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2293
Liver Embolizations of Patients with Malignant
Neuroendocrine Gastrointestinal Tumors
B. K. Eriksson, M.D., Ph.D.1
E. G. Larsson, R.N.1
B. M. Skogseid, M.D., Ph.D.1
A. M. Löfberg, M.D.2
L. E. Lörelius, M.D., Ph.D.2*
K. E. Öberg, M.D., Ph.D.2
1
Department of Internal Medicine, Uppsala Hospital, Uppsala, Sweden.
2
Department of Diagnostic Radiology, University
Hospital, Uppsala, Sweden.
* Deceased.
BACKGROUND. Patients with neuroendocrine gastrointestinal tumors usually
present with inoperable metastatic disease and severe hormonal symptoms. Specific chemotherapy, interferon-␣ (IFN), and somatostatin analogs are established
therapies for these patients, but all of them eventually fail. Hepatic arterial embolization can provide reduction of both hormonal symptoms and tumor burden in
these patients.
METHODS. Between 1981 and 1995, a total of 55 liver embolizations with gel foam
powder were performed on 41 patients with histopathologically verified neuroendocrine tumors; 29 had carcinoid tumors and 12 had endocrine pancreatic tumors
(EPTs). All patients had received medical treatment, including chemotherapy (n ⫽
18), IFN (n ⫽ 31), and octreotide (n ⫽ 19), and were experiencing treatment failure
when liver embolization was performed at a median of 37 months after diagnosis
of liver metastases. Medical treatment was continued after embolization.
RESULTS. An overall objective response was noted in 15 of 29 patients with
carcinoid tumors (52%). The median duration of effect was 12 months in patients
with midgut carcinoid tumors. An overall objective response was observed in 6 of
12 patients with EPTs (50%), with a median duration of effect of 10 months.
Adverse events were observed, and, in agreement with earlier reports, the rate of
serious complications was 10%. Survival analyses showed a median survival of 80
months and a 5-year survival rate of 60% from the performance of embolization on
patients with midgut carcinoid tumors, whereas for patients with EPTs the median
survival from embolization was only 20 months.
CONCLUSIONS. Liver embolizations performed relatively late in the clinical course
in our series appeared to be as effective as “early” embolizations in other series of
patients with carcinoid tumors. The results for those with EPTs were poorer, and
earlier embolizations may result in better outcomes for these patients. Considering
the morbidity associated with the procedure, it is imperative to select patients
according to extent of liver involvement, severity of carcinoid heart disease, and
somatostatin receptor status. Cancer 1998;83:2293–301.
© 1998 American Cancer Society.
KEYWORDS: carcinoid tumor, endocrine pancreatic tumor, gel foam powder, liver
embolization, p-chromogranin, U-5-hydroxyindoleacetic acid.
M
Supported by the Swedish Cancer Foundation.
Address for reprints: Barbro Eriksson, M.D., Ph.D.,
Department of Internal Medicine, University Hospital, S-751 85 Uppsala, Sweden.
Received December 24, 1997; revision received
March 30, 1998; accepted April 23, 1998.
© 1998 American Cancer Society
ost patients with neuroendocrine gastrointestinal tumors, i.e.,
carcinoid tumors and endocrine pancreatic tumors (EPTs),
present with disseminated disease and involvement of the liver at the
time of diagnosis.1,2 Debilitating symptoms associated with hormonal
excess are usually present. Treatment of localized hepatic metastases
is surgical, if feasible. In the more frequent cases of multifocal lesions
in the liver, a multidisciplinary approach, including systemic chemotherapy3,4 and biotherapy, i.e., interferon-␣ (IFN)5,6 and somatostatin
analogs,7,8 should be used in the management of these patients.
2294
CANCER December 1, 1998 / Volume 83 / Number 11
Although such medical therapies can control both
hormonal symptoms and tumor growth for extended
time periods, they are rarely curative, and eventually
most tumors become resistant to them.
Hepatic metastases from neuroendocrine gastrointestinal tumors are usually hypervascular, and this
provides a good rationale for interrupting the arterial
blood supply as a therapeutic measure.9,10 Palliative
treatment with arterial embolization of hepatic tumors was initially described for hepatocarcinomas.11
Since then, several reports have demonstrated that
hepatic arterial embolization can provide both reduction of hormonal symptoms and reduction of tumor
burden in patients with neuroendocrine gastrointestinal tumors.12–14 However, the exact role and timing of
the procedure (i.e., on which patients it should be
performed and when in the clinical course of the disease) is unclear.
In this study, we report the results of embolizations with gel foam powder in a large cohort of patients with neuroendocrine gastrointestinal tumors.
The embolizations were performed relatively late in
the clinical course, i.e., in most cases when the patients were experiencing failure with medical treatment.
MATERIALS AND METHODS
Patients
Over a 14-year period (1981–1995), a total of 55 liver
embolizations with gel foam powder were performed
on 41 patients (23 males, 18 females). All patients had
histopathologically verified diagnoses of neuroendocrine tumors of the gastrointestinal tract. Twenty-nine
patients had liver metastases from carcinoid tumors
(21 midgut, 4 foregut, and 4 hindgut), and they were
diagnosed at a median age of 53 years (range, 36 –73
years) and embolized at a median age of 56 years
(range, 40 –73 years)( median age for patients with
midgut carcinoid tumors, 59 years). The median duration of disease from the time of diagnosis was 37
months for patients with midgut metastases and 28
months for those with foregut or hindgut metastases.
Twelve patients had liver metastases from endocrine
pancreatic tumors (1 insulinoma, 2 gastrinomas, 5
nonfunctioning tumors, 3 vipomas, and 1 somatostatinoma); they were diagnosed at a median age of 46
years (range, 34 – 69 years) and embolized at a median
age of 52.5 years (range, 35–71 years), and the median
duration of their disease from the time of diagnosis
was 37 months. Two patients with EPT (one with vipoma and one with a nonfunctioning tumor) had multiple endocrine neoplasia (MEN) type 1.
Previous Treatment
All patients had received medical treatment before
embolization. Among the carcinoid patients, 24 had
received IFN, 15 octreotide, and 6 chemotherapy; and
among EPT patients, 12 had received chemotherapy, 7
IFN, and 4 octreotide. Responses were of varying duration. All patients were showing signs of disease progression when the decision to embolize the liver was
made. Informed consent to perform the procedure
was obtained from all patients. The medical treatment
was continued after embolization. Eleven patients underwent more than one procedure, and the frequency
at which the embolizations were performed was primarily dictated by the patients’ symptoms and/or biochemical or tumor status, i.e., when signs of progression occurred. Two patients had another embolization
of the same lobe within 2– 4 months (without signs of
progression) to enhance the effect.
Embolization Procedure
Arteriography of the superior mesenteric artery and
celiac axis was done routinely before the embolization
to assess arterial anatomy and define the patency of
the portal vein. Depending on which hepatic lobe
contained more tumor, or where progression of metastases had been demonstrated, very selective catheterization of either the left or the right hepatic artery
was performed; because of the risk for severe postembolic complications, embolization of the proper hepatic artery was avoided whenever possible (it was
performed, however, on 10 patients in whom selective
catheterization could not be achieved). Gelfoam powder (Spongostan, A/S Ferrosan, Denmark) with a particle size of 50 –150 ␮m mixed with iodinated contrast
was used as embolic material. The amount of gel foam
powder was individually determined for each patient
and administered until arterial blood flow ceased
completely as assessed by angiogram. The mixture
was injected slowly to avoid backflow and spillover to
the gastroduodenal, splenic, dorsal pancreatic, or gastric arteries.
After embolization, the patients were carefully
monitored (up to 1990, in the intensive care unit for
the first 24 hours) with regard to vital signs, including
pulse, blood pressure, body temperature, weight, hepatic functions (transaminases, alkaline phosphatase,
and lactate dehydrogenase), renal functions (creatinine), and routine biochemistry (hemoglobin, leukocyte count, and electrolytes). With a few exceptions
early in the study, all patients were carefully hydrated
(a diuresis of ⬎3 liters per day was required) and, if
necessary, were also given diuretics for the first 4 –5
days after embolization to ensure protection of the
Liver Embolizations for Neuroendocrine Gastrointestinal Tumors/Eriksson et al.
kidneys. From 1985, all patients with hormonal symptoms were given a continuous intravenous infusion of
octreotide 50 –100 ␮g/hour, started immediately after
the embolization procedure was finished and then
continued for 24 – 48 hours, followed by subcutaneous
injections 2–3 times daily to avoid hormonal crisis.
Analgesic treatment (pethidine hydrochloride 50 –100
mg intravenously) was given during the embolization
procedure and then when required during the days
that followed. No prophylactic antibiotics were given.
Evaluation of Biochemical and Radiologic Responses
The therapeutic effect was evaluated by both measurements of biochemical tumor markers (including
urinary 5-hydroxyindoleacetic acid [U-5-HIAA] in carcinoid tumor patients and serum gastrin, insulin, pancreatic polypeptide, plasma glucagon, and vasoactive
intestinal polypeptide in patients with EPTs) and radiology (computed tomography [CT] or ultrasonography) every 3 months. Since 1989, plasma chromogranin has routinely been used as a tumor marker in
all patients.15 In the CT studies, the size of the metastases before and after embolization was determined
by multiplying the longest diameter by the greatest
perpendicular diameter of the hepatic tumor mass.
Response Criteria
An objective biochemical response was defined as a
⬎50% reduction of hormone levels. An objective radiologic response was defined as a ⬎50% reduction in
tumor size at CT. An overall objective response required an objective biochemical and/or radiologic response. Stable disease (SD) was defined as a ⬍50%
reduction of hormone levels and tumor size and progressive disease (PD) as a ⬎25% increase in tumor
markers and/or tumor size.
Statistics
Survival analyses, with death from any cause as the
outcome (related or unrelated to neuroendocrine tumor disease), were performed by the Kaplan–Meier
method. An unpaired Student’s t test was used to test
for differences between diagnostic groups, and analysis of variance was used to test for differences between
response groups.
RESULTS
The therapeutic effect of all the 55 embolizations are
given in Tables 1 and 2. Carcinoids and EPTs were
evaluated separately. To avoid excessive detail, results
per patient are given in the following text, whereas
results per embolization are given in the tables.
2295
Carcinoid Tumors
Response
Results for patients with carcinoid tumors are presented in Table 1. Eleven of 21 patients with midgut
carcinoid tumors (52%) showed an overall objective
response (OR), with a median duration of effect of 12
months, whereas 2 of 4 patients with foregut carcinoid
tumors and 2 of 4 with hindgut carcinoid tumors
responded objectively, with a median duration of effect of 11 months. In 8 of 21 midgut carcinoid patients
(38%), a biochemical response (⬎50%) was noted, and
a radiologic response (⬎50%) was also demonstrated
in 8 of 21 patients (38%). One midgut carcinoid patient
who achieved both a biochemical and a radiologic
response showed progression of metastases in the untreated lobe (not indicated in Table 1). Two of four
patients with foregut and one of four with hindgut
carcinoid tumors responded biochemically, whereas a
radiologic response was noted in one foregut and two
hindgut carcinoid patients.
An overall stabilization (SD) was achieved in 6 of
21 midgut carcinoid patients (38%) with a median
duration of 7 months, whereas 1 foregut carcinoid and
2 hindgut carcinoid patients showed SD with a median duration of 8 months.
All together, eight patients were reembolized. Five
patients with midgut carcinoid tumors who had
achieved OR (n ⫽ 3) or SD (n ⫽ 2) at first embolization, 2 foregut carcinoid patients who had both
achieved OR, and 1 hindgut carcinoid patient who had
achieved SD were reembolized. In 2 of these patients,
reembolizations were performed within 2– 4 months,
without signs of progression, to enhance the effect. In
the other 6, reembolizations were performed at signs
of progression, with an OR achieved in 2 patients (1
midgut and 1 hindgut) and SD (n ⫽ 3) and PD (n ⫽ 1)
achieved in the remaining 4 patients.
Progressive disease was seen in 4 of 21 patients
with midgut carcinoid tumors (19%).
When pretreatment levels of U-5-HIAA and chromogranin in patients with midgut carcinoid tumors
were compared, there was no significant difference
between responding (OR) and nonresponding (SD,
PD) patients. Median duration of disease from diagnosis in the two groups did not differ either.
For midgut carcinoid patients, survival analyses
showed a median survival of 120 months and an 83%
rate of survival 5 years after diagnosis. In the same
patient category, the median survival and rate of survival 5 years after the first embolization were 80
months and 60%, respectively. For the smaller group
of foregut-hindgut carcinoid patients, the median survival from diagnosis and median survival from first
2296
CANCER December 1, 1998 / Volume 83 / Number 11
TABLE 1
Effects of Hepatic Arterial Embolization on Patients with Carcinoid Tumors
Biochemical response
Tumor type
Midgut
Midgut
1
2
3
Midgut
1
2
Midgut
Midgut
Midgut
1
2a
Midgut
Midgut
Midgut
Midgut
Midgut
Midgut
Midgut
Midgut
Midgut
Midgut
1
2
Midgut
1
2
Midgut
Midgut
Midgut
Midgut
Foregut
1
2
Foregut
1
2a
Foregut
Foregut
Hindgut
Hindgut
1
2
Hindgut
Hindgut
Overall response
duration (mos)
%
Duration (mos)
Radiologic response
duration (mos)
Posttreatment
OR
7
55
7
SD
20
IFN
OR
SD
SD
16
5
3
75
49
0
24
5
—
OR
SD
SD
16
2
10
IFN, Oct
IFN
IFN
OR
OR
OR
OR
10
20
7
12
50
20
36
—
10
20
36
—
OR
OR
OR
OR
24
96
7
12
IFN
IFN
IFN
IFN
OR
—
OR
OR
OR
OR
OR
SD
SD
SD
SD
60
—
7
17
3
3
5
5
12
3
4
0
0
59
60
77
90
55
37
0
23
8
—
—
7
20
3
3
5
5
—
3
4
OR
—
OR
OR
SD
SD
OR
SD
SD
SD
SD
60
—
19
17
12
3
5
10
12
24
4
None
STZ, 5-FU
IFN
IFN
Oct
IFN, Oct
IFN, Oct
IFN
IFN
IFN, Oct
IFN, Oct
SD
SD
5
3
38
20
5
3
SD
SD
11
9
Oct
Oct
SD
PD
PD
PD
PD
un
8
—
—
—
—
—
43
PD
PD
85
20
un
8
—
—
12
18
—
SD
SD
SD
PD
PD
un
11
8
7
—
—
—
IFN
IFN, Oct
Oct
IFN, Oct
IFN; Oct
IFN
OR
SD
11
10
60
47
11
10
SD
SD
11
10
IFN, Oct
IFN, Oct
OR
OR
SD
un
OR
15
—
4
—
11
81
0
44
un
—
15
—
4
—
—
OR
—
SD
un
OR
24
—
6
—
11
IFN, Oct
IFN, Oct
STZ, 5-FU, IFN
Oct
IFN
SD
OR
SD
SD
1
3
24
3
7
51
—
30
4
3
—
3
SD
OR
SD
SD
1
9
24
3
IFN-␣, -␥
IFN-␣, -␥
IFN
none
OR: objective response; SD: stable disease; PD: progressive disease; IFN: interferon-␣; Oct: octreotide; STZ: streptozocin; 5-FU: 5-fluorouracil; un: undetermined.
a
Reembolization was performed within 2–4 mos without any signs of progression but rather regression, to enhance the effect.
embolization were 85 and 40 months, respectively,
and the 5-year survival rates were 67% and 40%, respectively.
Causes of Death
Among the 21 midgut carcinoid patients, 10 have died;
tumor progression was the cause of death for 9 of
Liver Embolizations for Neuroendocrine Gastrointestinal Tumors/Eriksson et al.
2297
TABLE 2
Effects of Hepatic Arterial Embolization on Patients with Endocrine Pancreatic Tumors
Biochemical response
Tumor type
Nonfunc
Nonfunc
1
2
Nonfunc
Nonfunc
1
2
Nonfunc
WDHA
WDHA
WDHA
1
2
3
4
Gastrinoma
Gastrinoma
Insulinoma
Somatostatinoma
Overall response
duration (mos)
%
Duration (mos)
Radiologic response
duration (mos)
Posttreatment
OR
6
77
6
SD
11
None
SD
PD
PD
6
—
—
32
PD
—
6
—
—
SD
PD
PD
12
—
—
IFN, Oct
IFN, Oct
None
PD
PD
—
—
—
—
—
—
PD
PD
—
—
STZ, DOX
STZ, DOX
OR
OR
6
12
77
87
8
12
SD
SD
6
12
Oct
STZ, DOX, IFN-␣, -␥
OR
OR
PD
PD
OR
PD
PD
OR
5
5
—
—
un
—
—
16
94
57
PD
PD
61
PD
50
48
5
5
—
—
un
—
1
16
OR
SD
SD
SD
SD
PD
PD
OR
7
—
—
—
un
—
—
22
IFN-␣, -␥
IFN-␣, -␥
IFN-␣, -␥
Cispl, VP16
IFN-␣
STZ, DOX, IFN
None
IFN
a
a
a
OR: objective response; SD: stable disease; PD: progressive disease; IFN: interferon-␣; Oct: octreotide; STZ: streptozocin; DOX: doxorubicin; un: undetermined.
a
The patient died within 3 days after embolization due to liver necrosis.
these patients, and the 10th died during surgery for
carcinoid heart disease. Five of eight patients with
foregut-hindgut carcinoid tumors died of tumor progression.
Endocrine Pancreatic Tumors
Response
The therapeutic effect of liver embolization in EPTs is
shown in Table 2. An overall objective response was
achieved in 6 of 12 patients (50%), with a median
duration of effect of 10 months. A biochemical response was demonstrated in 5 of 12 patients (42%),
and a radiologic response was noted in 2 (17%). One
patient (the case of somatostatinoma), who achieved
both a biochemical and a radiologic response, showed
progression in the untreated liver lobe 3 months
postembolization (not indicated in Table 2). Three
patients were later reembolized at signs of progression, with no effect achieved in two patients and a
biochemical response achieved in one patient who
then failed to respond to two further embolizations.
One of 12 patients (8%) achieved SD with a duration of 6 months, whereas 2 patients (16%) had PD and
3 died of postembolic complications (2 hepatorenal
syndrome, 1 liver necrosis).
Survival analyses in EPTs showed a median survival of 60 months from diagnosis and a median sur-
vival of 20 months from first embolization. The 5-year
survival rate from diagnosis was 50%. There was no
patient with EPT alive 5 years after embolization.
Eleven of 12 patients have died, 3 of whom had complications from embolization. Other causes of death
were tumor progression for five patients, myocardial
infarction for one, and disseminated intravascular coagulation for one.
Adverse Events
All patients had some degree of postembolization syndrome (Table 3). Pain requiring injections of morphine analgesics, a febrile reaction, and leukocytosis
were noted in the majority (⬎80%) of patients, reaching a maximum after 2–3 days. Nausea was experienced by 33% of patients. Persistent fever for longer
than 1 week was noted in 7 patients, and in 5 a urinary
infection probably caused by the urinary catheter (to
ensure diuresis) was found. The other two patients
had septicemia requiring systemic antibiotics.
Elevations in liver enzymes occurred in ⬎90% of
patients, indicating damage to normal liver parenchyma (transaminases) and possibly also tumor necrosis (lactate dehydrogenase) with a maximum on
Day 2–3 after embolization. However, we found no
significant difference in the increase of lactate dehydrogenase between responding and nonresponding
2298
CANCER December 1, 1998 / Volume 83 / Number 11
TABLE 3
Summary of Complications of 55 Hepatic Arterial Embolizations in 41 Patients with Neuroendocrine G-I
Tumors
Complications
Frequency
Comments
Pain
Pyrexia (⬎37.5°C)
48/54, 1 un
51/54, 1 un
Infection
7/23, 32 un
Leukocytosis
40/49, 6 un
No. of days analgesics required: md 4 (range, 0–27)
No. of days: md 7 (0–18)
No prophylactic antibiotics
4 patients with persistent pyrexia received cortison
5 patients with persistent pyrexia had urinary
infection, possibly due to catheter
2 patients with persistent pyrexia had septicemia
Maximum value: md 13.65 (4.4–25.5)
Day of maximum value: md 4.6
Nausea
Hepatic enzyme derangement
GOT
16/49, 6 un
GPT
53/54, 1 un
52/53, 2 un
Alkaline phosphatase
48/51, 4 un
Bilirubin
33/49, 6 un
LD
52/54, 1 un
Renal insufficiency
2/55
Liver necrosis
1/55
Extrahepatic embolization
1/55
Carcinoid crisis
0/29
Maximum value: md 5.9 (0.55–59)
Day of maximum value: md 2
Maximum value: md 2.6 (0.5–27)
Day of maximum value: md 2
Maximum value: md 9.9 (2.9–63)
Day of maximum value: md 7
Maximum value: md 25 (7.9–114.3)
Day of maximum value: md 3
Maximum value: md 33 (4.7–347)
Day of maximum value: md 2
Two early patients; thereafter avoided by hydration
and forced diuresis
Occurred 36 hours after embolization with fatal
outcome. Septicemia with Clostridium
perfringens and previous surgery (Whipple’s
operation) could have contributed
Small intestinal iscemia due to spillover of embolic
material: the patient had an arterial anomaly
Avoided by continuous infusion of octreotide the
first 24 hours
No. of days of hospitalization: md 12 (range, 6–52).
GOT: glutamic–oxaloacetic transaminase; GPT: glutamic pyruvic transaminase; LD: lactate dehydrogenase; un: undetermined; md: median.
patients. Moderate elevations of alkaline phosphatase
and bilirubin levels were also noted in the majority of
patients.
Our first two patients in the early 1980s, with very
advanced hepatic metastases of EPT, developed hepatorenal failure with fatal outcome. Since then, all the
patients have been kept on a strict hydration scheme,
and no renal complications have occurred.
Serious adverse events were noted in two more
patients. One patient, who had undergone Whipple’s
operation because of a nonfunctioning EPT several
years earlier, died of liver infarction on the third day
after unilobar embolization. Retrospectively, there appeared to be nothing exceptional about the procedure,
and the patency of the portal vein had been established. Blood cultures showed growth of Clostridium
perfringens in this patient. The other patient, who was
embolized despite an anomaly of the arterial tree (the
right hepatic artery originated from the mesenteric
artery), developed signs of intestinal ischemia with
dilated small intestine and diffuse abdominal pain 5
days postembolization. Exploratory laparotomy revealed gangrene of a portion (1 meter) of the small
intestine, which was resected. The patient survived
several other postoperative complications and showed
a dramatic biochemical response (90%).
The median number of days the patients needed
to recover from the postembolic complications, i.e.,
hospitalization days, was 12 days (range, 6 –52 days).
DISCUSSION
Neuroendocrine gastrointestinal tumors commonly
metastasize to the liver, and the clinical consequences
of these tumors are mainly seen as disabling symptoms related to the secretion of hormonal substances:
the carcinoid syndrome with flush and diarrhea, or
symptoms associated with EPTs, such as hypoglycemia, multiple ulcers, diarrhea, skin rash, and diabetes.
Liver Embolizations for Neuroendocrine Gastrointestinal Tumors/Eriksson et al.
Chemotherapy with streptozocin plus 5-fluorouracil
or doxorubicin produces biochemical and/or tumor
responses in about 50% of EPTs, which can last for
approximately 2–3 years,3 whereas midgut carcinoid
tumors are resistant to this treatment.4 In both carcinoid tumors and EPTs, IFN treatment is relatively
effective, with responses in approximately 40 –50% of
patients that have a duration of 2–3 years.5,6 The role
for octreotide and other somatostatin analogs has
been established in several series,7,8 and recently the
importance of the presence of somatostatin receptors
in the tumors for the therapeutic outcome has been
demonstrated.16
The hepatic metastases of neuroendocrine gastrointestinal tumors derive almost all of their blood supply from the hepatic artery. The normal liver parenchyma receives only 20 –25% of its blood supply from
this artery, whereas 75– 80% is supplied by the portal
vein.17 Occlusion of hepatic arterial branches will
cause varying degrees of necrosis of hepatic metastases, whereas the normal liver parenchyma is protected
from infarction by its dual blood supply. Therefore,
occlusion of the portal vein is a contraindication to
arterial embolization. Because endocrine tumors and
metastases are usually hypervascular, they should, at
least theoretically, be sensitive to devascularization.
Various particulate embolization materials have
been used, e.g., gel foam powder, polyvinyl alcohol
particles, to achieve peripheral arterial embolization,
which is preferred to the proximal embolization used
earlier (ligation of hepatic artery or the use of metal
coils), because the collateral circulation will be less
effective and the tumor necrosis therefore greater. Peripheral arterial embolization also allows repeated
embolizations, because the vessels undergo recanalization.
Our overall response rates of approximately 50%
for both carcinoids and EPTs were somewhat lower
than the 80 –90% that others have reported,12–14 but
the duration of effect (median, 12 months for midgut
carcinoids and 10 months for EPTs) was similar to the
11–15 months in other series.13,14 It is important to
remember that all of our patients had advanced stage
disease, having had their neuroendocrine tumor with
liver metastases diagnosed for a median of 37 months,
and having received systemic medical treatment during that time. The lower response rate could be explained by the advanced stage; but among our midgut
carcinoid patients, which was the largest group, we
could not find a significant difference in the duration
of disease before embolization or pretreatment hormone levels between responders and nonresponders.
It could also be that others have recommended repeated embolizations (up to 8),14 whereas we per-
2299
formed only one embolization on the majority of patients (11 of 41 patients were reembolized).
When should patients be embolized? At least theoretically, the approach of reducing tumor burden
first and then giving medical treatment appears to be
preferrable. In a relatively recent randomized study,18
carcinoid patients were treated at the time of diagnosis with IFN with or without prior liver embolization,
and the objective response rate after 1 year was higher
in the embolized group (86%) than in the group that
received IFN only (42%). However, embolization could
not be shown to have any significant effect on survival.
In this series, the 5-year survival rate was 38%.
Several reports from another group have advocated embolization early in the clinical course of midgut carcinoids.19,20 Aggressive surgery, followed by octreotide treatment and unilobar or bilobar liver
embolizations in 40 patients with midgut carcinoids,
produced a 55% reduction of U-5-HIAA, which had
still been maintained after 71 ⫾ 11 months, and the
5-year survival rate was 56%. Survival was calculated
from the time of diagnosis of the carcinoid syndrome.
In our current study, the median survival after
diagnosis for patients with midgut carcinoids and liver
metastases was 120 months, and the 5-year survival
rate from diagnosis 83%. Liver embolizations were
undertaken at a median of 37 months after diagnosis,
but still the patient’s life expectancy after embolization was a median of 80 months and the 5-year survival rate 60%, indicating that “late” embolization was
also very effective. Our data on malignant EPT embolized at a median of 37 months after diagnosis indicated that the median survival postembolization was
only 20 months (from diagnosis, 60 months), suggesting that in this group earlier embolization may improve the results.
The rate of occurrence of complications in patients with postembolic syndrome, including pain, fever, nausea, leukocytosis, and liver enzyme derangements, in our study was about the same as in other
series.12–14 Severe complications, i.e., renal failure,
liver necrosis, and intestinal ischemia, occurred in a
total of 4 patients (10%), and 3 of them (7%) died.
However, two of these patients were embolized in the
early 1980s, when the risk for renal damage was not
recognized. Since then, all our patients have been
vigorously hydrated after the procedure, and we have
had no further problems with renal insufficiency.
One patient died of acute liver infarction 36 hours
after embolization. At autopsy, this patient had a fresh
portal thrombosis (the patency of the portal vein had
been established before the embolization). Blood cultures also showed septicemia with Clostridium perfringens. It was unclear whether this had any signifi-
2300
CANCER December 1, 1998 / Volume 83 / Number 11
cance and whether prophylactic antibiotics may have
helped the patient. It is also unclear whether the
Whipple’s operation she had undergone made embolization more risky.
The fourth patient, who had an extrahepatic spillover and accidental embolization of the small intestine, which was manageable with surgery, had an
anomaly of the superior mesenteric artery that may
have contributed to the occurrence of this complication. However, this type of anomaly is quite common,
and other patients with the same anomaly have been
safely embolized without complications.
No hormonal crises occurred in our patients, possibly because of the octreotide infusion administered
to patients with hormonal symptoms. To avoid reducing the blood flow to the liver before the embolization,
which, at least theoretically, may have reduced the
effect of embolization, we usually started the infusion
of octreotide when the embolization had just been
finished.
This study began in the early 1980s, and both the
embolization technique and the postembolization
care has improved during this time, but the procedure
is still associated with considerable toxicity and morbidity, which usually subside within 1–2 weeks. In our
study, the median number of days of hospitalization
was 12. Thus, hepatic artery embolizations are costly
procedures not only for society, but also for the patients, in that their quality of life is impaired. However,
this impairment is temporary, and if the embolization
is successful it usually improves hormonal symptoms
and hormone levels much more quickly than other
therapies, i.e., biotherapy and chemotherapy.
Which patients should be embolized? This question also remains to be answered. With the knowledge
that we have acquired, that the procedure is associated with significant morbidity even in experienced
hands, we think patient selection is imperative. We do
not recommend embolization for patients with inoperable but few small lesions in the liver. The risk for
complications also disqualifies patients with poor performance status (e.g., due to severe carcinoid heart
disease) and patients with massive involvement of the
liver who have very little normal liver parenchyma left.
One group of patients that should definitely be considered for embolization is the relatively small group
(10 –20%) who are somatostatin receptor negative according to octreotide scintigraphy. These patients
would not benefit from standard treatment with currently available somatostatin analogs.
In conclusion, it is very difficult to compare data
regarding treatment results and survival between different groups of patients and also between treatment
centers with different therapeutic traditions. In our
study, with patients embolized “late” in the clinical
course of the disease, the median survival from embolization for patients with midgut carcinoids was as
long as 80 months, and the 5-year survival rate was
60%, similar to what others have achieved with “early”
embolizations. We cannot see an obvious advantage
to early embolization for patients in this category, and
we suggest that both the individually chosen medical
treatment (IFN and somatostatin analogs) and the
embolization have contributed to the relatively long
survival (median, 120 months after diagnosis) and the
high 5-year survival rate of 83% for this patient category.
Although the response rate was similar for patients with advanced EPTs who had received chemotherapy, IFN, and somatostatin analogs before embolization, the median survival after embolization was
only 20 months. Even though the median survival after
diagnosis of 60 months and the 5-year survival rate of
50% was better than in other series of malignant EPTs,
earlier liver embolization (possibly before biotherapy)
may improve the results.
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