Document 149871

REVIEW ARTICLE
Treatment of the Carcinoid Tumor and the Malignant Carcinoid
Syndrome
By Charles G. Moertel
T
an uncommon
TUMOR,
CARCINOID
HE not
but
rare neoplasm,
offers an exciting and
multifaceted challenge for oncologic management-a challenge that demands informed multidisciplinary interaction of surgical and medical
oncologists as well as diagnostic radiologists and
laboratory scientists. It is a disease that presents
many paradoxes-among the rarest sites for malignant disease the carcinoid is the most common
of tumors-for example, the appendix, Meckel's
diverticulum, and the small bowel; whereas
among the most common sites for neoplasia the
carcinoid is among the most rare of tumors-for
example, the lung, colon, breast, and stomach.
In surgical management only the most conservative of procedures is indicated for the early and
most curable disease whereas very aggressive
surgical treatment may be indicated in the patient
who already has distant metastasis. In medical
management frequently no treatment is the best
treatment.
The carcinoid tumor is a member of that fascinating family of neuroendocrine or APUD
(amine precursor uptake and decarboxylation)
tumors. Although it has been reported in essentially all tissues taking origin from the primitive
entoderm, the overwhelming majority of these
neoplasms begin in only three sites: the small
intestine (usually in the terminal ileum), the appendix (usually in the tip), and the rectum (usually in a small area from 4-13 cm above the dentate line). In the latter two sites tumors are
generally incidental findings and most require
only local treatment. Carcinoids of truly malignant behavior most commonly originate in the
small bowel and well over 90% of patients with
the malignant carcinoid syndrome will have tumors primary to this origin. From the standpoint
of histopathology, it is important to note that the
pathologist cannot distinguish between benign
and malignant forms of this disease by microscopy nor can he distinguish in ordinary hemotoxylin and eosin-stained preparations between the
carcinoid and the other common gastrointestinal
Journal of Clinical Oncology, Vol. 1, No. 11 (November) 1983
APUD tumor, the islet-cell carcinoma. Histochemical and immune staining may provide assistance but an overlap in polypeptide hormone production between these two neoplasms will still
frequently blur distinction. In this regard it is
noteworthy that rectal carcinoids seldom contain
serotonin and are seldom, if ever, associated
with the carcinoid or other endocrine syndromes
even in the presence of massive metastasis.
In a discussion of management of carcinoid
tumors, the disease can for practical purposes be
divided into three stages: localized, regional, and
distant metastasis.
MANAGEMENT OF LOCALIZED CARCINOID
TUMORS
The great majority of localized carcinoid tumors are encountered as interesting curios at the
time of appendectomy or proctoscopic examination that was performed for other reasons. Treatment strategy and prognosis are determined by
the size of the tumor. From 70%-90% of these
lesions will be very small, one centimeter or less
in diameter. ,2The only real threat that tumors of
this size present to the patient with an appendiceal or rectal primary is when he is treated by an
overzealous and injudicious physician. Very
conservative local removal is all that is required,
that is, simply appendectomy or fulguration of
rectal lesions (Table 1). Cure rates of essentially
100% may be anticipated. Any risk of late metastasis is miniscule and greatly exceeded by the
risk of radical surgery. The patient should be
firmly reassured and there should be no subsequent periodic determinations of urine 5hydroxyindoleacetic acid (5HIAA) or other follow-up procedures.
From the Mayo Clinic and Mayo Medical School, Rochester,
Minn.
Submitted July 22, 1983; accepted July 29, 1983.
Address reprint requests to CharlesG. Moertel, MD, Comprehensive CancerCenter,Mayo Clinic,Rochester, MN 55905.
© 1983 by American Society of Clinical Oncology.
0732-183X/83/0111-0010$2.00/0
727
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CHARLES G. MOERTEL
728
Table 1. Results of Local Therapy For Rectal
2
and Appendiceal Carcinoid Tumors"'
Recurrence Rate*
Primary Site
Rectum
Appendix
Therapy
Fulguration or local
excision
Simple appendectomy
At 5
Years
At 10
Years
0/85
0/41
0/108
0/83
NOTE. All tumors in the rectum were * 1 cm in diameter; 72% of the tumors in the appendix were < 1.0 cm,
22% were 1.0-1.4 cm, and 6% were 1.5-1.9 cm in diameter.
*Data are no. patients who recurred/no. patients followed.
In contrast, primary tumors measuring 2 cm or
larger have a strong propensity to metastasis
(80% or more) and these lesions should be treated by aggressive cancer operations, that is, right
hemicolectomy for appendiceal lesions and anterior or AP-resection for rectal tumors.
A disturbing gray zone is presented by those
tumors measuring 1-2 cm in diameter where approximately half of the patients will have either
regional, nodal, or distant metastasis. In many of
these patients, the presence of metastasis will be
apparent at the time of clinical or surgical examination. For those with apparently localized disease, clinical judgment must be applied based on
actual size of the tumor (closer to 1 cm, closer to
2), degree of local invasion, necessity for AP
versus anterior resection for rectal lesions, age of
the patient, and estimated operative risk. Rectal
lesions should be removed, at minimum, by wide
local excision; if patients are so managed they
should be carefully followed. Appendiceal lesions from 1-1.4 cm in diameter can probably be
safely treated by simple appendectomy since we
have observed no metastases among 24 such patients followed from five to more than 10 years.
If only appendectomy is elected for appendiceal
lesions 1.5-2.0 cm, such patients may represent
one of the rare indications for a later planned
second-look operation.
Since the primary tumor for small intestinal
carcinoids is usually small in size and arises in
the deep mucosa, it rarely disturbs the physiology of the host sufficiently to cause clinical
symptoms. A symptomatic tumor almost always
has invaded the mesentery and usually has metastasized at least to regional nodes. Localized
disease, therefore, is usually an incidental find-
ing at necropsy or, less commonly, at surgery
performed for other purposes. Similar to rectal
and appendiceal tumors, these localized tumors
are usually less than one centimeter in diameter.
Metastasis may occur from such diminutive
small bowel primaries but this is uncommon,
there were only two of 104 patients with lesions
less than one centimeter in diameter in our
study. 3 Conservative local resection would seem
adequate for such lesions, whereas wider segmental resection with dissection of the mesentery
should be accomplished for lesions one centimeter or greater in diameter.
A problem peculiar to carcinoids of the small
bowel and stomach is a marked tendency to multicentricity. In our study of small bowel carcinoids, 29% of 207 patients presented with more
than one primary lesion,3 and in a review of the
literature 7% of 90 gastric carcinoids had multicentric primaries.' Frequently these are only two
or three closely approximated lesions and require
little or no extension of the usual surgical resection. Much more challenging is the patient who
has many lesions extending over the entire stomach or throughout the entire small bowel where
the surgical procedure required for complete removal would either be incompatible with life or
could produce serious nutritional disability. Here
the most appropriate surgery would seem to be
subtotal gastrectomy or segmental small bowel
resection encompassing the larger tumors or
those producing or threatening small bowel obstruction, but leaving in place the smaller tumors
(< 1 cm in diameter) unless they are easily accessible to limited local excisions. A reasonable
hope can be entertained that these smaller lesions
will never metastasize or will require many years
to do so. Periodic endoscopic examination can be
used to monitor unresected gastric lesions. For
small bowel tumors a case could again be made
for a planned second-look operation.
MANAGEMENT OF CARCINOID TUMORS WITH
REGIONAL SPREAD
All patients with carcinoid tumors and metastasis confined to regional nodes should be treated
with aggressive cancer surgery. Resection of
more remote nodal involvement or extensive regional invasion, which might seem to be useless
and excessive surgery for gastric or colorectal
adenocarcinomas, will produce a high frequency
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CARCINOID TUMOR AND SYNDROME
of apparent cures or very long-term survival in
patients with carcinoid tumors. Among 17
patients with peritoneal and nodal metastases
where all visible malignant disease could be resected, we recorded a 71% five-year survival
rate.3 It must be remembered, however, that in
this indolent disease five-year survival does not
necessarily indicate cure. Among 10 such patients who developed recurrence after initial resection we found the median interval to recurrence was seven years and nine months with a
range to 20 years. It is also of interest that among
eight patients we found to have disease confined
to regional nodes or peritoneum which was unresectable, 38% survived five years. There is no
surgical adjuvant treatment that should be applied to patients with resected carcinoid tumor
since none is known to be effective and none has
been tested.
If regional disease cannot be resected, heroic
efforts at partial resection or "debulking" are
probably not justified. Certainly, however, every
attempt should be made to bypass existing or
impending areas of small bowel obstruction. Radiation therapy has occasionally been attempted
for locally unresectable carcinoid tumor with reports of regression seen on second-look operation;' but there is no evidence that such treatment contributes to patient survival, which will
generally be very long with no treatment at all.
MANAGEMENT OF MALIGNANT CARCINOID
TUMORS WITH DISTANT METASTASIS AND
WITH THE MALIGNANT CARCINOID SYNDROME
Most patients with distant metastasis of carcinoid tumor will have a small-bowel primary
and the great majority will have liver involvement which will usually be the clinically dominant site of disease. Osseous metastasis may occasionally be troublesome. Metastatic carcinoid
tumor has an unusual predilection for the eye and
the orbital region, and a surprising 21 such cases
have been recorded in the literature. 6 Other metastatic sites are rare and usually are seen only as
the patient approaches terminal status. The clinical presentation of metastasis often will be complicated by the malignant carcinoid syndrome
which will most frequently consist of flushing
and/or diarrhea of varying severity. Approximately 20% of such patients will develop carcinoid heart disease detectable by usual clinical
729
means, 7 although it appears that a substantially
larger proportion may have subclinical valvular
involvement detectable by echocardiography or
discovered at necropsy. Tricuspid regurgitation
and/or stenosis and pulmonary stenosis are the
most common lesions. In our experience less
than 10% of carcinoid syndrome patients will
develop symptomatic cardiac disease and only
about 5% will die a cardiac death. Other manifestations such as asthmatic attacks, osteoarthropathy, or pellagra are still less common. Although
in general the frequency and severity of symptoms of the syndrome are related to serotonin
production as reflected by urine 5HIAA excretion, there are frequent exceptions with florid
syndromes in patients with minimal 5HIAA excretion as well as marked elevation of 5HIAA to
500 or more mg per 24 hours with no manifestations of the syndrome at all. For the syndrome to
occur it seems necessary that tumor products
have direct access to the systemic circulation
with no intervening hepatic detoxification. Usually (>95%) this implies metastasis to the liver
although pelvic metastasis or local tumor invading the right peritoneal gutter can also provide
the required systemic access. Very rarely the
syndrome may occur without metastasis in patients with carcinoids in ovarian or testicular teratomas where, in contrast to other carcinoids, the
primary tumor may be quite bulky. As a dogma it
can be stated that if the patient has clinically
detectable hepatic metastasis and no elevation of
urine 5HIAA, he does not have the carcinoid
tumor. Certainly there have been reported cases
of patients only excreting 5-hydroxytryptophane
or other substances but such patients are exceedingly rare. It is far more likely that the patient
without 5HIAA elevation has an islet-cell carcinoma or other neuroendocrine tumor that has
been misinterpreted by the pathologist as carcinoid. A second dogma is that if the patient
flushes and does not have either an elevated
5HIAA or liver metastasis detectable by usual
diagnostic studies, he does not have the carcinoid
syndrome. Again, exceptions can be quoted but
they are so exceedingly rare that patients would
probably be better off if physicians forgot they
existed.
A unique feature of carcinoid tumor metastatic
to liver, shared with islet-cell carcinoma, is that
the patient may have extensive involvement and
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CHARLES G. MOERTEL
730
considerable hepatomegaly but little or no impairment of nutrition or activity level or other
associated symptoms. Liver function tests will
characteristically show disproportionately little
impairment when compared to those in patients
with a comparable extent of liver involvement by
other carcinomas.
Another unique feature of metastatic carcinoid
tumor which contrasts with other malignant diseases is a characteristically indolent clinical
course. Among 60 patients with the malignant
carcinoid syndrome we found the median survival from first flush to be 38 months and from first
determination of an elevated 5HIAA to be 23
months.7 The range extended to 17 years. In an
Eastern Cooperative Oncology Group (ECOG)
study the median survival of 76 such patients
chosen for chemotherapy was 22 months from
the diagnosis of unresectable malignant disease. 8
It is not uncommon for patients with metastatic
carcinoid tumor to live many years with no treatment and eventually die of unassociated cause
with their malignant disease having no apparent
influence on their longevity.
SURGICAL TREATMENT
Even if the patient initially presents with
established hepatic metastasis, high levels of
5HIAA, and a clinically manifest carcinoid syndrome, the first therapeutic option to be considered should be surgical. The symptoms of diarrhea, abdominal pain, and weight loss are more
likely to be due to a partially obstructing small
bowel lesion than to circulating hormones. The
simple expedient of bypassing the site of obstrucTable 2.
tion may provide years of comforable life in spite
of advanced malignant disease. It should be emphasized that with partial obstruction due to carcinoid tumor a small bowel roentgenogram will
usually be negative.
For carefully selected patients, the most successful and reliable means of treating the syndrome itself is resection of hepatic metastasis.9
Patients selected for this procedure should have
an isolated metastatic mass or cluster of masses
confined to a single surgically accessible area of
the liver and obviously they should be good operative risks. We have employed hepatic lobectomy or wedge resection in five patients with a
symptomatic carcinoid syndrome who appeared
preoperatively to have solitary metastatic masses
(Table 2). At surgery, however, two of these
patients had unsuspected smaller lesions; and in
one of these, small nodules were palpated that
could not be resected. All five of these patients
had striking relief of their carcinoid syndrome
with a complete biochemical response and these
responses were of long duration. Two additional
patients without a symptomatic syndrome had
resection of hepatic metastasis which was found
incidentally at the time of small bowel surgery.
One of these patients developed recurrence after
nine years and died of disease at 12 years. The
other remains alive without recurrence at 11
years. Certainly for appropriate patients such
treatment can be of substantive value, but this
endorsement should not be extended to simply
whittling away at areas of a diffusely involved
liver for the sake of producing a partial reduction
of 5HIAA. The operative risk is not justified
Treatment of Carcinoid Tumor by Resection of Hepatic Metastasis
Greatest
Diameter
Sex/Age
(Years)
ofSexAge
Resecteddof
Lesion(s)
Urine 5HIAA (mg/24 hr)
Preoperative
Postoperative
F/52
14 cm
81
<6
M/59
15 cm
219
<6
5.5 cm
26
<6
3 and 10 cm
56
<6
0.5 (3 lesions),
1, and 10 cm
0.7 and 1.3 cm
2.5 and 3.5 cm
94
<6
19
<6
<6
<6
F/72
M/60
F/69
M/68
F/57
End Result
Complete relief of syndrome; recurrence at 27 mo; living 3
years
Complete relief of syndrome; osseous metastasis 4.5 yrs;
death 5 yrs
Complete relief of syndrome; living, no recurrence at 16.5
mo
Complete relief of syndrome; mediastinal metastasis at 7 mo;
death 26 mo
Complete relief of syndrome; death with heart disease at 3
yrs, 11 mo
No syndrome preoperatively; living, no recurrence 11 years
No syndrome preoperatively; recurrence 8 yrs; death 11 yrs
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731
CARCINOID TUMOR AND SYNDROME
under such circumstances and hepatic artery occlusion probably provides a safer and equally
effective means of accomplishing this purpose
(vide infra).
A third possible area of surgical intervention
would be valve replacement for severe and disabling carcinoid heart disease. Although the
technology is available for such a procedure, it
would seem obvious that cardiac surgery of such
magnitude should only rarely be considered in a
patient who has known advanced cancer. We
have found that most of our patients with carcinoid heart disease die of cancer rather than cardiac failure. Nevertheless there will be the exceptional patient who has shown an extraordinarily
indolent course of his malignant disease and who
is otherwise in excellent general condition where
the possibility of surgical correction of a cardiac
disability could be entertained.
In reviewing 13 such valve replacements recorded in the literature prior to 1980, Strickman
et al found one operative death, six deaths at
periods ranging from one month to six years after
surgery, and six patients alive at from four
months to eight years.1 o The mean and median
survival for all of these patients will probably
exceed two years.
Two other indications of a less common nature
for possible surgical intervention should also be
considered. The first is mesenteric arterial occlusion. We have observed this on several occasions
as a catastrophic cause of death and we have also
seen several instances of impending mesenteric
thrombosis in patients operated on for presumed
mechanical obstruction. This is a unique complication of mesenteric abdominal carcinoid tumor
presumably because of the often associated
marked fibrotic reaction. The diagnosis should
be considered in patients who seem to have abdominal pain problems disproportionate to the
effects of tumor per se and certainly in any patients who have signs of peritoneal irritation. Resection of the involved bowel segment can be
lifesaving. Another rare complication of metastatic carcinoid tumor requiring surgical correction is extrinsic obstruction of the low sigmoid
colon by a mass of carcinoid tumor with associated fibrosis localized to the pelvis. Radiologically
the patient will have a smooth concentric napkinring type narrowing of the low sigmoid but no
evidence of any mucosal involvement. Under
these circumstances a colostomy will be required.
CHEMOTHERAPY
Because the patient with metastatic carcinoid
tumor may frequently have a very long and comfortable life expectancy without treatment, and
because of the very limited and transient accomplishments of currently available chemotherapy,
it would seem appropriate for the oncologist to
restrain any urge to offer cytotoxic drugs to the
patient with early stage disease who has either
minor or no symptoms of tumor or syndrome.
Such therapy should be reserved until symptoms
are significantly interfering with the patient's activities or until poor prognostic signs develop
such as clinical evidence of carcinoid heart disease (median survival, 14 months) or urine
5HIAA excretion in excess of 150 mgs per 24
hours (median survival, 11 months). 7
In selecting carcinoid tumor patients for chemotherapy it is important to be certain that one is
indeed treating carcinoid tumor. There would
seem to be little doubt when dealing with the
patient who has previously had a small bowel
primary identified surgically, who has high level
of 5HIAA in the urine, and who has a liver biopsy histologically consistent with a neuroendocrine tumor. The problem arises in patients who
have liver metastasis but no elevation in 5HIAA
or who have liver metastasis and an elevated
5HIAA but no identified primary. In the former
instance one must be very suspicious that the
tumor has been misdiagnosed by light microscopy examination of a liver biopsy core that was
perhaps inadequate for confident interpretation.
In the latter instance one must raise the question
of a noncarcinoid tumor that may be more responsive to other specific treatment approaches.
Under these circumstances the pathologist can
frequently be very helpful through electron microscopy which can be diagnostic for at least a
neuroendocrine tumor. Silver staining and immunohistologic techniques can be helpful in
identifying the presence of serotonin or other
hormonal substances. A computerized tomographic scan of the pancreatic area can also be a
very useful investment. In this further study one
is specifically pursuing evidence for islet-cell
carcinoma, which may be either nonfunctioning
or serotonin producing, and where streptozoto-
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732
CHARLES G. MOERTEL
cin-based regimens may be of much more substantial benefit. In ECOG studies for example,
the combination of 5-fluorouracil (5-FU) and
streptozotocin produced a 63% response rate in
islet-cell carcinoma with a median response duration of 17 months whereas this same regimen
produced only a 33% response rate in carcinoids
with a median duration of only seven months. 8"'
Small-cell carcinoma of the lung may also be
confused with carcinoid and demands an entirely
different treatment approach. One is also trying
to avoid subjecting patients with drug resistant
noncarcinoid tumors to essentially useless therapy. In the ECOG study mentioned above, response rates were substantially reduced in patients with no known site of primary and with no
5HIAA elevation. 8
Chemotherapy of the carcinoid tumor has frequently been reported in a rather sketchy fashion
with the usual study involving only a handful of
patients on any given regimen. Criteria for response have varied and are often not clearly stated. This discussion will center on our Mayo Clinic experience as well as a few other reports with
adequate patient numbers to provide a reasonable
therapeutic perspective.
In all of our studies we have required tissue
confirmation of metastatic carcinoid tumor and a
measurable indicator of response to theapy. Acceptable indicator lesions included a tumor mass
measurable in two dimensions, malignant hepatomegaly if the liver contains proven metastasis
and measures at least 5 cm below the costal margin or xyphoid on quiet respiration, or a urine
5HIAA excretion on two consecutive occasions
of at least 25 mg per 24 hours (normal to 6 mg).
To declare an objective response we have required a 50% reduction in the product of perpendicular diameters of a mass lesion, a 30% reduction in the sum of liver measurement below the
costal margins and xyphoid, or a 50% reduction
in 24-hour urine 5HIAA excretion. An ECOG
evaluation has shown that 5HIAA excretion is a
Table 3.
Correlation of Measured Tumor Response
and Urine 5HIAA Responses
Tumor Measurement Response
5HIAA Response
Improved
Stable
Progression
Improved
Stable
Progression
8
5
...
4
14
2
...
2
2
useful marker for therapeutic effect that corresponds very closely to measured change in tumor
mass (Table 3). Our own experience as well as
that of Feldmanl2 has shown that the blood serotonin level is not a useful marker since it may
fluctuate widely from time to time in any given
patient and has reduced sensitivity for diagnosis
of metastatic carcinoid when compared to 24hour urine 5HIAA. The obvious limitation of
urine 5HIAA is the reliability of compliance
whenever patients are entrusted with specimen
collection.
Our Mayo Clinic experience, encompassing
more than 200 individual patient treatment studies, is displayed in Table 4. All patients had
advanced and symptomatic disease and all had at
least biochemical evidence of the carcinoid syndrome. All patients, however, were ambulatory
and maintained a good state of nutrition. Single
drug treatment was administered in standard dosTable 4.
Chemotherapy of the Malignant Carcinoid
Tumor (Mayo Clinic Experience)
Regimen
Single agents
Adriamycin
5-Fluorouracil
Actinomycin D
DTIC
Tamoxifen
Cisplatinum
Melphalan
Streptozotocin
(STZ)
Fluorometholone
Mitomycin C
BCNU
Cyclophosphamide
(CTX)
Hydroxyurea
Other (1 each)
Drug combinations
STZ + 5-FU
Methotrexate
+ CTX
STZ + CTX
5-FU + BCNU
5-FU + Methyl CCNU
+ Adriamycin
Other (1 each)
Response
Objective Duration
No. of Response Median
(Mo)
Patients
(%)
33
19
17
15
11
10
7
6
5
4
3
2
2
6
43
12
7
5
1
2
(21)
(26)
(6)
(13)
3.5
3
...
4.5
1 (10)
1
1
...
14 (33)
...
12
3
2
1
4
3*
...
7
*STZ + BCNU, 5-FU + mitomycin C, 5-FU + CTX +
prednisone.
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CARCINOID TUMOR AND SYNDROME
age regimens. Drug combinations were either
administered in dosage schedules recommended
by others or established by us as producing definite but clinically tolerable toxicity. Because our
early experience as well as the experience of
others had indicated that chemotherapy may occasionally trigger off a potentially lethal carcinoid crisis, patients with a clinically florid carcinoid syndrome or with a 24-hour 5HIAA
excretion exceeding 150 mg were administered
first courses of therapy at 50% of the planned
total dosage. If this is well tolerated we have then
escalated later courses to full dose.
Adriamycin
Our largest single agent experience has been
with Adriamycin (60 mg/m 2 every three weeks)
and 21% of our patients responded for a median
time of three months. The ECOG reported an
identical 21% response rate among 81 patients.
Workers at M.D. Anderson Hospital and Tumor
Institute, Houston, reported frequent responses
among patients treated with a variety of Adriamycin-containing combinations as well as with
Adriamycin-DNA complex.14
5-FU
Our experience with 5-FU given by rapid IV
injection in an intensive course (500 mg/m 2 per
day for five days every five weeks) showed a rate
and duration of response comparable to that we
have observed with Adriamycin. The ECOG has
also recorded an 18% response rate with the same
regimen of 5-FU among 11 patients. 8 Rochlin et
al reported three responses among seven patients.'5 The M.D. Anderson group, however,
reported no responses among 12 patients treated
with systemic 5-FU by various dosages and
schedules.'14
Dacarbazine (DTIC)
DTIC also appears to have some activity as
demonstrated by our results'6 as well as those of
Kissinger et al who treated two patients and reported objective improvement in one and subjective improvement in the other." The ECOG is
currently evaluating this agent in a larger patient
group to put its activity into perspective.
Actinomycin D
In 1967 Dolinger and Golbey reported, in abstract form, three responses among five carci-
733
noid tumor patients treated with actinomycin
D.'8 Our experience is less favorable with only
one partial response among 17 patients.' 6 This
single patient, however, has had striking clinical
improvement maintained over eight years of continuous therapy.
Alkylating Agents
Although the alkylating agents melphalan and
cyclophosphamide had been reported in years
past to show activity,'9 our results among nine
patients treated with these agents were entirely
negative as were the results with cyclophosphamide among eight patients treated by the ECOG,8
six patients treated by Melia et al, 20 and three by
Legha et al. 14Rochlin et al reported no response
in three patients treated with melphalan.'5 It
seems doubtful that alkylating agents have an
important role in the management of the carcinoid tumor.
Streptozotocin
Since streptozotocin has considerable activity
in a related gastrointestinal neuroendocrine tumor, the islet-cell carcinoma, it was our hope
that activity might be shared with the carcinoid.
Although we demonstrated only one clear-cut
response out of six patients treated, two additional patients had interesting mixed responses with
definite regression of some lesions and progression of others. Stolinsky et al reported one response among four patients treated with streptozotocin, 2' and activity was also recorded by
Feldman et al. 22 Schein et al, however, reported
no responses among eight patients.23 Whereas
streptozotocin may have some activity in carcinoid tumor, it would seem evident that this in no
way matches the therapeutic effect of this agent
in islet-cell carcinoma.
Tamoxifen
We evaluated tamoxifen because of scattered
reports of estrogen receptor (ER) positivity of
carcinoid tumors and because of two very favorable single case reports. The first involved symptomatic improvement but no objective benefit
was documented. 24 The second case report, however, also reported clear evidence of tumor regression plus reduction of urine 5HIAA from 174
to 15 mg per 24 hours. 25 Although we have also
observed occasional borderline or slightly elevat-
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Copyright © 1983 American Society of Clinical Oncology. All rights reserved.
734
ed ER titers in carcinoid tumors, we did not observe any evidence of antineoplastic activity
among 11 patients treated with tamoxifen at a
dosage of 40 mg daily. Only one of nine patients
with clinically evident carcinoid syndromes had
substantive symptomatic improvement.
Other Single Agent Approaches
Because of the relative rarity of metastatic carcinoid tumor a number of important antineoplastic agents have yet to have an adequate phase II
study in this disease. Experience with cisplatinum has not, as yet, been reported. We have
observed one definite objective response among
10 patients treated with a dosage of 90 mg/m2 and
our studies of this agent are still in process. VP16 (Etoposide) has considerable activity in the
related small-cell carcinoma of the lung and the
ECOG group is currently conducting a phase II
trial of this agent. Certainly the four patients we
have treated with mitomycin C represent an inadequate evaluation but even in this small number
we have observed one response. Another interesting and, as yet, unpursued report from the
Royal Marsden Hospital, London, involved the
striking response of a single patient to cyprohepatadine treatment.26 There was marked regression of hepatic metastasis and a grossly elevated
urine 5HIAA reduced to undetectable levels.
They also reported a second objective response
in a nonfunctioning APUD tumor metastatic to
liver.
Another interesting report from the University
of Uppsala, Uppsala, Sweden, has indicated possible activity of human leukocyte interferon. 27
These investigators observed marked symptomatic relief with modest but consistent reductions
in 5HIAA excretion among six patients with the
malignant carcinoid syndrome. These patients
did not meet the criteria for objective response
stated above, but on the other hand they were
treated with very low doses of interferon. Higher
dose treatment is now possible using recombinant DNA-produced interferon and a study of
this approach is currently ongoing at the Mayo
Clinic.
Since metastatic carcinoid tumor tends to be
strongly dominant in the liver, hepatic arterial
administration of cytotoxic drugs is attractive in
theory and there have been scattered case reports
claiming success. Perhaps the most definitive re-
CHARLES G. MOERTEL
port to date is that of Melia et al who treated 12
patients with 5-FU by hepatic artery infusion and
three by portal vein infusion. 20 Only one (7%) of
these 15 patients experienced symptomatic relief
and only two (13%) showed some evidence of
partial objective response. As with hepatic artery
infusion of cytotoxic drugs for other tumors, it
would appear that no advantage has been clearly
demonstrated when compared to much simpler
and less costly systemic administration.
Drug Combinations
Combination chemotherapy of metastatic carcinoid tumor was first reported by Mengel and
Shaffer who used methotrexate plus cyclophosphamide and reported a 55% response rate in 11
patients. 19 Since this is the most favorable response rate reported in a major oncology test,
CancerMedicine, this regimen has been accepted by many as standard therapy for this disease.
Regrettably, according to the criteria for response stated above, our group did not observe a
single response among 16 patients and only one
of these patients could conceivably be credited
with minor and transient symptomatic improvement. 28
Our later experience centered around streptozotocin combinations because this agent seems
to have some activity and has minimal bone marrow toxicity. It, therefore, can be combined with
essentially full doses of other cytotoxic drugs.
Based on our initial favorable experience with
streptozotocin plus 5-FU, this combination together with the streptozotocin plus cyclophosphamide combination was brought into phase III
study by the ECOG. 8 The latter combination was
studied because Mengel and Shaffer had reported
activity with cyclophosphamide as a single
agent."' Streptozotocin was given in a five day
course of 500 mg/m 2 per day every five weeks. 5FU also was given in five day courses at 400 mg/
m2 per day by rapid intravenous injection concomitant with courses of streptozotocin. Cyclophosphamide was given IV at 1,000 mg/m 2 on
days 1 and 22 of each cycle. Although a somewhat more favorable response rate was achieved
with the 5-FU and streptozotocin combination,
this difference was not statistically significant
nor were differences in duration of response, interval to progression, or survival. Response rates
were more favorable in patients with good per-
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CARCINOID TUMOR AND SYNDROME
735
formance status, in those with a documented carcinoid syndrome, and in those with small bowel
primaries versus pulmonary or unknown primaries. Response durations were disappointing with
a median of only seven months in both the ECOG
study overall and in our Mayo Clinic experience
with streptozotocin and 5-FU. Because treatment
with the streptozotocin regimens were characterized by substantial nausea, vomiting, and anorexia that seemed to counterbalance any favorable antineoplastic effects, a more recent ECOG
study evaluated giving the five day courses of
streptozotocin at a longer 10-week interval with
courses of 5-FU repeated every five weeks. 3 Regrettably nausea and vomiting remained a significant problem and the response rate was 23%
in comparison to 33% with the initial study regimen.
The studies done by other groups have primarily involved combinations including 5-FU,
Adriamycin, cyclophosphamide, and streptozotocin. 29-31 Response rates have been in the
20%-40% range, and although case numbers
are small, none of these combinations appear
to be outstanding in therapeutic effectiveness
(Table 5).
HEPATIC ARTERY OCCLUSION
The facts that metastatic carcinoid tumor is so
often clinically limited to the liver, that the carcinoid is a very vascular tumor, and that metastatic carcinoid tumor to the liver seldom produces significant impairment of liver function
until very late stage disease combine to make
hepatic artery occlusion an attractive treatment
consideration. This is a rational approach because it will take away approximately 90% of
oxygenation from the tumor causing cell death
Table 5.
Recent Studies of Combination Chemotherapy For Metastatic Carcinoid Tumor
Reporting Group
Eastern Cooperative Oncology Group 8
Eastern Cooperative Oncology Group 12
M.D. Anderson 29
Southwest Oncology Group 30
New York Memorial 31
whereas normal liver will lose only 50%. The
remaining oxygenation for normal liver comes
from portal vein flow and this is usually sufficient to sustain viability until rearterialization occurs. Hepatic artery ligation for most cancers has
not been notably successful since by the time the
patient with hepatoma or metastatic colon cancer
or metastatic pancreatic carcinoma recovers from
the operation, the cancer has usually grown right
back. The carcinoid, however, takes a long time
to grow back.
In a review of the literature through 1982 we
found 32 reasonably well-documented experiences with surgical ligation of the hepatic artery
for treatment of the carcinoid syndrome. 20 ,32 It is
obvious that this is not an innocuous procedure.
There have been a number of significant complications including acute hepatic necrosis, liver
abscess, carcinoid crisis or acute cardiovascular
collapse, and an instance of perforated gallbladder in a patient who did not have a concomitant
cholecystectomy. Seven patients died in the
postoperative period for an operative mortality of
22%. Among the 25 patients surviving surgery,
however, 18 were reported to have shown either
striking improvement or a complete clinical response. In eight patients these results have apparently been maintained for in excess of one year.
It is difficult to know how much validity to accord such a cumulative review of the literature
since the largest single series is only four patients
who survived surgery; it is unlikely that anyone
would report just one, two, or three cases of
treatment failure or that any journal would accept
such a report. We felt that a larger consecutive
series would provide a more representative picture. We therefore studied a total of 11 patients
all of whom had significant symptoms of the
Regimen
Streptozotocin (STZ)* + 5-FU
STZ + cyclophosphamide (CTX)
STZ** + 5-FU
5-FU + Adriamycin + CTX
5-FU + Adriamycin +
methyl CCNU; + mitomycin C
5-FU + Adriamycin + CTX + STZ
5-FU + CTX + STZ
STZ (weekly) + Adriamycin
Objective Response Rate (%)
14/42 (33)
12/47 (26)
18/80 (23)
3/8
2/9
7/20 (35)
2/5
4/10 (40)
*Streptozotocin in five-day courses repeated every six weeks.
**Streptozotocin in five-day courses repeated every 10 weeks.
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736
CHARLES G. MOERTEL
carcinoid syndrome with a median preoperative
5HIAA level of 207 mg per 24 hours (range, 64438 mg) (Table 6).9 One patient did not have the
planned ligation because portal vein flow was not
demonstrated in preoperative angiogram. Surgery for the remaining 10 patients was relatively
standard involving ligation of the hepatic artery
just distal to the gastroduodenal as well as vessels
in the hepatic round and triangular ligaments.
Cholecystectomy was performed because of the
possible threat of an infarcted gallbladder with
perforation. Although we did not cover our patients with antiserotonin agents they tolerated anesthesia very well and there were no carcinoid
crises. One patient died six days postoperatively
with a hepatorenal syndrome. In all surviving
patients there was a prompt and striking increase
of a serum glutamic oxaloacetic transaminase
reaching as high as several thousand units as well
Table 6. Treatment of Malignant Carcinoid
Syndrome by Hepatic Artery Ligation
(Mayo Clinic Experience)
Urine 5HIAA
(mg/24 hr)
Sex/Age Preop- Postop(Years) erative erative
F/45
245
23
F/66
64
35
M/53
107
34
M/51
112
19
M/59
215
40
F/51
369
78
M/53
361
138
M/40
438
138
F/48
109
103
M/72
198
...
End Result
Complete relief of syndrome; progressive disease
at 10 mo; death at 11 mo
Complete relief of syndrome; osseous metastasis
at 4 mo; living at 30 mo
Complete relief of syndrome; progressive disease
at 5 mo; living at 32 mo
Complete relief of syndrome; progressive disease
at 16.5 mo; living at 36 mo
Complete relief of syndrome; progressive disease
at 4.5 mo; living at 31 mo
Complete relief of syndrome; progressive disease
at 2 mo; living at 26 mo
Complete relief of syndrome; progressive disease
at 5 mo; death at 12 mo
Marked relief of syndrome;
pulmonary metastasis at
3.5 mo; death at 10.5 mo
No relief of syndrome; living at 13 mo
Death postoperatively day
6 of hepatorenal syndrome
as less dramatic increases in the alkaline phosphatase and occasional slight increases in serum
bilirubin. Within seven days these values had
returned to normal. Fever in these patients was
universal and lasted for a week or more but there
were no episodes of abscess or sepsis. A single
patient had a transient renal shutdown. Eight of
the nine surviving patients showed a rapid decrease in urine 5HIAA to less than 50% of pretreatment levels. This was associated with
prompt and usually complete relief of symptoms
of the syndrome. Whereas these responses were
clinically impressive, in no instance did the urine
5HIAA return completely to normal. The median
5HIAA level at the time of best response for all
patients was 40 mg per 24 hours. Two of our
patients have shown evidence of metastasis to
other sites after just a few months and the remainder have had slow regrowth of their hepatic
metastasis with increasing levels of urine 5HIAA
and recurrence of flushing. The median duration
of response in our entire group was only five
months. More recently we have been evaluating
hepatic artery occlusion accomplished by percutaneous catheterization and plugging with either
gel foam or Ivalon (Unipoint Industries, High
Point, NC). Our early results would indicate that
dearterialization can be accomplished and clinical results are probably comparable to those
achieved with the open surgical procedure. Nevertheless, it seems evident that although hepatic
artery occlusion will produce a high frequency of
objective responses and relief of the carcinoid
syndrome, it does not provide long-term control
of the disease.
TREATMENT OF THE CARCINOID SYNDROME
Symptomatic therapy of the malignant carcinoid syndrome at present is in a fascinating state
of confusion reflecting a parallel state of confusion regarding the pathophysiologic mechanisms
involved in generating the flush, the diarrhea, the
pulmonary symptoms, and the cardiac lesions.
Attempts have been made to classify varieties of
flushing according to primary tumor site and presumed site-specific hormonal excesses. Intense
persistent flushing with cyanosis, conjunctival
injection, and facial edema has been classified as
"foregut" and has been related to a higher 5hydroxytryptophan production in tumors primary to the lung, stomach, or thymus. The more
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737
CARCINOID TUMOR AND SYNDROME
commonly observed transient erythema of the
face and upper trunk has been classified as "midgut" and related to bradykinin and/or serotonin
release in association with primary tumors of the
ileum or cecum. Although there may be some
trend towards site-specific flushing characteristics, practical experience indicates there are
broad overlaps. The very rare "histamine" flush
with generalized patchy, spreading, intensely
pruritic areas of cutaneous erythema and edema
does seem to be characteristic of gastric carcinoids and clearly associated with excessive circulating histamine.
What is essentially today's state of the art
knowledge of pharmacology of the carcinoid
syndrome was thoroughly and lucidly summarized by Sandler in 1968.33 The carcinoid flush
may be stimulated by exertion, emotional stress,
food intake, alcohol intake, calcium infusion,
epinephrine, norepinephrine, pentagastrin, or
dopamine. Much of this spectrum suggests the
possibility of an adrenergic trigger mechanism.
Although serotonin may be the primary mediator
of the flush and diarrhea for most patients, this
concept has been challenged because flushes are
not usually accompanied by increases in circulating serotonin. Since carcinoids have also been
found to produce kallikrein, it has been hypothesized that adrenergic stimuli mediated through
catecholamines lead to kallikrein release which
in turn acts on a serum globulin, kininogen, to
release and activate bradykinin. Bradykinin is
thought by some to be the ultimate mediator of
the flush by its induction of dilatation of small
blood vessels. Increases in bradykinin, however,
have also not been consistently associated with
flushing so alternative mediators have been suggested such as prostaglandins or other substances
yet to be identified. An attractive hypothesis is
that flushing may represent a synergistic interaction of bradykinin and serotonin.
This lack of clear definition of mechanisms
involved in the production of the carcinoid
syndrome is reflected by a lack of clear definition
of effective treatment methods. The many and
varied pharmacologic approaches suggested for
therapy are listed in Table 7, classified according
to possible mechanisms of action. Each of these
agents have been claimed effective either alone
or in combinations. These therapeutic claims,
however, have almost always been anecdotal in
Table 7. Agents Reported To Produce
Symptomatic Relief of Carcinoid Syndrome
According To Suggested Mechanism of Action
Adrenergic blocking agents
Clonidine34
3 5 36
Phenoxybenzamine ,
36
Phentolamine
37
Propranolo1
Kinin antagonist
38
Chlorpromazine
synthesis
of
serotonin
Inhibition
38
a-methyl dopa
40
5-Fluorotryptophan
41
Parachlorophenylalanine (PCPA)
Peripheral serotonin antagonists
42
Cyproheptadine
43
Methysergide
H1 histamine receptor antagonist
Cyproheptadine42
H2 histamine receptor antagonist
Cimetidine"44
Unknown mechanisms of action
Corticosteroids45
Somatostatin46
nature based on experience with very few patients, sometimes only one. Quantitation of
therapeutic effect has often been imprecise and
controls have usually been lacking. It is evident
that none of the listed agents are reliably effective in palliating all symptoms of the syndrome in
all patients. It is also apparent that for occasional
patients some of these agents may be quite
helpful.
The adrenergic blocking agents presumably
exert their effect by inhibiting catecholamine
triggering of the kallikrein-bradykinin sequence.
These agents as well as the histamine antagonists
have seemed, by casual review of the literature,
to have their greatest frequency of favorable
therapeutic effects in patients with pulmonary or
gastric primary tumors or in patients with the
"foregut" type flush. Phentolamine is the least
desirable of these agents because of a high incidence of intolerable side effects at therapeutic
doses.
Chlorpromazine is presumed to act as a kinin
antagonist but may simply exert its effect (it is
not often effective) by blocking the emotional
stimulus to flushing.
Among the inhibitors of serotonin synthesis,
alpha methyldopa has been disappointing and
any useful effects have really only been shown at
very high doses (4-6 g per day) which would not
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Copyright © 1983 American Society of Clinical Oncology. All rights reserved.
738
be tolerable in clinical practice. 5-Fluorotryptophan is not currently available and its documented credentials probably do not justifty availability. Parachlorophenylalanine will reduce 5HIAA
excretion, will frequently help diarrhea, and will
rarely help flushing. These gains are minor and
more than counterbalanced by the side effects of
the drug which include psychiatric and hypersensitivity reactions, both of which preclude longterm management.
The peripheral serotonin antagonists, cyproheptadine and methysergide, presumably block
serotonin receptors. They will occasionally relieve diarrhea but seldom effect flushing.
Although other antihistamines such as chlorpheniramine or diphenylhydramine have occasionally been tried, their effectiveness has not
been well documented. Among drugs of this
class, cyproheptadine is recommended because
of its activity as a serotonin antagonist as well as
a histamine antagonist. Evidence for useful
therapeutic activity of cimetidine, an H2 antagonist, is still fragmentary.
Among those agents with an unknown mechanism of action, corticosteroids have occasionally
shown some benefit, particularly in patients with
bronchial primaries, but unless the gain is striking it will be outweighed by the side effects of
long-term administration. Somatostatin at present can only be given by parenteral route and
therefore would be unsuitable for chronic therapy. It could play some role in the management
of a carcinoid crisis, but effectiveness under
these circumstances has not, as yet, been reported. An interesting recent study has documented
that fenfluramine caused reproducible decreases
in 5HIAA excretion, in a patient with a symptomatic syndrome, presumably by causing serotonin depletion.47
From a practical clinical standpoint for most
patients with the carcinoid syndrome, a strong
case can be made for therapeutic nihilism. Flushing is usually only a minor nuisance that is easily
managed by a word of reassurance. Diarrhea is
usually mild and frequently responsive to timehonored bowel-slowing nostrums, for example,
codeine, tincture of opium, diphenoxylate, or
loperamide. A vigorous and costly pharmacologic assault on such minor symptoms holds a greater risk of producing disability than the symptoms
themselves. For those patients who are experi-
CHARLES G. MOERTEL
encing major discomfort or disability, a trial and
error approach may be used perhaps first attempting the adrenergic and histamine antagonists or corticosteroids for patients with "foregut" syndromes and first attempting the peripheral serotonin antagonists for patients with
the more common "mid-gut" syndromes. Failure, particularly in reducing flushing, must be
anticipated.
Clearly in the symptomatic management of the
carcinoid syndrome there is need for well controlled clinical trials involving adequate numbers
of patients so that a reasonable perspective can be
obtained regarding rational and effective pharmacologic therapy.
SUMMARY
Certainly in treatment of the carcinoid tumor
surgery has a well-established curative and palliative potential. The primary challenge is a
knowledgable marriage between stage of disease
and aggressiveness of operative procedure.
Nonsurgical treatment of the malignant disease per se has thus far not produced optimum
results and, in the opinion of this author, should
still be confined to a clinical research setting. It
would seem very doubtful, however, that the
more mundane types of trials, empirically testing
drug after drug and arbitrarily concocted drug
combinations, is the most productive road to follow. There is an evident need for more sophisticated approaches to this tumor, which has unique
metabolic characteristics that should be pharmacologically exploitable. Past experience has indicated that such a setting may permit dramatic
therapeutic accomplishment. There is a strong
need for animal models or established cell lines
which would facilitate preclinical therapeutic
exploration.
The carcinoid syndrome presents an unparalleled opportunity for fundamental physiologic
observations and for experimental therapeutic
study that can have applicability not only in palliating the syndrome itself but also in the management of other pathophysiologic states that
may involve more subtle abnormalities of the
same hormonal mechanisms.
The patient with the carcinoid tumor should
not just be a fascinating curio for grand rounds
exhibition. He should be a focal point for research involving an experienced, multidiscipli-
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CARCINOID TUMOR AND SYNDROME
nary clinical team supported by devoted basic
scientists. If our patient resources and efforts can
be concentrated in this manner, the carcinoid
should be a strong candidate for the next medically curable human cancer.
REFERENCES
1. Caldarola VT, Jackman RJ, Moertel CG, et al: Carcinoid
tumor of the rectum. Am J Surg 107:844-849, 1964
2. Moertel CG, Dockerty MB, Judd ES: Carcinoid tumors of
the vermiform appendix. Cancer 21:270-278, 1968
3. Moertel CG, Sauer WG, Dockerty MB, et al: Life history
of the carcinoid tumor of the small intestine. Cancer 14:901912, 1961
4. Pestana C, Beahrs OH, Woolner LB: Multiple (seven)
carcinoids of the stomach. Mayo Clin Proc 38:453-456, 1963
5. Kean TJ, Rider WD, Harwood AR, et al: Whole abdominal
radiation in the management of gastrointestinal carcinoid tumor.
Int J Radiat Oncol Biol Phys 7:1519-1521, 1981
6. Riddle PJ, Font RL, Zimmerman LE: Carcinoid tumors of
the eye and orbit. Human Pathol 13:459-469, 1982
7. Davis Z, Moertel CG, McIllrath DC: The malignant carcinoid syndrome. Surg Gynecol Obstet 137:637-644, 1973
8. Moertel CG, Hanley JA: Combination chemotherapy trials
in metastatic carcinoid tumor and the malignant carcinoid syndrome. Clin Cancer Trials 2:327-334, 1979
9. Martin JK, Moertel CG, Adson MA, et al: Surgical treatment of functioning metastatic carcinoid tumors. Arch Surg
118:537-542, 1983
10. Strickman NE, Rossi PA, Massum Kharis GA, et al:
Carcinoid heart disease. Curr Prob Cardiol 6:1-41, 1982
II. 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
303:1189-1195, 1980
12. Feldman JA: Serotonin metabolism in patients with carcinoid tumors. Gastroenterology 75:1109-1114, 1978
13. Engstrom P, Lavin P, Folsch E, et al: Streptozotocin plus
fluorouracil vs. Adriamycin for metastatic carcinoid tumor. Proceedings of the American Association of Cancer Research
24:139, 1983 (Abstr)
14. Legha SS, Valdivieso M, Nelson RS, et al: Chemotherapy
for metastatic carcinoid tumors. Cancer Treat Rep 61:16991703, 1981
15. Rochlin DB, Smart CR, Silva A: Chemotherapy of malignancies of the gastrointestinal tract. Am J Surg 109:43-46, 1965
16. VanHazel GA, Rubin J, Moertel CG: Treatment of metastatic carcinoid tumor and dactinomycin or dacarbazine. Cancer
Treat Rep 67:577-579, 1983
17. Kessinger A, Foley FJ, Lemon HJ: Use of DTIC (Dacarbazine) in the malignant carcinoid syndrome. Cancer Treat Rep
61:101-102, 1977
18. Dolinger M, Golbey R: Actinomycin D in the treatment of
the carcinoid tumors. Clin Res 15:335, 1967 (Abstr)
19. Mengel CE, Shaffer RD: The carcinoid syndrome, in
Holland JF, Frei E: Cancer Medicine. Philadelphia, Lea & Febiger, 1973, p 1584-1593
20. Melia WM, Nummerley HB, Johnson PJ, et al: Use of
arterial devascularization and cytotoxic drugs in 30 patients with
the carcinoid syndrome. Br J Cancer 46:331-339, 1982
739
21. Stolinsky DC, Sadoff L, Braunwald J, et al: Streptozotoc in in the treatment of cancer: Phase 11study. Cancer 30:61-67,
1972
22. Feldman JM, Quickel RE Jr, Muracek RL, et al: Streptozotocin treatment of metastatic carcinoid tumors. South Med J
65:1325-1327, 1972
23. Schein PS, O'Connell MJ, Blom J, et al: Clinical antitumor activity and toxicity of streptozotocin. Cancer 34:9931000, 1974
24. Stathopoulos GP, Karvoantzis GG, Yiotis J: Tamoxifen
in carcinoid syndrome. N Engl J Med 305:52, 1981
25. Myers CF, Ershler WB, Tannenbaum MA, et al: Tamoxifen and carcinoid tumor. Ann Intern Med 96:383, 1982
26. Harris AL, Smith IE: Regression in carcinoid tumour with
cyproheptadine. Br Med J 285:475, 1982
27. Oberg K, Funs K, Aim G, et al: Effects of leukocyte
interferon on clinical symptoms and hormone levels in patients
with mid-gut carcinoid tumor. N Engl J Med 309:129-132,
1983
28. Moertel CG, O'Connell MG, Reitemeier RJ, et al: An
evaluation of combined cyclophosphamide and methotrexate
therapy in the treatment of metastatic carcinoid tumor and the
malignant carcinoid syndrome. Cancer Treat Rep (in press)
29. Ajani JA, Legha SS, Karlin JA, et al: Combination chemotherapy of metastatic carcinoid tumors with 5-FU, Adriamycin, and Cytoxan and 5-FU, Adriamycin, Mitomycin, and
Methyl CCNU. Proceedings of the American Association of
Cancer Research 2:124, 1983 (Abstr)
30. Bukowski RM, Stephens R, Oishi N, et al: Phase II trial of
5-FU, Adriamycin, cyclophosphamide, and streptozotocin
(FAC-S) in metastatic carcinoid. Proceedings of the American
Society of Clinical Oncology 2:130, 1983 (Abstr)
31. Kelsen DP, Cheng E, Kemeny N, et al: Streptozotocin
and Adriamycin in the treatment of APUD tumors. Proceedings
of the American Association of Cancer Research 23:433, 1982
(Abstr)
32. Metz SA, Haller JR, Porte D, et al: Suppression of plasma
catecholamines and flushing by clonidine in man. J Clin Endocrinol Metab 46:83-90, 1978
33. Sandler M: The role of 5-hydroxyindoles in the carcinoid
syndrome. Adv Pharmacol 6:127-142, 1968
34. Arnold AC, Leichter SB: Use of novel pharmacologic
agents in carcinoid syndrome. Milit Med 142:949-950, 1977
35. Levine RJ, Sjoerdsma A: Pressor amines and the carcinoid flush. Ann Intern Med 58:818-828, 1963
36. Ludwig GD, Cushard W, Bartuska D, et al: Effects of
beta-adrenergic blockade in the carcinoid syndrome. Ann Intern
Med 68:1188, 1968
37. Sjoerdsma A, Weissbach H, Terry LL, et al: Further
observations on patients with malignant carcinoid. Am J Med
23:5-15, 1957
38. Sjoerdsma A, Oates JA, Zaltzman P, et al: Serotonin
synthesis in carcinoid patients; its inhibition by alpha-methylDOPA, with measurement of associated increases in urinary 5hydroxytrytophan. N Engl J Med 263:585-588, 1960
39. Costello C: Carcinoid tumor metastases. Am J Surg
130:756-759, 1975
40. Sjoerdsma A, Lovenberg W, Engelman K: Serotonin
now: Clinical implications of inhibiting its synthesis with parachlorophenylalamine. Ann Intern Med 73:607-629, 1970
41. Vroom FQ, Brown RE, Demsey H, et al: Studies on
Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission.
Copyright © 1983 American Society of Clinical Oncology. All rights reserved.
740
several possible antiserotonin compounds in a patient with the
functioning carcinoid syndrome. Ann Intern Med 56:941-945,
1962
42. Melmon KL, Sjoerdsma A, Oates JA, et al: Treatment of
malabsorption and diarrhea of the carcinoid syndrome with
methysergide. Gastroenterology 48:18-24, 1965
43. Wilkin JE, Rountree CB: Blockade of carcinoid flush with
cimetidine and clonidine. Arch Dermatol 118:109-111, 1982
CHARLES G. MOERTEL
44. Sjoerdsma A, Melmon KL: Severe flushing reactions
responsive to steroids in patients with bronchial carcinoid. Lancet 2:791-792, 1964
45. Frohlic JC, Bloomgarden ZI, Oates JA, et al: The carcinoid flush: Provocation by pentagastrin and inhibition by somatostatin. N Engl J Med 299:1055-1057, 1978
46. Stahl SM, Levin B: Serotonin depletion by fenfluramine
in the carcinoid syndrome. N Engl J Med 306:429, 1982
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Copyright © 1983 American Society of Clinical Oncology. All rights reserved.