Professional Documents
Culture Documents
Embolotherapy
Embolotherapy
Hepatic Artery Embolotherapy of Hepatic Metastases from Carcinoid Tumors: Value of Using
a Mixture of Cyanoacrylate and
Ethiodized
Oil
Friedrich
W. Winkelbauer1 Bruno Niederle2 Flavia Pietschmann3 Sigfried Thurnher1 Reinhard Wildling Rupert Prokeschi Johannes Lammer1
Received
revision
1
September
8, 1995.
after
March
OBJECTIVE. Transcatheter embolization of the hepatic arterial supply is a well-known palliative treatment of tumor deposits in the liver. We performed a prospective study to evaluate the use of a mixture of N-butyl-2-cyanoacrylate and ethiodized oil with which a permanent vascular occlusion can be obtained, as an embolizing agent for transcatheter hepatic artery embolization for treatment of carcinoid hepatic metastases. SUBJECTS AND METHODS. Six patients had clinical symptoms from hormonal release by carcinoid hepatic metastases as well as elevated levels of 5-hydroxyindole acetic acid (5-HIAA) in the urine. Unilobar sequential transcatheter embolization of both the hepatic artery and the segmental hepatic arteries of both lobes of the liver was performed with a mixture of N-butyl-2-cyanoacrylate and ethiodized oil. CT and CT arterial portography (CTAP) were done to assess hepatic metastases and were used to monitor follow-up. Each patient had three CTAP studies; the third CTAP, performed 3 months after complete arterial devascularization, was compared with the first CTAP to evaluate tumor size. CT studies were performed routinely every 3 months thereafter and were compared with the initial CT scan to evaluate further tumor regression or progression. Tumor decrease and biochemical and symptomatic response rates were defined according to World Health Organization criteria. All complications and side effects of the treatment were documented. RESULTS. All patients showed complete symptomatic relief after embolization. The previously elevated levels of 5-HIAA in the urine returned to normal in three patients and in the other three patients were reduced by a mean of 89% of preembolization values. A decrease in tumor size by more than 50% was demonstrable in one patient; in five patients, hepatic lesions decreased in size by 25-50%. No new sites of metastatic liver disease were demonstrable in any patient during follow-up. No deaths or serious complications were directly attributable to the embolization procedure. All patients are alive after 12, 17, 18, 19, 19, and 19 months (mean, 17.3 months), respectively, with permanent relief of symptoms so far. CONCLUSION. Transcatheter embolization of both the hepatic artery and the segmental hepatic arteries with a mixture of N-butyl-2-cyanoacrylate and ethiodized oil provided excellent palliation in patients with carcinoid hepatic metastases. Complete and long-lasting relief of symptoms, a significant decrease or normalization of levels of 5-HIAA in the urine, and a reduction of metastatic tumor in the liver seem most likely to be the effect of sustained ischemia obtained with this permanent embolizing agent.
AJR
Department
phy and Interventional Radiology, enna, W#{225}hringer G#{252}rtel 8-20, 1 Austria. Address correspondence bauer.
1995;165:323-327
of General Hospital
9, A-
of Intemal
Bruder, Groje
Medicine,
Mohrengasse
American
Roentgen
Ray Society
Carcinoid tumors, although rare, are the most frequent of all endocrine tumors of the gut [1]. The release of a great variety of biologically active hormones and amines directly into the systemic circulation by hepatic metastases causes symptoms of the carcinoid syndrome and severely compromises the patients lifestyle [2, 3]. Embolization of the arterial supply of hepatic tumors is an accepted palliative treatment to achieve ischemia and subsequent necrosis of tumor tissue. Embolic agents such as stainless steel coils, gelatin sponges, polyvinyl alcohol
324
WINKELBAUER
ETAL.
AJR:i65,
August 1995
foam, and glues act at different levels in the arterial system and differ in physical properties, vascular reaction, toxicity, duration, and quality of obstruction [4-6].
N-butyl-2-cyanoacrylate is an adhesive that polymerizes
almost instantaneously on contact with ionized material such as blood or endothelium. It belongs to the group of liquid embolizing agents with a low viscosity, allowing injection through very small catheters. Permanent occlusion of the vessel is the result, as demonstrated in animal experiments and in human trials [5]. In several animal studies, neither general toxicity nor carcinogenesis has been observed. However, in the United States cyanoacrylates are classified as investigational devices by the Food and Drug Administration and are limited to life-threatening indications [5]. This may be the reason only few reports exist on the use of cyanoacrylates for hepatic arterial occlusion. The rationale for the use of a mixture of N-butyl-2cyanoacrylate and ethiodized oil in our study was the peripheral, complete, and permanent arterial occlusion that can be obtained to achieve sustained ischemia. The resulting higher degree of necrosis of metastases should positively influence the symptomatic, biochemical, and morphologic responses to the embolization treatment. We report preliminary results obtained with a mixture of N-butyl-2-cyanoacrylate and ethiodized oil as an embolic agent for embolotherapy of carcinoid hepatic metastases.
Subjects
Six
and
patients
Methods
(five women, one man) from 47 to 63 years old
(mean age, 55.6 years) were referred to our institution for transcatheter embolization of hepatic metastases from midgut carcinoid tumors. All patients had the carcinoid syndrome. Five patients had daily flushes, six had diarrhea with more than five stools per day, and two had pulmonary manifestations. Five patients had previously undergone treatment with a somatostatin analogue; two of them were treated additionally with interferon-a2B. To be entered into the prospective protocol, the patients had to meet the following criteria: histopathologic confirmation of a midgut carcinoid tumor with maximal surgical reduction of the primary tumor, removal of regional lymph nodes, and cholecystectomy; metastatic liver disease present in two or more nonadjacent segments of the liver; symptoms of flushing or diarrhea; urine levels of 5hydroxyindole acetic acid (5-HIAA) exceeding two times the upper reference value; no other contemporary malignant neoplasms; no severe coronary heart disease; patency of the portal vein; and written informed consent. The study was approved by the ethics committee of the University of Vienna. Octreotide (Sandostatin; Sandoz, Basle, Switzerland, 0.2-0.4 mg/day) was given subcutaneously to five patients 1 week before treatment and was continued thereafter at a dosage of 0.2 mg/day in all patients. IV sedation with 2.5 mg midazolam (Dormicum, Sandoz) was given before embolization. Pain was controlled with a morphine antibiotics derivative were (Fentanyl; not Janssen, Beerse, routinely. Belgium) All procedures as needed; were peradministered
helical CT study and a CT arterial portography (ClAP) [7] before starting the treatment. CTAP was used to monitor the morphologic response to treatment. The decrease in tumor size was evaluated 3 months after bilobar embolization and was compared with the baseline CTAP. CT examinations of the liver were done every 3 months thereafter for follow-up. These studies were compared with the baseline CT study to evaluate further changes of metastatic tumor. Celiac and superior mesenteric angiography were done by standardized technique. Identification of the hepatic arterial anatomy and verification of the patency of the portal vein were followed by transcatheter embolization of both the segmental hepatic arteries and the right or left hepatic artery via a femoral access. We used a mixture of N-butyl-2-cyanoacrylate (Histoacryl blue; B. Braun Melsungen AG, Melsungen, Germany) and ethiodized oil (Lipiodol Ultrafluide; Guerbet, ZUrich, Switzerland) as an embolizing agent in a ratio of 1 :4. A total of 0.2 ml of the cyanoacrylate was aspirated into a i -ml syringe followed by aspiration of 0.8 ml of the ethiodized oil, then the two substances were intensively mixed. To avoid polymerization within the catheter, the system was flushed with a 10% glucose solution before the embolization procedure and immediately thereafter. The mixture was applied under fluoroscopic control without force until stasis of the arterial blood flow was achieved. The exact amount was determined fluoroscopically. Special care was taken to avoid backflow and catheter fixation. After initial peripheral embolization of the lobe bearing the greater tumor bulk, embolization of the remaining lobe was performed 1-2 months later, depending on the severity of nausea and pain after embolization. Follow-up angiography was done in all patients at the time of repeated hepatic embolization to verify the completeness of occlusion. Any collateral vessels to the liver were occluded in a superselective manner during the following angiographic studies. Arterial devascularization of both lobes of the liver and occlusion of collateral vessels to the liver 3 months after bilobar embolization were considered the end of treatment without any more invasive investigations unless deterioration occurred in the patients clinical status. All patients completed the scheduled treatment plan. Survival time was calculated from the time of the first embolization treatment. The patients outcomes were last evaluated in January i 995. Tumor response was evaluated in three categories-morphologic, biochemical, and symptomatic responses-and was defined according to standard World Health Organization criteria (complete morphologic response: total resolution of all treated tumor [with a complete disappearance of all recognizable tumor in the liver]; partial morphologic response: more than 50% decrease in the product of the cross-
sectional
25-50%
the treated
dimensions of treated lesions; minor morphologic response: decrease in the product of the cross-sectional dimensions of
lesions; stable disease: no significant change in the size of
the lesions; progressive disease: the appearance of new lesions or more than 25% increase in the product of the cross-sectional dimensions of the treated lesions; biochemical response: partial remission defined as a 50% decrease in elevated urinary excretion of 5-HIAA, calculated as the difference between the values before the first embolization and 3 months after the completion of embolization therapy; complete symptomatic response: disappearance of symptoms of the carcinoid syndrome; partial symptomatic response: more than 50% reduction in the frequency of flushing or diarrhea; minor symptomatic response: 25-50% reduction in the frequency of flushing and diarrhea; no response).
formed with hemodynamic monitoring (blood pressure, electrocardiography, pulse oximeter). All complications and side effects of treatment were documented. Tumor status was assessed on the basis of symptoms of the carcinoid syndrome and 5-HIAA levels in the urine, which were deter-
Results
mined before and after each procedure and at the time of follow-up CT studies, together with routine laboratory data. Each patient had a
Hepatic arteriography before embolization revealed multiple small hypervascular lesions, sometimes confluent, involving both lobes of the liver in each patient (Fig. iA).
AJR:165,
August
1995
CT OF HEPATIC
ARTERY
EMBOLOTHERAPY
325
r.p
C
Fig. i .-Effect of permanent transcatheter in 53-year-old woman with carcinoid hepatic embolization metastases. of arterial supply of liver obtained with mixture of N-butyl-2-cyanoacrylate and ethiodized oil
A, CT scan obtained during arterial portography done before first embolization shows confluent metastatic lesions in right and left lobes of liver. Patient has symptoms of carcinoid syndrome and elevated level of 5-HIAA in urine. B, SuperselectIve transcatheter application of mixture of N-butyl-2-cyanoacrylate and ethiodized oil in hepatic segmental arteries of right lobe of liver causes permanent arterial occlusion. Arteriogram of celiac trunk during first embolization shows defect in arterial perfusion. C, CT scan obtained during arterial portography done before embolization of left lobe of liver i month later. Ethiodized oil is captured within polymerized cyanoacrylate clots and can be depicted as hyperdense rods in segmental hepatic arteries. Hypodense areas (gas) within tumor indicate ne-
crosis.
Patients
symptoms
improved,
decreased.
Embolizations
were
technically
feasible
in all patients
and
hr). HIAA
Lowest urinary
after had
embolization decreased
from
6.1 to 26.4
resulted in complete occlusion of the treated hepatic arteries as confirmed by follow-up angiography (Fig. 1 B). In two
patients, collateral vessels originating from the right inferior
phrenic artery were There detected 3 months after bilobar emboA
mg/24
patients, three 97% patients,
hr (mean,
and patients (mean,
12.7 mg/24
biochemical respective were
control, obtained
92%, These
5in
and
in three
reductions
lization
tive reotide
successfully
was
embolized without
in a superselecmortality.
three evalua(partial
manner.
no procedure-related
however, regression
carcinoid
in the
was One
patient
prophylactic
We (body saw
octno
tions of 5-HIAA
Marked
levels confirmed
in tumor
these results.
by more bilobar Minor Gas could 50%
symptomatically.
signs of nontarget
or septicemia. bolization first vation sient
embolization
had found than levels. enzyme
or postprocedural
a fever
infection
temperature
morphologic
follow-up compared occurred confluent
response)
CTAP with in the lesion, the initial
could
at the
when time a in one comwithin
signs of infection.
to be more after Nausea severe subsequent
indicating density
of elebe
patient
studies,
at the second
tumor
helical CT
could level
in all patients
with symptomatic
Tranof
pared with that seen on CT scans obtained before embolization. Recent CT studies did not reveal further significant
reduction disease in tumor in the liver size; were however, apparent no new in any sites of our of metastatic patients dur-
lactic dehydrogenase
to 10 times embolization, decreased laboratory Immediately showed patients were
(LDH, normal
(range, 687-1236 observed in within 2 weeks
120-240
U/I) up
and to
24 to 48 hr after
ing the observation period. All patients 19, 19, and 19 months (mean, 17.3
preembolization
tion procedure.
values.
No other
be causally
significant
linked to the
changes
embolizapatients three
in
a normal
lifestyle
relief.
the
first
a complete
symptomatic
Discussion The hepatic necrosis, tumors, goal of embolization is to tumor produce deposits to a decrease of the arterial size blood and liver supply subsequent can be sucof
of the
other lobe.
Preprocedural hr) ranged from of 5-HIAA to 276.3
mg/24
mg/24
[2]. In carcinoid
hr (mean,
326
WINKELBAUER
ET AL.
AJR:i65,
August
1995
cessfully
reduced;
more
important,
the
secretion
of biologi-
sponse
was
complete
in eight
of ii
patients,
partial
in two,
cally active substances by the metastases may be stopped, and symptoms and biochemical parameters of the carcinoid syndrome may decrease. The rationale for the use of a mixture of N-butyl-2cyanoacrylate ischemia, nent The occlusion sion, more the arterial smaller less necrosis and obtained occlusion, damaging the effective tumor particle more without [1]. The ethiodized with that oil in this peripheral, should nontumorous size, peripheral the collateral necrosis the more and circulation, study complete, provide structures. distal will the and be the occluthe thus persistent is the sustained and maximal permatumor
in one. Morphologic
response
were complete
end of the
Ruszniewski
et al. [1 6] treated
a complete who could three. patients
18 patients
symptomatic be evaluated Three
remaining
patients
effective
complete biochemical response, and eight patients showed a partial biochemical response. Morphologic responses were
complete four patients in two patients, partial in four, and minor in five;
The polymerization time of cyanoacrylates can be prolonged in proportion to the volume of oily contrast material added to the glue [1 0]. In our study, polymerization time was prolonged to 8-10 sec, allowing the mixture to be transported
into ture peripheral radiopaque segmental and was and subsegmental within hepatic the arteries
disease.
Geterud
had stable and three patients had progressive Median duration of the responses was 14 months.
et al. [ii] used gelatin sponge powder in 17 patients.
response was
Symptomatic
in two patients;
response
before
polymerization
occurred.
the mix-
in 15 patients,
captured
polymerizing
glue clots, blood stasis could be well visualized fluoroscopically during the procedure. In no case did the glue reach the peribiliary arterial plexus, as was also confirmed by the absence of any clinical evidence of biliary abnormalities, nor
could it be seen in the portal vein or systemic circulation.
Polyvinyl
alcohol
foam
particles
150-250
im
in size
may
reach capillaries; however, there is a risk of tissue necrosis, as the human liver tolerates emboli as small as 250 im [ii]. Animal experiments with 1 75-jim microspheres resulted in liver dysfunction [ii 12]. Liquid agents may cause damage
,
obtained. Morphologic changes were not reported. Five patients had major procedure-related complications. Carrasco et al. [2] used polyvinyl alcohol foam particles for hepatic artery embolization in 25 patients. They showed an 87% initial symptomatic improvement, a decrease of 5-HIAA levels in 18 patients, and a decrease in the extent of hepatic metastases in 17 patients, with a median duration of ii months. Fifteen patients are alive after a mean of 16 months; however, the authors report a 9% procedure-related mortality rate. Although many studies are not comparable because they use different response criteria, treat various tumors, or use
more than one embolic agent [1 5, 1 9, 22, 23], our results are
to the
peribiliary
arterial
plexus
with
subsequent
sclerosing
cholangitis, as reported for ethanol [13]. Nonpermanent agents such as gelatin sponges are reported to be advantageous, allowing repeated treatment sessions. The time of recanalization of the hepatic artery, however, is not known precisely [12, 14]. Taourel et al. [14] recently demonstrated a reversal of postembolization flow changes in the hepatic artery within 2 days after embolization with 1- to 2-mm gelatin sponges. Thus, quick reestablishment of blood flow to the metastases must be considered and may adversely influence the degree of necrosis. Recently, chemoembolization has been favored by many authors [1 15-18]. Ethiodized oil is used as a carrier for various
,
close and sometimes superior to those obtained with small particles or with chemoembolization. In our study, symptomatic response was complete in all six patients (1 00%). Biochemical response was complete in three patients (50%) and partial in three patients (50%), with a significant decrease in 5-HIAA levels. Morphologic response was partial in one patient (17%) and minor in five patients (83%). Notably, all patients subjected to this treatment are alive after a mean of 17.3 months. Morphologic response may be difficult to quantify when there are numerous small metastatic lesions
in the liver [1]. Severity of postembolization syndrome and ele-
cytotoxic cytotoxic
drugs.
Subsequent tissues
embolization
of the hepatic
artery
wash-out
and increased
levels of the
determination
of optimal
ethiodized
of stable emulsions
of the
of treatment [1 , 20]. The mechanism that lization effective is not yet clear; additional will be required to assess the influence
of either
tration of cytotoxic drugs or repetitive occlusive treatment patients with hepatic metastases [20, 21]. Therasse et al. [1] used comparable response criteria
23 patients with carcinoid They hepatic report be metastases a complete assessed. treated symptomatic chemoembolization.
in in
with
vation of liver enzyme levels both correlated with the degree of ischemia [6, 8, 19] obtained in the metastases and suggested greater areas of necrosis than were seen. Stuart et al. [1 7] report on the phenomenon that the degree of tumor reduction does not correspond to the efficacy of treatment and therefore included minor responses as significant. They believe that the conservative criteria used are responsible for the failure to show any complete responses in tumor decrease. It is likely that abnormal areas seen on follow-up CT studies represent residual scar rather than viable tumor tissue. The sustained symptomatic response and the significant reduction of 5-HIAA levels, reflecting tumor necrosis, also support this hypothesis. However, symptomatic responses may be difficult to evaluate if
symptoms are partly controlled by octreotide. Five of six
response
patients
in seven
of 10 who
patients
could
and a partial
response
Biochemical
in three
re-
patients
had previous
trials of octreotide
therapy
alone, but in
CT OF HEPATIC
ARTERY
EMBOLOTHERAPY
327
none of them could complete symptomatic response be achieved. However, duration of symptomatic response may be influenced by long-term administration of octreotide. In our study, embolizations were well tolerated with neither procedure-related mortalities nor major complications. Because of multifocal and widespread tumor deposits in the liver, we embolized the arterial supply to an entire hepatic lobe at one time. Reports on embolization of the entire liver at one time being tolerated as well as partial embolization by patients have been published [9, 15, 24, 25]. However, in some studies, a more selective treatment of specific tumors is performed. We believe that our approach is justified, as repeated invasive treatment sessions distress the patient and carry a risk that must not be underestimated. Application of the mixture of N-butyl-2-cyanoacrylate and ethiodized oil as an embolic agent was easy and did not raise technical problems. As the process of polymerization was visible, damage to the penbiliary arterial plexus could be avoided, and thus the risk of damage to nontumorous structures could be minimized. Decrease in the size of hepatic metastases
and-more striking-complete and long-lasting relief of symp-
P, Doyon
D. Vascular
occlusive
toms of the carcinoid syndrome and a significant decrease of levels of 5-HIAA in the urine could be achieved. We assume that these results are the effect of permanent arterial occlusion obtained with this specific embolizing agent. Because of its prospective character, our study contains only a small number of patients. Our preliminary results are encouraging; however, the length of follow-up has to be
extended, and additional
recommend
6. Pentecost MJ, Teitelbaum GP, Katz MD, Daniels JR. Chemoembolization in hepatic malignancy. Semin Intervent Radioll992:9:28-36 7. Graf 0, Dock W, Lammer J, et al. Determination of optimal time window for liver scanning with CT during arterial portography. Radiology 1994:190:43-47 8. Carrasco CH, Chuang vP, Wallace S. Apudomas metastatic to the liver: treatment by hepatic artery embolization. Radiology 1983:149:79-83 9. Chuang vt, Wallace S. Hepatic artery embolization in the treatment of hepatic neoplasms. Radiology 1981:140:51-58 10. Cromwell LD, Kerber CW. Modification of cyanoacrylate for therapeutic embolization: preliminary experience. AJR 1979:132:799-801 ii . Geterud K, Tylen U, Jansson 5, Stenqvist 0, Tisell, Ahlman H. Hepatic arterial embolization in the treatment of the midgut carcinoid syndrome and other advanced endocrine tumors metastatic to the liver. J Intervent Radiol 1990:5:69-76 12. Doppman JL, Girton M, Kahn ER. Proximal versus peripheral hepatic artery embolization: experimental study in monkeys. Radiology 1978:128:577-588 13. Wallace S. Charnsangavej C, Carrasco CH, Bechtel W. Ethanol for hepatic artery embolization. Radiology 1984:152:821-822 14. Taourel P, Dauzat M, Lafortune M, Pradel J, Rossi M, Bruel JM. Hemodynamic changes after transcatheter arterial embolization of hepatocellular carcinomas. Radiology 1 994; 191:189-192 15. Hajarizadeh H, lvancev K, Mueller CR, Fletcher WS, Woltering EA. Effective palliative treatment of metastatic carcinoid tumors with intra-arterial chemotherapy/chemoembolization combined with octreotide acetate. Am J Surg 1992:163:479-483 16. Ruszniewski P, Rougier P, Roche A, et al. Hepatic arterial chemoembolization in patients with liver metastases of endocrine tumors. Cancer
1993:71:2624-2630
observation
of clinical
status
and
biochemical
and morphologic
responses
this procedure.
is required
before
17. Stuart K, Stokes K, Jenkins R, Trey C, Clouse M. Treatment of hepatocellular carcinoma using doxorubicin/ethiodized oiVgelatin powder chemoembolization. Cancer 1993:72:3202-3209 18. Charnsangavej C. Chemoembolization of liver tumors. Semin lntervent Radiol 1993:10:150-160 1 9. Stokes KR, Stuart K, Clouse ME. Hepatic arterial chemoembolization for metastatic endocrine tumors. J Vasc Inter, Radiol 1993:4:341-345
we can strongly
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