An evaluation of human recombinant α interferon in patients with metastatic gastrinoma

GASTROENTEROLOGY

An Evaluation of Human Recombinant With Metastatic Gastrinoma

1993;105:1179-1183

a Interferon in Patients

JOSEPH R. PISEGNA,* GRACE G. SLIMAK,* JOHN L. DOPPMAN,* DORIS B. STRADER,” DAVID C. METZ,* RICHARD V. BENYA,* MURRAY ORBUCH,* VITALY A. FISHBEYN,* DOUGLAS L. FRAKER,§ JEFFREY A. NORTON,§ PAUL N. MATON,* and ROBERT T. JENSEN* *Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases; ‘Surgical Metabolism Institute; and *ClinIcal Center, Department of Radiology, National Institutes of Health, Bethesda, Maryland

Background: Metastatic gastrinoma is becoming increasingly recognized in patients with Zollinger-Ellison Syndrome. The mean 5-year survival of these patients is ~20%. Chemotherapeutic regimens are of limited benefit. The aim of this study was to evaluate the use of interferon in these patients because a preliminary report suggested it might be effective. Methods: The efficacy and toxicity of interferon was assessed in 13 consecutive Zollinger-Ellison syndrome patients with liver metastases. Patients were treated with human recombinant a interferon (5 million IU, subcutaneously [SC]) daily and followed up at 3-month intervals with multiple imaging studies. At each follow-up, toxicity of therapy was assessed and fasting serum gastrin concentrations were obtained. Results: No patient showed a reduction in tumor size at any follow-up. One patient died after 2 months. At 6 months, six patients (46%) had stable tumor size in the liver, although new bone metastases developed in one patient. Three patients showed stable disease for up to 21 months. Changes in serum gastrin correlated with tumor response at 6 months. All patients developed some side effects of therapy. Thirty-one percent required dose reduction, and one patient (8%) had to have interferon therapy interrupted briefly. Conclusions: These results fail to define a therapeutic role for interferon in the treatment of metastatic gastrinoma.

W

ith the increased

ability

to control

symptoms

of

hormonal excess using octreotide or other medical therapies, the natural history of most functional

islet cell tumors is becoming an increasingly important determinant of long-term survival.‘*2 Except for insulinomas, all other islet cell tumors are malignant in >60% of the cases;‘T2 however, surgical cure is only possible in <30% of cases. ‘-’ With the use of increasingly sensitive imaging studies and extended followup, increasing numbers of patients are now being identified with metastatic disease. For example, in various of all patients with gastrinomas series, 2-6 25%-40%

have metastatic that

patients

tumors

disease identified. with

in the liver

metastatic have

Sectlon, National Cancer

Recent disease

a lower

studies

from

survival

islet

show cell

rate than

previously thought with 5-year survival rates of <30% being reported. l-3*’ Therefore, it is becoming increasingly important for effective therapies to be developed in patients with metastatic islet cell tumors. Streptozotocin-based ported to be effective variety of metastatic

chemotherapy has been rein 40%60% of patients with a islet cell tumors.‘*2*8-‘o In four

studies*-” in patients with metastatic gastrinoma, streptozotocin-based chemotherapy resulted in an objective response rate of 5%-52%. However, responses were generally short-lived and all patients developed significant side effects. lo,’’ Aggressive surgical resection of limited however, potentially

metastatic

disease

may be of benefit2*‘;

it is not applicable to most patients because resectable metastases occur in only 15% of

patients with malignant gastrinoma.’ Interferon has been reported to be effective in various studies on patients with metastatic islet cell tumors,‘2-14 and in one study,‘* 77% of patients were reported to show an objective response. In this latter gastrinoma were series, l2 few patients with metastatic included, and objective response was determined by changes in tumor size as well as functional parameters, such as the effects of interferon on plasma hormone or tumor marker levels. Therefore, the potential longterm benefit of interferon in patients with metastatic gastrinoma, the most common malignant functional was not defined. The present study islet cell tumor,‘,2 was designed to prospectively assess the potential clinical usefulness of interferon therapy in patients with progressive metastatic gastrinoma. Abbreviations used in this paper: CT, computed tomography; MRI, magnetic resonance imaging; ZES, Zollinger-Ellison syndrome. This is a U.S. government work. There are no restrictions on its use. 00 16-5085/93/$0.00

1180

PISEGNA

GASTROENTEROLOGY

ET AL.

Materials and Methods Thirteen

consecutive

with Zollinger-Ellison the current not surgically

informed

approved tional

consent

Institutes

pg/mL), cium

infusion

secretin

provocative histological

had histologically

during

the 3 months

either

imaging

[CT], magnetic dominal

angiography.

neoplasia

type

congestive

heart

nine clearance

computed

imaging

[MRI])

No patient

1. Exclusion failure,

proteinuria

test for human

or a positive excluded

>300

platelet

taneously

IU of human

every

every

2-4

cal

for the

hospitalized

the patients

to assess

Measurements serum taking

subcu-

initially

blood

count

of therapy.

After

a complete side

for evalu-

history

of systems effects

concentration,

was per-

and a physito interferon

antisecretory

gastric

values:

acid secretion

response

was assessed regression

detectable

tumor

mass by any radiological

could

fasting

serum gastrin

be unequivocally

positive

was defined

disease

on a given

result for the presence

regression

was defined

size of any other

at least two imaging

modalities

of hepatomegaly modalities.

to meet criteria together

ities. Tumor diameter

Tumor

in any malignant

lesion

or the development If the metastases

ing modality,

then that imaging

follow-up

If patients

period

sound,

clearance, studies

and were

CT, abdominal

different abdominal cause in a previous

protein

excretion.

using

MRI, and bone

Tumor

imaging

studies varied size in different

ography4

was repeated Because

by any imag-

was used solely to progression

Patients

at any

the interferon

who continued

to exhibit

were maintained

on in-

acid output and the level of acid sethe next dose of gastric antisecretory as previously

reported.2

Serum

gas-

trin

scintigraphy.

Three

(New York, NY), and all samples were diluted into the normal range for accurate determination of higher values.‘5 The intra-assay coefficients of variation for a known standard within the normal range, minimally elevated (interme-

to detect change

Selective

if any of the above of the possibility

in

ultra-

in their sensitivities patients.

drug were determined

modal-

increase

abdominal

imaging studies were performed bestudy, lo it was shown that the various

in tumor

was equivocal.

24-hour performed

tumor

of treatment,

cholesterol, evaluation of

Basal and maximal cretion 1 hour before

as a >25%

modality

triglycerides, antibodies,

imaging

in any measur-

on at least two imaging

showed

after 6 months

was terminated.

as

tumor

were seen on only one imag-

bin, prothrombin time, albumin, antithyroid antibodies, antinuclear atinine

was defined

of new lesions

ing modality.

as as-

or partial

increase

was defined

protocol

of cre-

stability

a <25%

was

disease)

complete

tumor stability or tumor regression terferon treatment indefinitely.

and measurement

(if hepatomegaly

lesion and no new lesions on imaging

assess response.

in

of new lesions on

of metastatic

progression

modalities

a

tumor

that the lesion was detected

for either

with

Partial

mass with no increase

mass or the development

sessed by imaging

to be

by at least 25% in diame-

tumor

expression

of any modality

was considered

of metastases.

or a 30% reduction

regression,

imaging

by the radiologist

as reduction

the predominant

reported.‘”

as absence

modality

total biliru-

urinalysis

was discontin-

levels. Any size lesion that

determined

electrolytes,

including

on the

dose was reduced

as previously

tumor

phosphatase,

renal function

serum

by interferon

If any of these abnormalities

alkaline

serum aminotransferases,

medication,

Tumor

able malignant 3

persistent

persisted

dose, the interferon

Complete

failure

was

and then

were made of the following

gastrin

to

of therapy

were readmitted

review for

(In-

be caused

dose, then the interferon

ter of the largest measurable

of the drug. Therapy

remainder

a detailed

a interferon

A complete

this admission,

including

examination

while

were

at home.

weeks

During

fasting

a

had to be

N]) was administered

week for the first month

of treatment,

therapy.

No patient

in the administration

was then continued done

ation.

>3 mg/dL, virus antibody,

results before

developed

ued.

metastatic


bilirubin

recombinant

each day. Patients training

formed,

creati-

range or increased

abnormalities

W/day.

(aspar-

or alkaline

with abnormal

that might

on this lower

and normal of

for any of these parameters.

tron A; Schering Corp., Union,

months

endocrine

mg/dL,

count

test in women.

ab-

the presence

immunodeficiency

pregnancy

Five million

receive

or selective

were

/,tL, white blood count <4 X 103,$L, positive

tomography

had multiple

criteria

<30 mL/min,

size

above the normal

symptoms

to 1.25 million

persisted

aminotransferase,

or if the patient

if the

if the triglycerides

if the liver chemistries

in patients

If any of these

lower interferon

X lO’,/mL,

by >30%,

alanine

increased

to ~2.2 X 103/pL,

to <50

decreased

above 800 mg/dL,

new clinical

with

were assessed

by 50% to 2.5 million

decreased

decreased

clearance

treatment.

in the study based on

(ultrasound,

resonance

meta-

of tumor

count

interferon,

further

gastrinoma

progression

before enrollment

studies

or a

described.‘x3

proven

static to the liver and documented

cal-

was reduced count

tate aminotransferase,

starting

studies

(J.L.D.).

if the leukocyte

more than twofold

(> 100

diagnosis,

IU/day

phosphatase)

acid hypersecre-

test, a positive

of these tests as recently

All patients

Diseases

gastrin

radiologist

No. 4

for at least 6 months

of all imaging

The dose of interferon

increased

of the patients

serum

by a single

creatinine

of the Na-

and Kidney Each

fasting

test, a positive

provided

were treated

The results

if the platelet

as part of a protocol

of Health.

elevated

a positive

combination

studied

for ZES with basal gastric

(> 15 mEq/h),

to

all patients

interferon. for

gastrinoma

Committee

Digestive

Institutes

met the criteria tion

to therapy Research

of Diabetes,

6 women)

lobes, and was therefore

All of the patients

by the Clinical

of the National

had metastatic

both hepatic

resectable.

(7 men,

(ZES) were considered

study. The patients

the liver that involved written

patients

syndrome

response,

Vol. 105.

abdominal

angi-

imaging

results

of a delayed

tumor

values

diate standard,

were

determined

170 pg/mL)

by Bioscience

and high known

1,aboratories

standard

(600

pg/mL) were 4%, 3.5%, and 6%, respectively. The interassay variations for these standards were 14%, 13%, and I lo/o,

October 1993

Table 1. Clinical Characteristics Metastatic Interferon

Gastrinoma

of 13 Patients With Before Treatment With

Age (yr: mean ok SEM)

bility

Gender (M/F) Fasting serum gastrln (pg/mL; mean k SEM) Range Basal acid output (mEq/h; mean -t SEM)

7/6 3813 2 1310 195-12,562 46 i- 7 14-77 56 t 9 17-109

Range Maximal acid output (mEq/h; mean ? SEM) Range Tumor progression In precedmg 3 months

13 (100)

(no. PI) Disease extent by site (no. [%I)” Pancreas Liver Bone Previous antitumor therapy (no. [%I)

angiography”

were

described.

characteristics

of the

13 patients

100% had liver metastases,

and

1 patient (8%) also had bone metastases. Fifty-four percent (7 of 13) of the treatment cohort had received some form of antitumor

therapy

before

enrollment

patients

stable

in none

in 5 patients

(54%)

(Table

progression

;LIRI, and

tumor

scan detected only modality

progression in two patients to detect tumor progression 4) in whom the fasting

by >20%

above

(O%), re-

(38%), and increased

2). CT,

each detected

Five

months. months taking without

in 7

ultrasound

in five patients.

and was the in 1 of the 2

it was positive. serum gastrin

the pretreatment

Bone

level level

in-

in all

tumor progression, and in 2 of 5 disease (Table 2). Analysis of the

in fasting

in

the current study. One patient died 2 months after interferon therapy was started because of progressive hepatic metastases and liver failure; thus, no imaging data is available for this patient. Eleven patients were evaluated after 3 months of follow-up. Imaging studies showed tumor stability in sis patients and tumor progression in five patients. One patient required a repeat angiogram to confirm stable tumor size. iXo patient showed new lesions on bone scan. Because of the possi-

Fisher’s

patients

gastrin

and increasing

Exact Test,

received

tumor

size

n = 2).

interferon

fo; longer

than

6

These (ranpe. \

patients were treated for a mean of 19 lo-24 months). Three patients are still L interfIr& for a total of 10, 14, and 24 months tumor

progression,

whereas

disease

progres-

sion occurred at 24 months in two patients. Three patients died 2, 13, and 33 months after first receiving interferon. They were treated with interferon for 2, 6, and 6 months, respectively. X11 of the patients developed side effects with inter-

Table 2. Effect of Interferon Treatment on Tumor Size and Fastmg Serum Gastnc Level After 6 Months of Treatment

Patient

with documented progressive gastrinoma in the 3 months preceding the initiation of this protocol are summarized in Table 1. Primary tumors were identified in 69% of patients;

mained

(P = 0.045;

Results ‘l’he clinical

the

of the patients

size decreased

increases

respectively. Secretin provocative tests using Kabi secretin (2 units,.‘kg body wt) given by intravenous holus injection wsre performed as previously described.‘5 MRI,” ultraabdominal

oc-

until

changes in fasting gastrin and changes in tumor size after 6 months showed a positive correlation between

1 (8) 1 (8) 1 (8)

as previously

might

interferon

tumor

seven patients with patients with stable

7 (54) 6 (46) 5 (38)

C’1‘,5 and selective

to interferon

were evaluated after 6 6 months of treatment,

creased

1 (8)

“Disease extent was determined by Imaging studies as described in Materials and Methods. bChemotherapy included a mlnimum of 12 courses of 5-fluorouracll. In four patients, one of whom later doxorubicln. and streptozotocin” also received dacarbazine. One patient received dacarbazine, etoposide. clsplatln, and chlorozotocin. ‘These treatment modalities were all used In the same patlent.

sound,‘”

response

All 13 survii-ing patients months of follow-up. After

patients (patient At 6 months,

9 (69) 13 (100)

Any Surgery Chemotherapyb OctreotldeC Hepatlc embolizationc Bone Irradiation”

that a delayed

cur, all patients were administered 6-month evaluation.

52 -t 3.2 37-62

Range

performed

1181

INTERFERON IN GASTRINOMA

1 2 3 4 5 6 7 8 9 10 11 12 13

Tumor size

t NC b ic Died at 2 months : NC t NC” f NC NC

Fasting serum gastnn (% pretreatment)a 142 96 221 144 Died at 2 months 457 453 80 224 339 208 25 213

f. increase: NC, no change. aFasting serum gastnns are expressed as the percentage of the pretreatment value. ‘Increase detected by both bone scan and hepatlc imaging studies. ‘Increase detected by bone scan only. “Angiography required to vlsuake metastases.

1182

PISEGNA

feron

treatment.

The most common

(occurring within flulike symptoms rhea,

anorexia,

tration

and

headaches,

abdominal

Dose adjustments

not required

were

observed.

quire dosage adjustments tinuation

of interferon because

creatitis

(Table

therapy

for

were

enough

to re-

metastatic

possible

variables

groups

in terms of extent

in both

all patients

with

progression

rates in our study

by Eriksson

not comparable disease

may have contrib-

in response

that reported

that the two different studies,

The median

of disease.

had evidence of metastases

metastases,

and in the study of Eriksson

all patients

and each of the four patients

the study study, tumor

gastrinoma

et al.,” 91% of with

size remained

(38%) with after

actively

6 months

stable growing

of interferon

by Eriksson

et al.‘* had previously

and failed chemotherapy.

Another

ity is that there may exist differences

et al.,12 there were no apparent

mean duration

interferon;

of response

was 10.7 months,

and only

one patient showed a 50% decrease in fasting serum gastrin concentration. Our results differ from those of Eriksson et al.,” who treated 22 patients with metastatic islet cell tumors

with

interferon,

patients had metastatic gastrinoma. 77% of all patients had an objective ing 3 of the 4 patients

with metastatic

was defined

mass or a > 50% reduction in tumor

levels.‘*

In that

of which In that response,

study,‘* includ-

gastrinoma.

as a >50% in serum study,‘*

four

An

reduction hormone a >50%

in the response patients

about ent

the possible islet

No. of

could

patients (%) 7 4 4 3 3 3

(54) (31) (31) (23) (23) (23)

1 (8) 1 (8) 1 (8) 1 (8)

NOTE. Late side effects occurred after at least 2 weeks of therapy. aOccurred In all 7 male patients ( 100%). bThese include penrectal abscess, one yeast vaginitis, one candida esophagitis, and one bronchitis. ‘Side effect was severe enough to requrre a downward dose-adjustment in 1 patient. dRequired downward dose-adjustment. eRequired brief drscontrnuation of therapy.

only

4 of the 22

for comparison.

Previous

difference to

possible

of differ-

chemotherapeutic explanation

rates between

be the difference

relastudies

of islet cell questions

in sensitivities various

to

in the methods

for the

these two studies used in assess-

ing changes in tumor size. MRI was not used in the study by Eriksson et al.,‘* and it is not apparent all of the patients

had both ultrasound

and CT

or selective angiography, if the results were equivocal. Therefore, it is likely that the two studies differed in the ability to detect additional hepatic lesions by the imaging

Decreased libido and/or Impotencea Chronic fatigue lnfectionsb Diarrhea Elevated liver enzymes’ Weight loss Pancytopenia Pruritic dermatitis’ Hypertriglyceridemia with acute pancreatrti9 Inability to concentrate and short-term memory lossd

study,

thus allowing

tumors

in response

differences

islet cell tumors

gastrinoma,

agents. ‘.2,8,9,‘7,‘*Another

or

Treatment

cell

rates

In the study

with streptozotocin-based chemotherapy tumors have raised similar, unresolved

whether Table 3. Late Side Effects of Interferon

in that

tively small numbers

differences

size was seen in 6 of the 17 patients,

however, had metastatic

in de-

to interferon.

rates of the different

possibil-

in response

of Eriksson

crease

gastri-

received

important

treatment. However, interferon did not produce complete or partial tumor regression in any patient. The

marker

liver

noma had liver metastases. Furthermore, .380/o of the patients in the present study and 80% of the patients in

13 patients

tumor

starting

had extensive

islet cell tumors

tumor

However,

before

pan-

3).

response

It is were

of advanced

of different

objective

et al.”

of patients

in one

Discussion in 5 of the

of different

with

response.

was 8.5 months.

In our study, all patients

of hypertriglyceridemia-induced

In the present

A number

Vol. 105. No. 4

interferon.

and discon-

3 weeks

had a complete

of response

uted to this difference

ob-

had at least one

in three patients

duration

compared

Late side effects

All patients

and 2 patients

concen-

due to early side effects were

late side effect. Side effects were severe

patient

were Diar-

also

decreased

cramps

for any patients.

also frequently

early side effects

the first 2 weeks of therapy) that occurred in all patients.

nausea,

span,

served.

GASTROENTEROLOGY

ET AL.

studies

used.

Because

20% of patients

with

progressive disease in the present study were only detected by bone scan, this could also be an important factor in the differences observed because 12% of patients with metastatic gastrinoma to the liver have bone metastases.” Furthermore, in the study by Eriksson et al.,‘* a 50% decrease in a tumor marker, such as serum gastrin levels in patients with ZES, was used to assess tumor response to interferon. Of the 17 patients, 50% of the responses only resulted from decreases in hormone levels.‘* In a previous study of chemotherapy in patients with metastatic gastrinoma,“) no correlation was found between changes in tumor size with chemotherapy and changes in fasting serum gastrin concentration. In the present study with interferon treatment, elevations in fastinggastrin occurred signifi-

October 1993

INTERFERON IN GASTRINOMA

more

cantly

disease.

frequently

However,

for the differences cause only

with

in the two studies

in the present

in fasting

progressive

also fails to account

in responses

one patient

SO% decrease

in patients

this difference

serum

study

gastrin

be-

showed levels

a

at 6 8.

months. In the present effects occurred temporary, orouracil,

study,

even

though

in all patients,

and much

chemotherapy treated

7.

regimen

side mild,

less severe

than

seen with

involvingstreptozotocin,

and adriamycin.” with interferon

interferon

they were usually

Each

our

9.

5-flu-

of the five patients

after previously

receiving

che-

10.

motherapy reported the chemotherapy regimen to be much more debilitating and to interfere significantly more with their quality men.

Although

of life than the interferon

the side effects

seen with streptozotocin-based mens

commonly

effect on tumor feron patients

used

patients,

size or progression metastatic

less than

suggests

11.

those

chemotherapeutic

in these

alone will be of limited with

were

regiregi-

the limited

12.

that inter-

value in the treatment

of

gastrinomas.

References

13.

14

1. Jensen RT, Norton JA. Endocnne neoplasms of the pancreas. In: Yamada T. Alpers DH, OwyangC. Powell DW, Silverstein FE, eds. Textbook of gastroenterology. Philadelphra: Lrppincott, 199 1: 1912-1937.

15.

2. Jensen RT, Gardner JD. Zolltnger-Ellrson syndrome: clinical presentation, pathology, diagnosis and treatment. In: Dannenberg A, Zakim D, eds. Peptic ulcer and other acrd-related diseases. Armonk. New York: Academic Research Associates, 199 1: 117212.

16.

17.

3. Norton JA, Doppman JL. Jensen RT. Curahve resection in patients with Zollinger-Ellison syndrome: results of a lo-year prospective study. Ann Surg 1992;2 15:8- 18.

18

4. Maton PN, Miller DL, Doppman JL, collen MJ, Norton JA. Vinayek R, Slaff Ji, Wank SA, Gardner JD, Jensen RT. Role of selective angiography in the management of Zollinger-Ellison syndrome. Gastroenterology 1987;92:913-919. 5. Wank SA, Doppman JL. Miller DL. Collen MJ, Maton PN, Vinayek R, Slaff JI. Norton JA, Gardner JD, Jensen RT. Prospective study of the ability of computed axial tomography to localize gastrinomas in patients with Zollinger-Ellison syndrome. Gastroenterology 1987;92:905-9 12. 6. Pisegna JR, Doppman JD, Metz DC, Norton JA, Jensen RT. Pro-

19

1183

spectrve assessment of MR imaging in patients with Zollrnger-Ellison syndrome. Dig Dis SCI 1993;38: 13 18- 1328. Norton JA. Sugarbaker PH. Doppman JL, Rowley RW, Maton PN, Gardner JD. Jensen RT. Aggressive resection of metastatic disease in selected patients with malignant gastnnoma. Ann Surg 1986;203:352-359. 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;303:1 1891192. Moertel CG. Lefkopoulo M. Lipsitz S. Hahn RG. Klaassen D. Streptozotocin-doxorubicln. streptozotoc:in-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 1992;326:5 19-523. von Schrenck T, Howard JM, Doppman JL. Norton JA. Smith F, Maton PN, Vinayek R. Frucht H, Wank !SA, Gardner JD, Jensen RT. Prospechve study of chemotherapy in patients with metastatic gastrinoma. Gastroenterology 1988;94: 1326- 1334. Ruszniewski P. Hochlaf S, Rougier P, Mignon M. Chimiotherapie intraveinensepar streptozotocine et fluoro-uracile des metastases hepatique du syndrome de Zollinger-Ellison. Gastroenterol Clin Biol 1991; 15:393-398. Eriksson B. Alm G, Lundqvlst G, Wilander E. Oberg K, Karlsson A, Andersson T. Wide L. Treatment of malignant endocrine pancreatic tumors with human leuocyte interferon. Lancet 1986;2: 1307-1309. Creutzfeldt W. Bartsch HH. Jacubaschke U, Stockmonn F. Treatment of gastrointestinal endocrine tumors with interferon-a and octreotide. Acta Oncol 1991;30:529-535. Oberg K. Treatment of neuroendocnne gut and pancreatic tumors with interferons. Acta Chir Stand Suppl 1989;549:56-62. Frucht H, Howard JM. Slaff JI, McCarthy DM, Maton PN, Wank SA, Vinayek R. Gardner JD. Jensen RT. Secretin and calcium provocative tests in patients with Zollinger-Ellison syndrome: A prospective study. Ann Intern Med 1989; 1 1 1:7 13-722. London JF. Shawker TH, Doppman JL, Frucht H, Vinayek R, Stark HA, Miller LS. Norton JA, Jensen RT. Gardner JD, Maton PN. Prospective assessment of abdominal ultrasound in patients with Zollinger-Ellison syndrome. Radiology 199 1; 178:763-767. Buchanan KD, O’Hare MMT, Russel CJF. Kennedy TL, Hadden DR. Factors involved in the responsiveness of gastrointestinal apudomas to streptozotocrn (abstr). Dig DIS Sci 1986;3 15 1 1s. Creutzfeldt W. Panel Discussron: S. Bloom, Moderator. Symposium on gastrointestinal endocnne tumors. Am J Med 1987;83(Suppl 58):96-99. Barton JC. Hirschowrtz BI, Maton PN, Jensen RT. Bone metastases in malignant gastrinoma. Gastroenterology 1986;9 1:9 15925.

Received November 23, 1992. Accepted June 3, 1993. Address requests for reprints to: Robert T. Jensen, M.D., Digestive Diseases Branch, National Institutes of Health, Building 10, Room 9C-103, Bethesda, Maryland 20892.