

ADR, adriamycin; DTIC, dacarbazine; 5-FIJ, 5-fluorouracil; IL-2, interleukin-2; LAK, lymphocyte activated killer cells; STZ, streptozotocin; VP-16, etoposide. a Duration of treatment is expressed as the number of cycles of chemotherapy with streptozotocin, 5-FU, and adriamycin. b An objective response was defined as 225% decrease in tumor diameter and the duration of the response was defined as the time from onset of the response to the time of failure of chemotherapy (i.e., '25% increase in tumor diameter or appearance of new lesions from previous assessment)

ment was 9.4 2 1.4 cycles (range 6-21 cycles). In the patients in whom chemotherapy resulted in a reduction in tumor size, the time of objective response lasted 9.7 k 2.8 cycles (range 6-18 cycles). Side effects of chemotherapy were observed in all 10 patients: 10 of 10 patients experienced vomiting, 8 of 10 developed alopecia, 4 of 10 developed transient proteinuria, and in 2 patients (patients 1 and 4, Table 3) leucopenia made reduction or postponement of chemotherapy necessary. The mean total dose of streptozotocin administered during the whole course of chemotherapy was 27 k 4.1 g/m2 [range 18-63 g/m’). Nine of 10 patients were treated subsequently with different chemotherapeutic agents after failing chemotherapy with streptozotocin, 5-FU, and adriamytin. None of the other chemotherapeutic regimes resulted in objective tumor regression. The survival time in the patients who responded to chemotherapy with streptozotocin, 5-FU, and adriamycin with a decrease in tumor size was not significantly different from the survival time in patients who showed increases in tumor size during chemotherapy with streptozotocin, 5-FLJ, and adriamycin (26 2 11 mo in responders, 15 k 4.8 mo in nonresponders, p > 0.1).

Discussion In the present prospective study in 10 consecutive patients with metastatic gastrinoma, treatment with streptozotocin, 5-FU, and adriamycin resulted in an objective response in 40% of all patients, however, this response was partial, with no patient demonstrating complete tumor regression. This response rate and the degree of response is lower than the response rate of 63% and the rate of 33% for complete responses reported by Moertel et al. (17) in 42 patients with various metastatic islet cell tumors treated with streptozotocin and 5-FU. However, comparison with the results of the study by Moertel et al. (17) is difficult for a number of reasons. Only 16% of the patients in the study by Moertel et al. (17) had metastatic gastrinoma, and some data suggest that different islet cell tumors may not be equally responsive to chemotherapy. Specifically, vasoactive intestinal polypeptide-producing tumors are generally very sensitive to streptozotocin and frequently show a complete tumor regression (29,30), whereas in the present study only 40% of the patients with metastatic gastrinoma responded to streptozotocin and none had a complete tumor regression. Furthermore, dacarbazine has been reported to be effective

1332

VON SCHRENCK

ET AL.

in patients with glucagonoma, in whom chemotherapy with streptozotocin had failed (30-32); in contrast, dacarbazine has no beneficial effect in metastatic gastrinoma that did not respond to streptozotocin (26). In addition, in the study by Moertel et al. (17), in several cases the authors defined the response to chemotherapy as a normalization of hormonal concentration or function. As shown in the present study, serum gastrin concentrations do not reliably reflect changes in tumor size assessed by imaging studies, and thus changes in hormonal function do not indicate the efficacy of chemotherapy. Finally, in the study by Moertel et al. (17), it is not apparent that all patients had extensive metastatic disease that increased in size over a 6-mo period before receiving chemotherapy, as was the case with all patients in the present study. The results of the present study are in agreement with a recent presentation of the worldwide experience of the efficacy of chemotherapy with streptozotocin and other drugs in patients with metastatic gastrinoma, in whom a response of 42% was found (22). However, in that presentation, 9 of 45 patients (20%) had a complete response defined as disappearance of the gastrinoma assessed by imaging studies. This complete response to chemotherapy has also been reported for other individual cases (1920). In the present study, no patient showed a complete response defined as complete disappearance of the gastrinoma during chemotherapy. The lack of complete response in the present study cannot be attributed to different total dosages of streptozotocin that have been administered to the patients during chemotherapy. In the present study, the mean total dose of streptozotocin was 27 g/m2 per patient and is greater than the dose of streptozotocin in the studies in which complete regressions of tumors have occurred (17,19,20,22). It has been reported that the response of gastrinomas to chemotherapy may be delayed (1922); however, this is unlikely to be the cause of the lack of complete responses in the present study because the duration of treatment was similar to that reported in other studies (17,19,20, 22), and the mean follow-up of the study was 24 mo with frequent reassessments during which delayed responses would have been detected. It is also unlikely that the differences in the degree of response are due to the route of administration of the chemotherapeutic agents. Although complete responses have been reported with intraarterial administration, in most cases patients were treated with intravenous administration, as in the present study. The different response rates do not seem attributable to the use of different imaging modalities. In some studies, changes in tumor size were measured by liver-spleen scan (l,ll-14,17,18), angiography (6,12,15,22,24),

GASTROENTEROLOGY Vol. 94, No. 6

CT scanning (16,22,24), or ultrasound (22). In the present study, all imaging techniques were used and CT and angiography were found to be more sensitive in detecting changes in tumor size than liver-spleen scan or ultrasound. The most likely explanation for the lower rate for responses in the present study is the fact that all the patients studied had extensive gastrinoma that was increasing in size over a 6-mo period before starting chemotherapy. Although there are no studies that clearly establish that in patients with less tumor burden the response to chemotherapy is more complete than in cases with extensive metastasis of the gastrinoma that is increasing in size, this possibility is suggested by a recent study that demonstrated that some patients with extensive metastatic disease had a prolonged disease-free interval after gross resection of tumor and subsequent chemotherapy (3). It has been reported that chemotherapy results in a decrease in gastric acid secretion (11,12,15) and that chemotherapy could be helpful in controlling gastric acid hypersecretion (11,12,15). In the present study, it was found that basal acid output was reduced but never normalized during chemotherapy. Furthermore, changes in basal or maximal acid output did not necessarily reflect changes in tumor size. Specifically, in 2 patients basal and maximal acid output decreased when the tumor decreased in size: however, a third patient demonstrated tumor growth in spite of decreasing basal and maximal acid output and in a fourth patient, the tumor decreased in size while basal and maximal acid output increased. As neither basal nor maximal acid output was found to reflect changes in tumor size, measurements of basal and maximal acid output were not included in the reassessments during chemotherapy for patients 5-10 (Table 1). Changes in tumor size were also not reflected in the sensitivity to inhibition of gastric acid secretion by a given dose of histamine HZreceptor antagonists. This finding demonstrates that effective chemotherapy did not result in an improvement in the ability of a fixed dose of antisecretory drug to control gastric acid hypersecretion. Furthermore, the daily doses of histamine HZ-receptor antagonists were not significantly changed by chemotherapy in any of the patients demonstrating an objective response. These findings indicate that neither changes in gastric acid secretion nor changes in antisecretory drug requirements can be used to determine the efficacy of chemotherapy. Furthermore, chemotherapy is not as effective as other treatments in controlling gastric acid hypersecretion. In several studies changes in serum gastrin concentrations have been used as indicators of the response to chemotherapy (11,12,14,15,17,18,20). However, in the present study, it was found that

rune 1988

changes in serum gastrin concentrations frequently do not reliably reflect actual changes in tumor size. When changes in serum gastrin concentration were correlated with changes in tumor size during the chemotherapy, in only 55% of the comparisons did changes in serum gastrin concentrations reflect actual changes detected by imaging techniques. For example, in 5 patients an increase in tumor size occurred while there was no change (n = 4) or a decrease (n = 1) in serum gastrin concentrations. It has been previously reported that serum gastrin concentrations can increase while a decrease in tumor size is observed (6,13), and the findings in the present study indicate that changes in serum gastrin concentration are unreliable indicators of changes in tumor size during chemotherapy. Computed tomography, angiography, liver-spleen scan, and ultrasound have been used in various studies to evaluate changes in tumor size during chemotherapy. Angiography appears to be the most sensitive method to detect hepatic metastases of gastrinoma (33) and CT has been found to be nearly as sensitive in detecting gastrinoma (34). However, the best imaging modality to assess changes in tumor size during chemotherapy has not been established. Passaro and Gordon (24) suggested hepatic CT scans and hepatic angiography as both being useful techniques to evaluate tumor growth after total gastrectomy. In the present study, CT scan and angiography were found to be approximately equally sensitive in detecting changes in tumor size during chemotherapy. Liver-spleen scan and ultrasound were both found to be relatively insensitive in detecting changes in tumor size during the course of chemotherapy and should, therefore, not be used to determine changes in tumor size during chemotherapy. During chemotherapy repetitive imaging studies are needed. Computed tomography is as sensitive as, but less invasive than, angiography. Computed tomography scanning is, therefore, the method of choice to determine changes in tumor size during chemotherapy. The present study indicates that chemotherapy with streptozotocin, 5-FU, and adriamycin is less effective in patients with metastatic gastrinoma than previously reported. The survival time in patients who showed a decrease in tumor size during chemotherapy was not significantly different from the survival time in the patients in whom the tumor increased during chemotherapy. Taking into account that only in the minority of patients incomplete responses occurred and that all patients experienced side effects of chemotherapy, alternate modes of therapy such as therapy with the long-acting somatostatin analogue (SMS 201-995) (35,361 or with interferon (37) should be considered in patients with aggressively growing gastrinoma. In the present

CHEMOTHERAPY IN METASTATIC GASTRINOMA

1333

study, the efficacy of chemotherapy was not evaluated in patients with metastatic disease that was not increasing in size before chemotherapy or in patients with minimal metastatic disease. It is possible that chemotherapy with streptozotocin, 5-FU, and adriamycin might have a beneficial effect in those patients with less extensive disease, as suggested by the positive results of chemotherapy after gross resection of metastatic gastrinoma (3). However, the efficacy of chemotherapy in that group of patients with less extensive or aggressive metastastic disease is not clearly established and has to be studied more extensively.

References 1. Fox PS, Hofmann JW, Decosse JJ, Stuart DW. The influence of total gastrectomy on survival in malignant Zollinger-Ellison tumor. Ann Surg 1974;180:558-66. 2. Zollinger RM, Ellison EC, Fabri PJ, Johnson J, Sparks J, Carey LC. Primary peptic ulcerations of the jejunum associated with islet cell tumors: twenty-five year appraisal. Ann Surg 1980;192:422-30. 3. Norton JA, Sugarbaker PH, Doppman JL, et al. Aggressive resection of metastatic disease in selected patients with malignant gastrinoma. Ann Surg 1986;203:352-9. 4. Hofmann JW, Fox PS, Wilson SD. Duodenal wall tumors and the Zollinger-Ellison syndrome. Arch Surg 1973;107:334-9. 5. Bonfils S, Landor JH, Mignon M, Hervoir P. Results of surgical management of 92 consecutive patients with Zollinger-Ellison syndrome. Ann Surg 1981;194:692-7. 6. Zollinger RM, Martin EW, Carey LC, Minton JP. Observations on the postoperative tumor growth behavior of certain islet cell tumors. Ann Surg 1976;184:525-30. 7. Jensen RT, Collen MJ, McArthur KE, et al. Comparison of the effectiveness of ranitidine and cimetidine in inhibiting acid secretion in patients with gastric hypersecretory states. In: Misiewicz JJ, Wood JJ, eds. Ranitidine: therapeutic advances. Amsterdam: Excerpta Medica, 1984:168-98. 8. Jensen RT, Pandol SJ, Collen MJ, Raufman JP, Gardner JD. Diagnosis and management of the Zollinger-Ellison syndrome. In: Hirschowitz BI, Spenney JD, eds. Receptors and the upper GI tract. J Clin Gastroenterol 1983;5(Suppl 1): 123-31. an 9. Howard JM, Collen MJ, Cherner JA, et al. Famotidine: effective Hz-antagonist for the therapy of Zollinger-Ellison syndrome. Gastroenterology 1985;88:1026-33. 10. McArthur KE, Collen MJ, Cherner JA, et al. Omeprazole as a single daily dose is effective therapy in Zollinger-Ellison syndrome. Gastroenterology 1985;88:939-44. 11. Murray-Lyon IM, Eddleston ALWF, Williams R, et al. Treatment of multiple-hormone-producing malignant islet-cell tumor with streptozotocin. Lancet 1968;ii:895-8. 12. Murray-Lyon IM, Cassar J, Coulson R, et al. Further studies on streptozotocin therapy for a multiple-hormone-producing islet cell carcinoma. Gut 1971;12:717-20. 13. Sadoff L, Franklin D. Streptozotocin in the Zollinger-Ellison syndrome (lett). Lancet 1975;ii:504-5. for malignant Zollinger-Ellison 14. Ruffner BW. Chemotherapy tumors. Arch Intern Med 1976;136:1032-4. 15. Stadil F, Stage G, Rehfeld JF, Efsen F, Fisherman K. Treatment of Zollinger-Ellison syndrome with streptozotocin. N Engl J Med 1976:294:1440-Z. syn16. Huard GS, Stephens RL, Friesen SR. Zollinger-Ellison

1334

17.

18.

19.

20.

21.

22.

23. 24. 25.

26.

27.

28.

29.

VON SCHRJZNCK ET AL.

drome. Streptozotocin therapy for metastatic gastrinomas. J Kans Med Sot 1981;82:21&21 Moertel CG, Hanley JA, Johnson LA. Streptozotocin alone compared with streptozotocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N Engl J Med 1980;303:1189-94. Moertel GC, Lavin PT, Hahn RG. Phase II trial of doxorubicin therapy for advanced islet-cell carcinoma. Cancer Treat Rep 1982:66:1567-g. Hayes JR, O’Connell N, O’Neill T, Fennelly JI, Weir DG. Successful treatment of a malignant gastrinoma with streptozotocin. Gut 976;17:285-8. Cryer PE, Hill GJ. Pancreatic islet cell carcinoma with hypercalcemia and hypergastrinemia. Cancer 1976;38:221721. Broder LE, Carter JK. Pancreatic islet cell carcinoma: II. Results of therapy with streptozotocin in 52 patients. Ann Intern Med 1973;79:108-18. Bonfils S, Ruszniewski PH, Haffar S, Lancormit H. Chemotherapy of hepatic metastases in Zollinger-Ellison syndrome. Report of a multicentric analysis (abstr). Dig Dis Sci 1987;31: 5105. Lamers CBH, Van Tongeren JHM. Streptozotocin in the Zollinger-Ellison syndrome. Lancet 1975;ii:1159-1. Passaro E, Gordon HE. Malignant gastrinoma following total gastrectomy. Arch Surg 1974;108:444-8. Jaffe BM, Walsh JH. Gastrin and related peptides. In: Jaffe BM, Behrman HR, eds. Methods of hormone-radioimmunoassay. New York: Academic, 1979:455-77. Jensen RT, Gardner JD, Raufman J-P, et al. Zollinger-Ellison syndrome. NIH combined clinical staff conference. Ann Intern Med 1983;98:59-75. McCarthy DM, Olinger EJ, May RJ, Long JW, Gardner JD. Hz-histamine receptor blocking agents in the Zollinger-Ellison syndrome. Ann Intern Med 1977;87:668-75. Collen MJ, Howard JM, McArthur KE, et al. Comparison of ranitidine and cimetidine in the treatment of gastric hypersecretion. Ann Intern Med 1984;100:52-8. Kahn CR, Levy AG, Gardner JD, Miller JD, Gordon P, Schein

GASTROENTEROLOGY Vol. 94, No. 6

30.

31.

32.

33.

34.

35.

36.

37.

PS. Pancreatic cholera: beneficial effects of treatment with streptozotocin. N Engl J Med 1975;292:941-5. Ch’ng JLC, Polak JM, Bloom SR. Miscellaneous tumors of the pancreas. In: Go VLW, Gardner JD, Brooks FP, Lebenthal E, DiMagno EP, Scheele GA, eds. The exocrine pancreas, biology, pathobiology and diseases. New York: Raven, 1985:76371. Prinz RA, Badrinath K, Banerji M, Sparagana M, Dorsch TR, Lawrence AM. Operative and chemotherapeutic management of malignant glucagon-producing tumors. Surgery 1981;90: 713-9. Strauss GM, Weitzman JA, Aoki T. Dimethyltriazenoimidazole carboxamide therapy of malignant glucagonoma. Ann Intern Med 1979;90:57-8. Maton PN, Miller DL, Doppman JL, et al. Role of selective angiography in the management of patients with ZollingerEllison syndrome. Gastroenterology 1987;92:913-8. Wank SA, Doppman JL, Miller DL, et al. Prospective study of the ability of computed axial tomography to localize gastrinomas in patients with Zollinger-Ellison syndrome. Gastroenterology 1987;92:905-12. Bonfils S, Ruszniewski PH, Laucournet H, Costil V, Rene W, Mjuse M. Long-term management of Zollinger-Ellison syndrome with SMS 901-995, a long-lasting somatostatin analog (abstr). Can J Phys 1986;July Suppl:63. Shepherd JJ, Senator GD. Regression of liver metastases in a patient with gastrin-secreting tumor treated with SMS 201-995 (lett). Lancet 1986:11:574. Erikson B, Oberg K, Alm G, et al. Treatment of malignant endocrine pancreatic tumors with human leucocyte interferon. Lancet 1986;ii:1307-9.

Received August 7, 1987. Accepted December 14, 1987. Address requests for reprints to: Dr. Robert T. Jensen, National Institutes of Health, Building 10, Room 9C-103, Bethesda, Maryland 20892. Dr. von Schrenck is supported by a grant from the Deutsche Forschungsgemeinschaft (DFG Schr 290/1-l). The authors thank Mary Lou Miller for secretarial assistance.