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Original Research |
1 Division of Interventional Radiology, Mallinckrodt Institute of Radiology,
Washington University School of Medicine, 510 S Kingshighway Blvd., Box 8131,
Saint Louis, MO 63110.
2 Department of Internal Medicine, Washington University School of Medicine,
Saint Louis, MO.
3 Siteman Cancer Center, Washington University School of Medicine, Saint Louis,
MO.
Received July 18, 2006;
accepted after revision October 31, 2006.
This study was not supported by government or corporate grants or
funding.
Abstract
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MATERIALS AND METHODS. Forty-six patients with carcinoid (n = 31) or islet cell (n = 15) tumors were treated. Overall and progression-free survival times starting with the first treatment were calculated. Potential factors affecting survival, including presence of extrahepatic disease and resection of the primary lesion, were analyzed. Relief of symptoms was subjectively determined for tumors with hormonal secretion.
RESULTS. The 46 patients underwent 93 hepatic artery chemoembolization or HAE sessions. The mean overall survival time for the entire group was 1,273 ± 185 days. The mean overall survival times for the carcinoid (1,255 ± 163 days) and islet cell tumor (1,311 ± 403 days) subgroups were similar (p = 0.66). The progression-free survival times for the carcinoid (602 ± 144 days) and islet cell (501 ± 107 days) tumor subgroups also were similar (p = 0.72). The survival time of patients without known extrahepatic metastasis (n = 18; 1,571 ± 291 days) trended toward significance compared with that of patients with known extrahepatic disease (n = 26; 770 ± 112 days; p = 0.08). Resection of the primary tumor in 19 of 46 patients did not affect survival (resection survival, 1,558 ± 400 days; nonresection survival, 1,000 ± 179 days; p = 0.44). Twenty of 25 patients with hormonally active tumors had relief of symptoms after one cycle of treatment. The 30-day mortality was 4.3%.
CONCLUSION. The overall survival time after hepatic artery chemoembolization or HAE among patients with neuroendocrine tumors is approximately 3.5 years. The progression-free survival time approaches 1.5 years. The presence of extrahepatic metastasis or an unresected primary tumor should not limit the use of hepatic artery chemoembolization or HAE.
Keywords: chemoembolization • digital subtraction angiography • oncology
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Systemic chemotherapy has a limited role in the treatment of patients with neuroendocrine tumors. Carcinoid tumors are essentially resistant to cytotoxic chemotherapy, and islet cell tumors have a response rate ranging from 30% to 70% [10-13]. Many neuroendocrine metastatic lesions in the liver are biologically active and secrete peptides that adversely affect the activities of daily life. Somatostatin analogues are the initial treatment for control of these hormone-mediated symptoms, but eventually the disease can become resistant [14].
Hepatic arterial chemoembolization with a combination of chemotherapy, ethiodized oil (Ethiodol, Savage Laboratories), and embolization particles or bland hepatic arterial embolization (HAE) are accepted treatment options. There is no definite survival advantage of one treatment technique over the other [7, 15]. Numerous studies have shown that HAE and hepatic artery chemoembolization are effective in controlling hormonal symptoms and reducing tumor size in patients with hepatic metastasis from neuroendocrine tumors [4-7, 9-13, 16-24]. However, published long-term outcomes with HAE and hepatic artery chemoembolization are limited, and most of the studies have had relatively small patient populations [4, 5, 21-26]. Excluding updated publications from the same treatment center, only three previous studies [5, 7, 26], to our knowledge, have shown outcome for more than 3 years with a study population exceeding 30 patients. We describe a long-term outcome experience that includes evaluation of clinical response and survival among patients with neuroendocrine hepatic metastasis treated with HAE or hepatic artery chemoembolization at a single center.
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The decision to perform HAE or hepatic artery chemoembolization was at the discretion of the attending interventional radiologist who performed the procedure. Informed consent for embolization was obtained from all patients. Patients underwent preoperative analysis of renal function (serum creatinine level), liver function (serum bilirubin, albumin, aspartate aminotransferase, and alanine aminotransferase levels), coagulation values (prothrombin time, international normalized ratio, and partial thromboplastin time), and hematologic status (complete blood cell count). Before the procedure, patients were hydrated with 100-150 mL/h of 5% dextrose in normal saline solution. Patients were premedicated with 500 mg IV metronidazole, 10 mg IV dexamethasone, and 16 mg IV ondansetron. For patients with carcinoid tumors, 150 µg subcutaneous octreotide was given before the procedure and every 8 hours afterward.
With the Seldinger technique, initial arteriography of the superior mesenteric artery and celiac axis was performed to ensure portal venous patency and define the hepatic arterial anatomy. Given the diffuse nature of the metastatic tumors, lobar infusions were used for almost all of the treatments. The selected hepatic artery was catheterized, and a chemotherapy mixture of 50 mg cisplatin, 20 mg doxorubicin, and 10 mg mitomycin-C mixed with 10 mL of ethiodized oil was introduced. After injection of the chemotherapy mixture, particle embolization of the artery was begun with 300- to 500-µm polyvinyl alcohol particles or gelfoam powder (Gelfoam, Pharmacia and Upjohn). The end point was relative stasis in the treated artery.
There were minor variations in the chemotherapy regimen. One patient with metastatic gastrinoma was treated with 1.5 mg of vincristine, 20 mg of doxorubicin, and 10 mg of mitomycin-C mixed with gelfoam powder. During the second half of 2005, powdered cisplatin was unavailable. Two patients underwent hepatic artery chemoembolization during that period and were treated with 50 mg of doxorubicin and 10 mg of mitomycin-C as the chemotherapeutic agents.
Patients were hospitalized for 1-4 days (median, 3 days) after the procedure, depending on the severity of postembolization syndrome and the presence of any postprocedural complications. Antibiotics were continued during hospitalization and discontinued when the patients was discharged from the hospital.
One liver lobe was treated during the first hepatic artery chemoembolization or HAE. The patients usually returned 4-6 weeks later for treatment of the contralateral lobe, particularly when bulky disease was present or if hormonal symptoms persisted. The two procedures were categorized as one cycle of hepatic artery chemoembolization or HAE in our study. The timing of subsequent treatment sessions after the initial visit was determined by the severity of the patient's symptoms or tumor status on follow-up imaging. Complications were tracked in our database and assessed with Society of Interventional Radiology standard criteria [27].
Follow-up and Definitions
Overall survival time was defined as the period from the first treatment to
time of death or date of last follow-up visit (January 1, 2006) for patients
alive at the last follow-up evaluation. Progression-free survival time was
defined as the period from the first treatment to the date of progression
determined by the presence of physical symptoms or imaging findings.
Progression of symptoms was documented by the referring oncologist as
worsening of hormonal activity after an initial response to endovascular
therapy. Progression by imaging referred to development of new tumors at
repeated imaging because all patients in the study had multiple metastatic
lesions at diagnosis. Progression referred specifically to intrahepatic
progression because the goal in the care of these patients was to limit
hormonal symptoms or prevent liver failure from an overwhelming metastatic
burden. Progression-free survival time among patients lost to follow-up was
calculated as the last known visit at which symptoms were tracked. In patients
without progression, patients had their progression-free survival censored on
January 1, 2006.
Relief of symptoms was determined for patients with biologically active and bulky tumors. At the first follow-up visit after the initial cycle of therapy, patients were asked whether there was subjective relief of hormonal symptoms or pain. Biochemical markers were not routinely followed for patients without symptoms of hormonal secretion. When these levels were rechecked after hepatic artery chemoembolization or HAE, it was often because of symptom recurrence. Therefore, we did not track hormonal markers as part of this study.
Statistical Analysis
The overall survival time for the entire group and the carcinoid and islet
cell patient subgroups was calculated with the Kaplan-Meier method.
Differences in overall survival time between subgroups were calculated with
the log-rank test. The progression-free survival time for the entire group and
the carcinoid and islet cell patient subgroups also was calculated with the
Kaplan-Meier method. Differences between the subgroups were calculated with
the log-rank test.
Factors potentially affecting survival of the entire population were evaluated with the Kaplan-Meier method. The analysis included difference in survival times with and without resection of the primary tumor and the presence or absence of extrahepatic metastasis at the initial treatment session. When separable, survival among patients with hormonal secretion syndromes was compared with that of patients with symptoms related to tumor bulk. Overall and progression-free survival times for patients treated with octreotide before referral for hepatic artery chemoembolization or HAE versus those not treated with octreotide were calculated with the Kaplan-Meier method.
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The mean and median overall survival times for the entire patient group were 1,273 ± 185 days and 978 days (Fig. 1A). The mean overall survival times for the carcinoid (1,255 ± 163 days) and islet cell (1,311 ± 403 days) tumor subgroups were similar (p = 0.66) (Fig. 1B). Survival probability for the entire group was 80% at 1 year, 66% at 2 years, 41% at 3 years, 38% at 4 years, and 29% at 5 years. For the carcinoid group, the 1-, 2-, 3-, 4-, and 5-year survival probabilities were 86%, 79%, 43%, 38%, and 32%, respectively. The same rates for the islet cell group were 73%, 52%, 52%, 52%, and 35%. The mean and median progression-free survival times for the entire group were 563 ± 99 and 444 days. The mean progression-free survival times for the carcinoid (602 ± 144 days) and islet cell (501 ± 107 days) tumor subgroups were similar (p = 0.72) (Fig. 2).
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Whether patients received octreotide as a standalone measure to control symptoms or disease progression was known for 37 patients. Overall survival time for patients treated with serial octreotide before the initiation of hepatic artery chemoembolization or HAE (n = 18; 992 ± 217 days) was not significantly longer than that of patients who did not receive octreotide as a temporizing measure (n = 19; 733 ± 133 days; p = 0.28). Progression-free survival time was not significantly altered with the use of octreotide (398 ± 87 days with octreotide; 376 ± 65 days without octreotide; p = 0.97).
Symptomatic Response
Clinical response was successfully evaluated for 27 of 29 patients who
underwent hepatic artery chemoembolization or HAE because of symptoms. This
group consisted of 25 patients with hormonal symptoms and four with pain
secondary to capsular distention. One patient died as a result of the
procedure, making evaluation impossible, and one patient had not yet returned
for follow-up evaluation at the conclusion of the study period. Twenty-one
(78%) of the patients evaluated reported relief of symptoms after the initial
cycle of treatment. When evaluated according to tumor type, 18 (78%) of 23
carcinoid patients and three (75%) of four islet cell patients had relief of
the presenting symptoms.
Sixteen (80%) of the 20 carcinoid patients treated for hormonal symptoms had subjective relief of hormonal symptoms after one cycle of therapy. Two (66%) of the three carcinoid patients treated for symptoms related to tumor bulk reported relief of pain. Among patients with islet cell tumors, two (66%) of the three patients treated for hormonal symptoms had relief of symptoms. The condition of the one patient treated for both pain and hormonal symptoms improved. Reduction of the presenting symptom was achieved in a similar manner in patients with and those without extrahepatic disease. Thirteen of 16 patients with extrahepatic disease and seven of nine patients with no sign of extrahepatic disease experienced relief of symptoms after one cycle of hepatic artery chemoembolization or HAE.
Radiologic Response
Baseline and follow-up imaging findings were available for 33 of the 46
patients (22 with carcinoid and 11 with islet cell tumors). None of the
patients had a complete response. Five (23%) of the patients with carcinoid
tumors had a partial response, and five (23%) had a minimal response. Disease
remained stable in seven (32%) and progressed in five (23%) of the patients.
Two (18%) of the patients with islet cell tumors had a partial response, and
three (27%) had a minor response. Disease remained stable in five (45%) and
progressed in one (9%) of the patients.
Complications and Side Effects
All patients experienced some form of postembolization syndrome (fever,
nausea and vomiting, abdominal pain, elevated liver enzyme levels) that
typically lasted 24-72 hours. Complications occurred after nine (9.7%) of the
93 embolization procedures. Eight complications were major, and one was minor.
The minor complication was a groin hematoma that resolved with observation.
The major complications are summarized in
Table 2. Two patients had
infectious complications. One had both chemical pneumonitis and bacteremia,
and one was readmitted to the hospital 3 days after discharge because of fever
and chills. The conditions of both patients improved with antibiotics. One
patient had supraventricular tachycardia 2 days after the procedure and was
treated successfully with a ß-blocker and digoxin. A duodenal ulcer
developed in one patient with gastrinoma and was managed conservatively with
pain control, nasogastric suction, antibiotics, and gastric acid suppression.
Nontargeted embolization was not detected during this procedure, which was
performed before the development of proton pump inhibitors.
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Four deaths occurred within 30 days of treatment, a 4.3% mortality. One patient died of myocardial infarction less than 24 hours after the procedure. Another patient died of hepatic failure secondary to fulminant sepsis 2 days after the procedure. This patient had an indwelling biliary stent, which was not appreciated as a risk factor for infection after hepatic artery chemoembolization in 1992, when the treatment was administered [28]. One patient experienced acute renal failure immediately after the procedure and was discharged in stable condition after 9 days but died 23 days after the procedure. No medical records were available for determining the ultimate cause of death. One patient died 18 days after the procedure, but the cause of death did not appear in the medical record.
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Systemic chemotherapy has had limited success in the treatment of patients with neuroendocrine tumors metastatic to the liver. Many of the trials have been conducted with small patient groups. The results have been limited, only a small portion of patients having an objective response [6, 10]. The benefits are often temporary because resistance to therapy develops quickly [6]. Toxicity also has contributed to poor outcome. Most important, this treatment has not prolonged patient survival.
Other treatments, including long-acting octreotide therapy with or without interferon, are commonly used before arterial therapy is initiated [35, 36]. Use of octreotide and interferon alone or in combination has resulted in limitation of tumor growth 1 year after treatment in more than one half of patients with neuroendocrine tumors, particularly those with midgut tumors, who make up our treatment population [35]. In this study, use of octreotide did not affect progression or survival after hepatic artery chemoembolization or HAE, even though use of octreotide therapy may have led to patients' presenting with more advanced disease. Other authors have not found a significant difference in survival with octreotide treatment before embolization [7]. As biologic therapies reach the limit of benefit, recommended treatments include surgical resection and hepatic artery chemoembolization [15], but most patients present with unresectable disease.
Previous studies of hepatic artery chemoembolization and HAE have shown median survival times of 20-62 months [4, 5, 7, 16, 20]. We found a comparable result, the mean and median overall survival times for the group as a whole being 42 months and 32 months, respectively. In our study, the mean overall survival time of carcinoid patients was similar to that of islet cell patients. This result differs from those in the report on the largest patient series thus far described, in which the survival time of carcinoid patients (33.8 months) was significantly longer than that of islet cell patients (23.2 months) [7]. Other studies have shown a difference in survival. In one study, the mean survival time of a subgroup of 29 patients with midgut carcinoid tumors was 80 months after embolization of metastatic lesions [20].
Previously described factors associated with poor outcome include an intact primary tumor, diffuse liver involvement, and the presence of extrahepatic metastasis (in the setting of islet cell tumors) [7, 37]. In our study population, survival was not adversely affected by the presence of an unresected primary tumor. In addition, the presence of an unresected primary tumor did not lead to a greater number of hepatic artery chemoembolization or HAE sessions. The 27 patients with intact primary tumors underwent an average of 2.1 sessions, and the 19 patients who had undergone resection of the primary tumor underwent an average of 1.9 sessions. We believe that an unresected primary neuroendocrine tumor should not limit use of hepatic artery chemoembolization in the management of hepatic metastasis.
Most of our patient population had advanced disease before undergoing hepatic artery chemoembolization or HAE. In this group, 89% of the patients had diffuse bilobar disease at the time of initial treatment. In contrast, 51% of the patients treated by Gupta et al. [7] had diffuse liver involvement. The diffuse liver involvement in our patient population may have been a contributor to their 4% 30-day mortality.
More than one half (57%) of our population had extrahepatic metastasis. In our group, there was a clear tendency for patients to have a shorter survival period with extrahepatic metastasis, but this value did not reach statistical significance (p = 0.08). Despite this presentation, patients with extrahepatic metastasis survived a mean of 770 days. Patients with extrahepatic metastasis from islet cell tumors had a much shorter survival time (352 ± 130 days) than patients with extrahepatic metastasis from carcinoid tumors (1,026 ± 127 days). Shorter survival in the setting of extrahepatic disease from islet cell metastasis has been found by other investigators [7, 37]. It is possible that with a larger patient population, this difference might have reached statistical significance, particularly in the islet cell subgroup. Sixteen of the patients with extrahepatic metastasis also had symptoms of hormonally active tumors, and 13 reported subjective improvement in the symptoms after treatment.
The limited survival time among patients with extrahepatic disease is worth noting, especially in consultations with patients before the procedure. The ability to diminish intolerable hormonal symptoms, improve quality of life, and survive for approximately 1 year (in the setting of extrahepatic disease from islet cell tumors) makes treatment worthwhile for a great percentage of patients. This situation contrasts to that of patients with primary tumors, such as colorectal carcinoma, that have spread to the liver. Among those patients, the expected survival period with extrahepatic metastasis is as short as 3 months [34]. Given the limited treatment options, we believe that hepatic artery chemoembolization is a reasonable treatment option for patients with extrahepatic metastasis.
The mean progression-free survival time for our entire group was 18.5 months. The mean progression-free survival times were similar for carcinoid and islet cell patients. Our results are similar to the reported progression-free survival time of 22.7 months for carcinoid patients and 16.1 months for islet cell patients [7, 37]. Progression-free survival was achieved by patients with advanced metastatic disease, most of whom had had therapeutic failures. This finding is additional evidence that hepatic artery chemoembolization is a viable treatment after other therapies fail. Intrahepatic progression-free survival times were similar with or without extrahepatic metastasis.
In our study, 85% of patients evaluated for a clinical response had symptoms caused by a hormonal syndrome. A clinical response occurred among 78% of patients with symptoms, a rate similar to that in previous studies [4-6, 20, 21, 23, 38]. These response rates are much higher than those of other existing treatment options, making hepatic artery chemoembolization and HAE the definitive treatments of patients with symptomatic neuroendocrine metastasis. No difference in survival times was found between patients with hormonal symptoms and patients with symptoms related to bulk or rapid growth.
A limitation of our study was the retrospective design with a nonrandomized patient population. Because neuroendocrine tumors are rare in the general population, a prospective study with an adequately sized sample would be nearly impossible. Our sample size was fairly small at 46 patients, which limited the number of patients in certain subgroup analyses. However, this population of patients with neuroendocrine tumors is one of the largest described to date. Different regimens were used in our study to manage metastasis, but a previous study did not show a difference in outcome when a variety of chemotherapeutic agents were used [6]. In addition, other authors [15] have confirmed that the assumption that one treatment method is superior to another remains theoretic and not scientifically proven. Other authors have found no difference in survival with hepatic artery chemoembolization for hepatocellular carcinoma with varying embolic regimens [39]. Whether the addition of chemotherapy to the embolization regimen is helpful remains unresolved. In the largest study to date, the addition of chemotherapy did not apparently increase the survival time among patients with carcinoid tumors, and it may have increased the survival time among patients with islet cell tumors [7].
Our results show that hepatic artery chemoembolization and HAE resulted in average progression-free survival and overall survival times of 1.5 and 3.5 years, respectively, even when most of the patients had extrahepatic metastasis and almost all of the patients had diffuse liver involvement. The presence of extrahepatic metastasis may decrease the overall survival time, but hormonal syndromes are still relieved in most patients after treatment. The presence of extrahepatic metastasis or an unresected primary tumor should not limit use of hepatic artery chemoembolization or HAE.
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