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1 Department of Radiology, Division of Angiography and Interventional Radiology,
University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
2 Department of Surgery, Division of General Surgery, Section of Endocrine
Surgery, University of Vienna, A-1090 Vienna, Austria.
Received May 6, 2002;
accepted after revision October 3, 2002.
Address correspondence to C. Loewe.
Abstract
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MATERIALS AND METHODS. Twenty-three patients underwent permanent embolization of the hepatic artery using cyanoacrylate and Lipiodol for treatment of liver metastases after radical resection of small-bowel neuroendocrine tumors. All patients received additional treatment including somatostatin, and most patients received interferon as well. Cumulative survival rates were estimated using the Kaplan-Meier method.
RESULTS. Overall, 75 embolizations (range, 1-10; mean, 3.3) were performed. Median survival time was 69 months, and the estimated cumulative survival rates reached 95.7% and 65.4% for 1 and 5 years, respectively. Two deaths (8.7%) occurred within 1 month of treatment, and one patient experienced a vascular complication at the time of embolization.
CONCLUSION. Permanent embolization of hepatic arteries as part of a multimodality treatment protocol is beneficial in long-term follow-up for patients with metastasized small-bowel neuroendocrine tumors. The use of cyanoacrylate as an embolic agent is safe and effective.
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Neuroendocrine tumors of the small intestine (midgut tumors) are indolent and can grow undiscovered for a long time without local complications [2, 3]. Because endocrine tumor products are secreted into the portal venous system and are deactivated by the liver, they do not reach the systemic circulation until produced in sufficient quantity by liver metastases. Therefore, when a neuroendocrine carcinoma becomes symptomatic because of its endocrine products, resection is not feasible for cure in most cases because of the presence of extensive liver metastases. For patients with metastases, nonsurgical alternatives are desirable to control tumor growth and systemic hormonal effects. These methods include treatment of the manifestations of hormonal symptoms, such as with antidiarrheal agents in patients having VIPomas, with proton pump inhibitors in case of gastrinomas, and treatment directed to the metastases itself.
Tumor-directed methods described in the literature are chemotherapy [4, 5, 6], biotherapy including interferon and somatostatin analogues [6, 7, 8], and chemoembolization and embolization [9, 10, 11, 12, 13, 14, 15]. At our institution, permanent transarterial embolization using a mixture of ethiodized oil (Lipiodol Ultrafluide; Guerbet, Villepinte, France) and cyanoacrylate was performed for patients with liver metastasis from neuroendocrine carcinomas of the gastrointestinal tract.
The purpose of this retrospective study was to assess the safety and mid- and long-term survival rates of patients with metastasized neuroendocrine tumors of the small bowel who were treated with transarterial hepatic embolization.
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Information concerning disease-related symptoms, laboratory values, types of surgery performed, and adjuvant treatment modality was obtained from patient reports. Special emphasis was placed on the stage of disease at the time of first embolization: the number, location, and diameter of the largest liver tumor were obtained by reevaluating the original CT scans and by the diameter of the largest liver tumor. Tumor stage using the TNM classification [16] was taken from pathologic diagnoses after resection of the primary tumor. Information regarding disease-related symptoms before embolization and the evidence of extrahepatic tumor spread was obtained by chart review.
Treatment
Patients were treated according to an institutional multimodality treatment
protocol that began with radical resection of the primary tumor along with
mesenteric lymphatic tissue. If possible, liver metastases were resected. The
surgical procedure was completed by cholecystectomy. Initial permanent
transarterial embolization of one liver lobe was performed 4-8 weeks after
surgery, and that was followed routinely by embolization of the other lobe at
4-week intervals. In case of detection of vital tumors in the previously
embolized lobe, a reembolization was performed.
To assess the vascular anatomy and blood supply of the tumors, we performed helical CT and CT during arterial portography before embolization in all patients [17]. Exclusion criteria for permanent transarterial embolization were complete portal vein thrombosis and contraindication of arterial vascular puncture (platelet count, <70,000/mm3; prothrombin activity, <50%). Informed consent was obtained from all patients before intervention.
Hydration to reduce the risk of embolization-induced renal failure; analgesics, including piritramide (15 mg) (Dipidolor; Janssen, Beerse, Belgium); and antiemetics, including ondansetron hydrochloride (4 mg) (Zofran; Glaxo Wellcome Operations, Greenford, England) were administered before treatment. Somtatostatin analogues (500 mg per day) (Sandostatin; Novartis Pharma, Basel, Switzerland) were administered before and after transarterial embolization and were continued after intervention.
A 6-French Simmons-I catheter (Johnson & Johnson; Cordis Division, Waterloo, Belgium) was placed in the abdominal aorta through femoral arterial access, and a diagnostic angiogram of the celiac trunk and superior mesenteric artery was performed. After identification of the hepatic vascular anatomy, a superselective catheter system (Tracker-18; Target Therapeutics, San Jose, CA) was advanced into the hepatic arteries with its tips placed in tumor-feeding segmental hepatic arteries. A mixture (ratio between 1:3 and 1:10) of N-butyl-2-cyanoacrylate (Histoacryl blue; Braun Melsungen, Melsungen, Germany) and ethiodized oil (Lipiodol) was then injected as an embolic agent [10, 18]. The ratio and polymerization time were estimated before embolization and depended on the desired occlusion level (ratio 1:10 for small peripheral arteries; ratio 1:3-5 for large proximal arteries). The embolic material was applied under fluoroscopic guidance until blood stasis was achieved. To avoid immediate polymerization of the emulsion within the microcatheter, we flushed the catheter using 5% glucose solution before embolization. A final arteriogram was obtained to confirm occlusion of the embolized vessels. After transarterial embolization, the patients were carefully observed, and postembolization syndrome was treated symptomatically. Liver function and amount of liver cell necrosis were evaluated by changes in laboratory values and by CT scans, respectively.
Follow-Up
Three-month follow-up after complete embolization of the hepatic arteries
consisted of biphasic helical CT and hepatomesenteric arteriography. The
presence of nonenhancing segments of the tumor was considered tumor necrosis.
In patients with a residual tumor or incomplete embolization, permanent
transarterial embolization was repeated to occlude remaining or new
tumor-feeding arteries followed by the 3-month follow-up including CT and
angiography as indicated. According to World Health Organization Response
Evaluation Criteria in Solid Tumors, response to treatment was defined as
complete (no evidence of neoplastic disease), partial (reduction in total
tumor volume of >50%), no change (reduction of <50% or increase of
>25%), or progressive disease (increase of >25%). Helical CT scans were
repeated every 3 months for 1 year and, in case of complete response, once a
year afterward.
Furthermore, some of the still surviving patients were consulted, using a standardized questionnaire about potential changes in their symptoms before and after treatment (including surgery and embolization). Questions about flush, local abdominal pain, body weight, and diarrhea were included.
Analysis
To evaluate the efficacy of permanent transarterial embolization with
respect to survival and disease-related death, we assessed survival for the
study population after surgery on the primary tumor. Survival curves were
calculated using the Kaplan-Meier life table to obtain median survival and
cumulative survival rates. Morbidity and 30-day mortality rates were assessed
in the study group with special attention given to intervention-related
complications. Finally, the relationship between morphologic response and
survival was evaluated.
The primary end point of the study was patient survival with regard to tumor-related death. Furthermore, the number and kind of treatment-related complications and side effects were documented.
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Of 23 patients, 14 (61%) had bulky liver metastases with diameters greater than 5 cm (mean, 6.0 cm; range, 1-20 cm) at the time of presentation for permanent transarterial embolization. Tumor stage was pT2 in four patients, pT3 in eight patients, and pT4 in eight patients. In three patients, exact tumor stage was not clarified, even after surgical resection. The primary tumor was located in the ileum in 21 patients (91%) and in the jejunum in two patients (9%). Mesenteric lymph nodes were positive for cancer in 11 patients (48%) (Table 1).
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In three patients, atypical liver resection was performed at resection of the primary tumor, including atypical resection of segments VI and VII in two patients and enucleation of one large metastasis in the third patient.
Overall, 75 embolizations were performed in 23 patients (mean, 3.3 interventions per patient; range, 1-10 interventions). More than the two initially planned embolization procedures were indicated in patients with hepatic tumor recurrence or progression detected at follow-up. In these 14 patients (61%), further transarterial embolization was performed superselectively by occluding the tumor-feeding arteries. The schema of routinely performed embolization of both liver lobes was executed in all 23 patients except two. One patient died after his first embolization. Another patient had only one large metastasis after atypical liver resection. In this patient, only the diseased lobe was initially treated.
The median survival rate of the study group (n = 23) was 69 months after resection of the primary tumor. The resulting cumulative survival rates reached 95.7%, 95.7%, 85.6%, 79.9%, and 65.4% for 1, 2, 3, 4, and 5 years, respectively (Fig. 1). The 10-year cumulative survival rate was 16.3%. Eleven (47.8%) of the 23 patients were still alive, after a mean follow-up of 48 months (range, 15-88 months).
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All the patients received biotherapy with synthetic somatostatin analogues, and 12 patients (52%) also received interferon. Six patients (26%) had concomitant chemotherapy, and three patients (13%) received both chemotherapy and interferon therapy (Table 1).
Treatment response after permanent transarterial embolization was evaluated according to the World Health Organization criteria for those patients (n = 22) who underwent CT before and after permanent transarterial embolization at our institution. Complete response after permanent transarterial embolization was initially observed in four (18%) of 22 patients. Three of them are still alive, surviving 53, 61, and 88 months without tumor recurrence. The fourth patient died 44 months after surgery because of tumor recurrence. Partial treatment response was found in 12 patients (55%), and five of them are still alive after a mean follow-up period (± SD) of 35 ± 11 months (range, 15-45 months). The 12 patients with partial treatment responses have shown a median survival time of 68 months with a cumulative 5-year survival probability of 60%.
In five patients (22.7%), no tumor response was seen after permanent transarterial embolization, and three of these patients were alive at the time of evaluation after a mean follow-up (± SD) of 52 ± 17 months (range, 28-66 months). One patient with tumor progression after embolization died 59 months after surgery because of generalized metastatic disease.
In 13 patients, serum values of 5-HIAA and of serotonin were measured before and after embolization. In eight of these patients, a decrease of more than 50% could be observed after the last embolization compared with the preembolization values. In the other five patients, no relevant changes were seen, and in three of these five patients, a slight decrease and a discrete increase of the serum values were diagnosed in two of these patients.
Nine of the patients still alive were examined using a questionnaire about potential changes in their quality of life and their symptoms. In five of these patients, localized pain in the abdomen was reduced after surgery and embolization. However, in two other patients, pain occurred for the first time after embolization. In another two patients, there was regression of diarrhea; however, in one further patient diarrhea continued after embolization. Of the three patients initially having flush, two reported complete regression of this symptom. Eight of the nine patients maintained their body weight, and in only one was a further decrease in weight observed.
After her second treatment session, in which some small branches of the previously embolized right hepatic artery and the entire left hepatic artery were embolized, one patient had severe lower leg pain in the right leg where the femoral artery had been punctured. A duplex sonogram of the inguinal region on the right leg revealed a dissection of the common femoral artery at the puncture site and an embolic occlusion of the tibiofibular trunk. The patient was treated conservatively with heparin. The flow in the common femoral artery continuously normalized; nevertheless, the tibiofibular trunk remained occluded, with sufficient collateralization.
One patient died of acute hepatic failure 6 days after his third treatment, at which time only a few residual tumor-feeding vessels were embolized. At autopsy, extensive liver cell necrosis was evident, despite a patent portal venous system. This complication was not anticipated.
Another patient died 28 days after the first embolization. Autopsy revealed generalized metastasis with lesions in the spleen, pancreas, lung, heart, and lymph nodes, as well as a subtotal liver necrosis. In this patient, the tumor volume of the multiple intrahepatic lesions exceeded 75% of the liver volume.
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A multimodality treatment protocol, including surgery of the primary tumor and metastases, transcatheter embolization, and adjuvant pharmacologic treatment (bioimmunotherapy and chemotherapy) has been established for metastatic small-bowel neuroendocrine tumors [26].
The efficacy and safety of permanent transarterial embolization as part of this concept was assessed by evaluating survival, side effects, and complication rates after transarterial embolization. Eleven patients in the study population are still alive after a follow-up period of 4 years (Figs. 2A, 2B, 2C and 2D).
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Transarterial chemoembolization has previously been shown to be beneficial in the treatment of primary and secondary liver cancer. This treatment approach is not new, and many different embolic agents have been used in different studies including Gelfoam ([gelatin sponge] Upjohn, Kalamazoo, MI) [27] or polyvinyl alcohol [13], alone or combined with chemotherapeutic agents [28]. Transarterial chemoembolization is a combination of selective administration of an emulsion of an anticancer agent and iodized oil (Lipiodol) followed by Gelfoam particles to occlude temporary tumor-feeding vessels. It was hypothesized that the combination of ischemia and enrichment of the anticancer agent increased tumor cell necrosis. Nevertheless, the proximal and temporary embolization induced with Gelfoam particles leads to an early revascularization via abnormal collateral vessels.
If proximal embolization of tumor-feeding arteries in hepatic metastases is performed using large particles or coils, peripheral hepatic circulation reconstitutes immediately through collateral vessels. The earlier the revascularization of the tumor, the more incomplete the necrosis is, necessitating repeated embolization. An occlusion of more peripheral vessels generates a nearly complete tumor necrosis [10, 13, 18]. However, embolization of more peripheral feeding arteries can be achieved only with small embolization particles.
This finding encouraged Winkelbauer et al. [18] to use N-butyl-2-cyanoacrylate, a liquid glue that polymerizes instantaneously on contact with blood or endothelium, as an embolic agent. Primarily used for uncontrolled bleeding or arteriovenous malformations [29], this agent was introduced to treat liver metastasis from malignant neuroendocrine tumors of the pancreas [10, 18]. Mixed with radiopaque Lipiodol, the polymerization time can be prolonged to 10-15 sec, depending on dilution [30]. Therefore, a peripheral embolization, which is advantageous for an embolic agent, can be achieved. Furthermore, cyanoacrylate causes a permanent and complete occlusion of the embolized arteries, whereas vessels occluded with Gelfoam particles were revascularized within 8 days [31].
In our study, we used a mixture of cyanoacrylate and Lipiodol to treat liver metastasis from gastrointestinal neuroendocrine tumors by transarterial embolization without anticancer agents.
Therasse et al. [28] reported chemoembolization of arteries in 23 patients with advanced metastatic carcinoids using adriamycin and Lipiodol, with a mean survival time of 24 months after initial embolization. In a study by Carrasco et al. [9], eight (35.8%) of 23 patients were dead after an 8-month follow-up, and the other 15 patients (74.2%) survived a mean time of 16 months. In another study reported by Hajarizadeh et al. [4], eight patients with carcinoids survived a mean time of 40 months after initial diagnosis. These patients were treated with chemoembolization using a mixture of doxorubicin, cisplatin, mito-mycin C, and Lipiodol. In a German study [11], mean survival of 11 patients with carcinoids was 19 months; however, three patients died within the first 2 years after chemoembolization. Perry et al. [12] reported a median survival time of 24 months after chemoembolization using an emulsion of doxorubicin and Lipiodol. Diaco et al. [26] reported a median survival in their study population of 53 months after diagnosis. In this study, patients were treated using a multimodality approach including somatostatin analogues, intraarterial chemotherapy, and hepatic arterial embolization using particles.
In comparison with the results of a study by Brown et al. [13] using polyvinyl alcohol as an embolic agent, which also causes a permanent embolization, the 5-year cumulative survival rate in the presented group was slightly longer than that reported (65% vs 54%) by Brown et al.
Compared with the data for transarterial chemoembolization reported in the literature, the effect on survival rates of the permanent embolization protocol used in our study seems to be favorable, with a median survival of 69 months. Similar survival rates have been reported only by Mitty et al. [27] with polyvinyl alcohol or Gelfoam embolization, but in this study, the survival time was assessed after primary onset of symptoms.
A possible explanation for the beneficial effect on survival rates of the embolization protocol used in our series could be the permanent occlusion of both the proximal and the peripheral tumor-feeding arteries, which should lead to a more complete tumor ischemia.
Most patients showed mild to moderate symptoms of postembolization syndrome, indicated by abdominal pain, nausea, or transient elevation of liver enzyme levels after intervention. Postembolization syndrome was found to be more severe after the initial embolization and tended to decrease afterward. Symptoms were successfully treated symptomatically. Major side effects that required prolonged hospitalization and medical treatment were seen after one intervention (1.3%). In this patient, the external iliac artery was dissected at the arterial puncture. Although this complication was treatment-related, it was not primarily related to the embolic agent itself but to the invasive nature of this treatment modality. The rate of major side effects reported in the literature ranges between 11% [10] and 21% [4].
Again, the mortality rate in our population was comparable with that previously reported: the 30-day mortality rate after 75 transarterial embolizations in our group was 8.6%. One male patient died because of extended liver cell necrosis followed by acute liver failure 6 days after the third embolization. The reason for this death is still unknown because only small feeding arteries were embolized in the third treatment session, and the portal venous system was proven to be patent before embolization. Another 75-year-old patient died 28 days after his first embolization. Autopsy revealed generalized metastasis, and the tumor volume within the liver was found to exceed 75% of the liver volume. According to the previously published data by Brown et al. [13], who reported treatment-related deaths in four patients (representing a mortality rate of 11%) in whom there was hepatic replacement of 75% or more, this treatment should not be used for palliation in case of generalized disease because of the risk of subsequent acute liver failure. Similar to the requirements of surgery, a hepatic reserve should be guaranteed before embolization. In case of extensive metastatic disease, hepatic arterial embolization seems to be dangerous and should be avoided.
Carrasco et al. [9] reported the death of two of 25 patients within the first 30 days after an interventional procedure, and in another study [10], severe complications led to death in 6% of the patients.
Necrotic cholecystitis and sclerosing cholangitis after embolization were reported in several studies [4, 11]. With the multimodality protocol presented in this study, cholecystectomy was routinely performed during the initial surgery for two reasons: long-term administration of octreotide results in high-risk for cholecystolithiasis, and accidental occlusion of the cystic artery during hepatic embolization could lead to necrotic cholecystitis, necessitating acute cholecystectomy.
A limitation of our study is the retrospective study design. However, because of the slow growth and the relatively low incidence rate of neuroendocrine carcinomas of the small bowel, inclusion of a large study population in a single institution in a prospective fashion would be difficult. Although designed retrospectively, this study evaluated permanent transarterial embolization of liver metastases from the small bowel as part of a multimodality treatment protocol in a large group of patients with advanced disease. The data suggest a benefit for multimodality treatment, including an advantage for transarterial embolization compared with treatment without transarterial embolization.
In our study, a more aggressive treatment approach for advanced functional neuroendocrine tumors was reported, including transarterial embolization of liver metastases regardless of the presence or lack of symptoms from hormonal tumor products after resection of the primary tumor. Therefore, treatment success was estimated only by morphologic criteria because indication for embolization was made independent of symptoms. This approach represents a distinct difference from most of the recently published studies.
The use of cyanoacrylate as an embolic agent for liver tumor embolization is still not approved by the United States Food And Drug Administration; however, in our study, we could confirm the safety of this agent as indicated by previous reports [10, 17, 30].
Another disadvantage could be the fact that a reintervention might not be technically feasible after the permanent embolization of all hepatic arteries. Nevertheless, disease control could be achieved in all patients for a substantial time after detection of metastatic disease with a small number of interventions. An explanation for the favorable effect of transarterial chemoembolization using a mixture of cyanoacrylate and Lipiodol might be the more peripheral embolization, which leads to almost complete tumor ischemia and prevention of collateral blood supply. Furthermore, because the permanent transarterial embolization was performed as part of a multimodality treatment schedule, including radical resection of the primary tumor followed by treatment of the liver metastases, the possibility of tumor seeding via the portal vein seems to be of less importance after resection of the primary tumor. Therefore, occlusion of the hepatic arteries, complicating endovascular access for reembolization, was not a problem in the study population presented in this study. Nevertheless, permanent embolization could be critical in patients in whom the primary tumor remains in situ and tumor seeding via the portal vein is still an issue; therefore, this treatment should be recommended only as part of a multimodality approach such as we presented.
In conclusion, permanent transarterial embolization using cyanoacrylate and Lipiodol is a safe and effective technique for the treatment of liver metastases of gastrointestinal neuroendocrine tumors. The addition of transarterial embolization to a multimodality treatment protocol for neuroendocrine tumors seems to be beneficial for mid- and long-term survival of patients having advanced and functional tumors. However, further prospective studies are warranted to confirm the positive effects on survival over time.
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on dotted lines). Numbers ([UNK] on solid line)
are numbers of patients alive at time of writing.
