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Liver-Directed Therapies for Metastatic Neuroendocrine Tumors
Hematol Oncol Clin N Am 21 (2007) 545–560
HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA
Liver-Directed Therapies for Metastatic Neuroendocrine Tumors Crain Garrot, MDa,b, Keith Stuart, MDb,c,* a
Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, MA 01805, USA b Harvard Medical School, Boston, MA, USA c Department of Hematology and Oncology, Lahey Clinic, 41 Mall Road, Burlington, MA 01805, USA
N
euroendocrine tumors are a broad group of neoplasms that are believed to derive from primitive neuroectodermal cells that are dispersed throughout the body during embryonic development. As a result, the sites of origin of these tumors are diverse. The biologic behavior of these neoplasms can be variable but they are generally low grade and indolent, such as pancreatic islet cell tumors and carcinoid tumors. These cancers usually arise in the gastrointestinal tract, although bronchopulmonary, ovarian, or thyroid carcinoid tumors are also encountered on occasion. Neuroendocrine malignancies typically have metastasized to the liver by the time of diagnosis and are usually detected because of local symptoms caused by tumor bulk (pain, early satiety, or palpable mass). Ninety-five percent of patients who have carcinoid syndrome already have liver metastases. These masses tend to grow slowly and patients may present with massive tumors causing vague, subclinical symptoms that in retrospect have been present for some time (Fig. 1). Treatment options for neuroendocrine tumors have historically centered around surgical resection. Hepatic metastatic lesions can be resected even if the primary is not identified. Surgical treatment of neuroendocrine tumors is covered elsewhere in this issue. Systemic or biologic therapies are of limited value and are often ineffective, although there is some degree of optimism with recent antiangiogenic approaches. Because hepatic metastases are responsible for most of the morbidity and mortality of these diseases, liver-directed therapies can be of great benefit for those in whom resection is not indicated. Alleviation of symptoms and prolongation of survival are the main goals, although the latter has been more difficult to quantitate.
*Corresponding author. Department of Hematology and Oncology, Lahey Clinic, 41 Mall Road, Burlington, MA 01805. E-mail address: [email protected] (K. Stuart). 0889-8588/07/$ – see front matter doi:10.1016/j.hoc.2007.04.003
ª 2007 Elsevier Inc. All rights reserved. hemonc.theclinics.com
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Fig. 1. CT of a patient who had a large carcinoid tumor who presented with mild vague pain in right upper quadrant and mild fatigue.
Hepatic metastases of neuroendocrine tumors are known to be highly hypervascular. This has led to the development of transarterial hepatic chemoembolization (TACE) as a means of treating this disease with palliative intent. Because of the hypervascularity of these lesions, reported response rates are as high as 70% to 90%. Morbidity is generally tolerable although significant adverse effects are encountered on occasion. Median survival of patients who have neuroendocrine tumors is variable but is generally about 2 years after diagnosis of hepatic metastatic lesions. Because of the extended natural history of these tumors and the lack of an appropriate control group, it is unclear whether there is any significant prolongation of survival. For this reason TACE is often reserved for patients whose tumors are already symptomatic or beginning to grow at a faster rate. Radiofrequency ablation (RFA) is another form of liver-directed therapy used as a means of treating smaller tumors. The growing experience with RFA in hepatocellular carcinoma and colorectal cancer metastases has led to its use in neuroendocrine tumors also. For those patients who present with more limited disease, RFA may be an extremely effective maneuver. In addition, for those lesions previously treated with resection or TACE, RFA may provide adjunctive treatment after regrowth or recurrence. Many alternative therapies may be considered for patients who have liverpredominant disease as noted in Table 1. A partial list of liver-directed treatments includes cryotherapy and percutaneous ethanol injection. There is little published experience of each of these lesser-used modalities and the use of any one of them is generally restricted to a small subset of patients who have hepatic malignancies. Radiation therapy and chemotherapy are used in selected cases but are not discussed here. Liver-directed therapies have a unique role in this class of neoplasms. They afford the ability to target the areas of disease leading to most morbidity and mortality. In the absence of effective systemic therapy, much investigation has focused on developing and testing means of local control to reduce hepatic
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Table 1 Available treatment options for hepatic metastatic neuroendocrine tumors Treatment modality
Limitations
Hepatic lobar resection
Three or fewer lesions, geographically restricted to one lobe Adequate hepatic function, patent portal vein Considerable local toxicity Three or fewer lesions, each <5 cm
Chemoembolization
Thermal ablation (radiofrequency, microwave, laser) Cryotherapy Intralesional ethanol
Conformal radiation Systemic or intra-arterial chemotherapy
Small lesions Rarely done percutaneously Few, small lesions Difficulty viewing during injections Requires multiple sessions Solitary lesion Toxicity, lack of efficacy
deaths. As a result, liver-directed therapies have become paramount in the treatment of neuroendocrine tumors over the last 2 decades and are now widely used procedures to cytoreduce intrahepatic tumor burden, alleviate systemic and local symptoms, and possibly improve survival. CHEMOEMBOLIZATION Rationale Chemoembolization developed conceptually from experience with intra-arterial chemotherapy and embolic therapy. It is well established that primary and secondary liver tumors derive their blood supply from the hepatic artery [1], whereas approximately 50% of the oxygen supply to normal liver is from the portal system [2,3]. In addition, nutrient flow from the hepatic artery to a tumor is twice that from the portal vein [4]. Experiments that gave chemotherapy during surgery demonstrated a 10 times higher intratumoral concentration when given through the hepatic artery rather than the portal vein [5]. This makes arterially directed treatment especially attractive from a delivery and a safety perspective because the tumor can be targeted while the uninvolved liver is spared. Moreover, the pharmacokinetic advantage of locoregional drug administration enhances the theoretic benefit [6–8]. Many drugs exhibit preferential extraction when delivered intrahepatically and they can achieve favorable liver/systemic drug concentration ratios, thus minimizing the systemic toxicities associated with chemotherapy. For instance, hepatic drug exposure has been estimated to be double for doxorubicin, sevenfold greater for cisplatin, eightfold higher for mitomycin, 10 times greater for 5-fluorouracil, and up to 400-fold higher for 5-fluorodeoxyuridine when delivered intrahepatically rather than intravenously [6].
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History and Development More than 50 years ago the vascular characteristics of liver metastases began to be elucidated. This knowledge led to investigation of alternative therapies for liver tumors based on the physiologic and theoretic advantages of a dual blood supply. Markowitz [9] first suggested in 1952 that disruption of the blood supply to hepatic tumors might be a palliative maneuver. Interest in this form of therapy grew in the 1960s when hepatic artery ligation was first attempted in humans and resulted in significant tumor necrosis [10–12]. Carcinoid metastases in particular seemed to respond especially well because of their reliably hypervascular nature. Despite the potential palliative effect, however, this procedure was not commonly performed, perhaps because of the reported operative mortality that ranged between 10% and 40%. Regional arterial infusion chemotherapy using surgically placed catheters was first attempted in the early 1960s [9]. The development of advanced interventional radiologic techniques enabled this idea to advance more rapidly. Percutaneous placement of intra-arterial catheters was subsequently developed and used for patients who had hepatocellular carcinoma and for metastatic lesions [13–15]. The addition of chemotherapy to the embolization mixture also began to evolve [16–19]. Moertel [20] did much to popularize this form of therapy and published the results of 111 patients who had neuroendocrine metastatic lesions treated with hepatic arterial occlusion either by surgical ligation or percutaneous catheter embolization. Hormonal and tumor responses were substantial, with about 80% showing some improvement. Toxicity was daunting, however, and in fact from this cohort Moertel documented a seminal case of a patient who had severe carcinoid crisis induced by hepatic artery ligation. The patient suffered distributive shock attributable to release of massive amounts of vasodilatory substances from the tumor and did not respond to any standard resuscitation measures. Within 2 minutes of receiving a single dose of a somatostatin analog, however, her blood pressure normalized [21]. Octreotide is now administered prophylactically in arterial or surgical procedures for carcinoid tumors to prevent this event. It is still encountered on rare occasion, however, despite prophylactic octreotide. Chemoembolization represents a combination of two partially effective therapies with the aim of improving on both. There are multiple variations on the technique and ingredients, but it has evolved into a common procedure in many institutions worldwide. Early studies demonstrated that extensive tumor necrosis could be produced and radiographic responses were reported as high as 83% [22–27]. Tissue levels of chemotherapy were found to be up to 40 times higher in tumor cells than in the surrounding liver and shown to persist for months [28–31]. Moreover, there is reason to believe that the ischemia and resulting hypoxia induced by the embolization component might actually enhance the cytotoxic action of the chemotherapy. As more reports were published it became clear that despite considerable side effects in the immediate time period surrounding the procedure, chemoembolization was relatively well
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tolerated, it led to significant symptom control, and there was hope that survival might be prolonged. Technique Chemoembolization is performed percutaneously in the angiography suite with the patient under conscious sedation. After infiltrating local anesthesia to the skin and subcutaneous tissues of the vascular access site, the Seldinger technique is used to gain access to the arterial vasculature. An initial diagnostic mesenteric and hepatic arteriography is performed with digital subtraction technique. A superior mesenteric artery injection reveals any hepatic arterial supply originating from this vessel and any problems with patency of the portal vein. The celiac artery is then studied and followed by selective arteriography to the common hepatic artery, then left or right hepatic arteries. It should be noted that larger tumors near the periphery of the liver can recruit arterial supply from the adjacent parietal arteries, such as the phrenic, internal mammary, or intercostal arteries. This may allow recurrence in parts of a previously embolized tumor. It is not possible to evaluate for this at the time of chemoembolization, however, and it is only noted several months or years later when the supplied portion of the tumor begins to grow. It is also noted on occasion that the gastroduodenal artery arises uncomfortably close to the origin of the middle or left hepatic arteries, or that the right gastric artery may arise from the right or common hepatic artery. Coil embolization of these vessels may then be performed to protect the stomach and duodenum from any reflux of the chemoembolic agents [32]. Once the catheter is lodged in the appropriate vessel supplying the tumor, the chemotherapy mixture is injected into the tumor. Many centers use a single agent, such as doxorubicin, whereas others add or substitute other chemotherapy agents, such as cisplatin, mitomycin, or 5-fluorouracil. Lipiodol (ethiodized oil) is a cottonseed oil–based contrast material that is commonly added to the mixture to form a chemoemulsion. This helps to increase the dwell time of the chemotherapy by slowing the arterial flow as the oily chemotherapy mixture flows though the vessels. In addition, it forms tiny micelles that serve to embolize small vessels and capillaries with diameters as small as 5 to 10 microns [33–36]. The chemotherapeutic agents are dissolved in a water-based contrast agent that has a high iodine content and therefore a high specific gravity (about 1.6) that is similar to the oil, allowing easy miscibility. Some centers mix larger embolic particles with the chemotherapy solution to deliver all agents simultaneously. It may produce a better result to perform the particulate embolization separately, however, immediately following delivery of chemoembolization. This allows more control over the arterial flow after complete delivery of chemotherapy is ensured. In this way multiple lesions may be treated simultaneously. The specific agent used for embolization varies by center; plastic particles cause a permanent thrombosis, whereas gelatin foam particles may allow for recanalization of the vessels and retreatment if necessary.
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In most centers patients are admitted to the hospital the day of the procedure for premedication and are hospitalized for a single day. Occasionally patients need an additional night of hospitalization, but this is rare. Patients are usually followed radiographically with a noncontrast CT scan the day after the procedure and subsequently at 1 month to evaluate lipiodol remaining in the treated lesion, which when present indicates successful devascularization of the tumor. Either the presence of necrosis or any diminution in tumor size can be interpreted as a partial response to chemoembolization (Fig. 2). The Benefit of Hypoxia The antitumor effects of intra-arterial chemotherapy and embolization are additive. The mechanism for this is unclear but may revolve around the metabolic changes induced in tumor cells under hypoxic conditions. These metabolic changes may interact with one mechanism by which tumor cells develop resistance to chemotherapy drugs. Many drugs, especially doxorubicin, are actively expelled from tumor cells because of the action of the transmembrane pump P-glycoprotein, the product of the multidrug resistance gene
Fig. 2. CT image of a patient who had large left lobe metastatic carcinoid lesions (A) before chemoembolism, (B) the day after the chemoembolization, and (C) one month after the procedure.
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[36–40]. P-glycoprotein is an ATP-dependent pump, and it is probable that the tissue hypoxia caused by the embolic portion of the procedure causes decreased ATP because of altered cellular metabolism. The likely result is an inhibitory effect on the efflux pump and increased levels of chemotherapy inside the cell. This is considerably important for the population of cells that may have an alternate blood supply (and would survive an ischemic insult) but still suffer hypoxia during and for a short time after the procedure. Higher chemotherapy levels will likely result in enhanced cell kill. This may explain the additive effects of embolization and intra-arterial chemotherapy. Patient Selection and Eligibility for the Procedure Because of the potential toxicity of chemoembolization, especially the local effects caused by hepatic ischemia, strict criteria for eligibility for appropriate patients must be met (Box 1). Generally, adequate hematologic and renal function must be present, and hepatic function should be relatively well preserved. In our center, we have found that patients who have a serum bilirubin greater than 3.0 mg/dL and an albumin less than 2.8 mg/dL have a significantly higher mortality rate. In addition, a patent portal vein is also essential. There are situations, such as a focal tumor with a discrete partial portal thrombosis, that still benefit from chemoembolization in a nonprotocol situation. Adverse Events Given the combination of chemotherapy and hepatic ischemia, side effects are common. There is a postembolization syndrome characterized by abdominal pain, fever, and malaise attributable to hepatocyte and tumor necrosis. Transaminases commonly increase as much as 100-fold, and a leukemoid reaction is commonly seen also. Rarely, patients may develop bacteremia, pneumonia, ascites, renal dysfunction, pleural effusions, arterial desaturations, or encephalopathy. Symptomatic hypothyroidism may occur as a result of the excess iodine load. Intrahepatic abscess or gallbladder ischemia is extremely rare but has been described. An increasing bilirubin level is a sign of irreversible hepatic Box 1: Chemoembolization for metastatic neuroendocrine tumors Indications Rapid enlargement of tumor mass Increasing symptoms of tumor bulk Patient preference for the procedure in lieu of other treatments Criteria Radiographically appropriate tumor Patent portal vein Total bilirubin <3 mg/dL Albumin >2.8 mg/dL Adequate hematologic and renal function
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necrosis and generally occurs in the setting of cirrhosis. In an effort to reduce hepatic toxicity, chemoembolization should be restricted to a single lobe or major branch of the hepatic artery at one time. In addition, acute doxorubicin cardiotoxicity has been described after chemoembolization in a recent case report [41] but this is likely a very rare if not idiosyncratic event. Patients can be brought back after 1 month once toxicities and abnormal chemistries have resolved to complete the procedure in the opposite lobe. Any new lesions can be treated subsequently if patients fulfill the original eligibility criteria. Clinical Experience with Chemoembolization in Neuroendocrine Tumors Neuroendocrine tumors with hepatic metastasis are uncommon in the general population, yet are a common indication for chemoembolization. Because of their slow growth and general hypervascularity, this type of metastasis is ideal for the use of TACE treatment to decrease tumor bulk and palliate symptoms. Morbidity is generally less than in the hepatocellular carcinoma population, because cirrhosis is rarely a complicating factor. As previously noted, median survival in many of these series is at least 2 years, although given the extended natural history of these tumors it is unclear whether this represents a significant prolongation of survival. For this reason, TACE is generally reserved for patients whose tumors are already symptomatic or are beginning to grow at a significant rate. There have been no randomized trials involving chemoembolization for neuroendocrine tumors. The existing literature consists mainly of single center reports of small numbers of patients. Over the last 2 decades many medical centers from around the world have demonstrated some success in treating neuroendocrine tumors with chemoembolization. Our group reported the results of 30 patients in 1994 [42]. All were treated with intra-arterial injection of an emulsification of doxorubicin, lipiodol, and water-soluble contrast followed by embolization with absorbable gelatin powder (Gelfoam). Twentyseven patients exhibited subjective improvement in clinical symptoms. Hormone markers and tumor size were reduced by at least 50% in 79% of patients. After minor responses were included the overall response rate was 92%. The median survival was 24 months. The treatment was tolerated well although the postembolization syndrome occurred in most patients. Some institutions continue to use embolization-only techniques as was reported by Schell and colleagues [43] in 2002. This group treated 24 patients who had metastatic carcinoid disease by giving lipiodol/Gelfoam by way of hepatic intra-arterial embolization. Fourteen patients suffered from carcinoid syndrome with symptoms qualified by a symptom severity score. Endpoints of the study included tumor response, symptom severity, and octreotide dose. Overall 19 patients demonstrated a decrement in tumor size and 4 others achieved stable disease. The mean symptom severity score decreased from 3.8 to 1.4 (P < .0001) and 64% of patients became asymptomatic. Forty-six percent of patients were able to discontinue octreotide. There were no treatment-related serious adverse events or deaths.
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Another report in 2003 from Austria described a small cohort of 14 patients treated with chemoembolization for metastatic neuroendocrine tumors as a first-line therapy [44]. These investigators used doxorubicin emulsified in lipiodol intra-arterial infusion followed by gelatin sponge particle embolization. Liver involvement was less than 50% in most patients and 10 patients had symptoms of carcinoid syndrome. An objective morphologic response was seen in 12 of 14 cases and 7 of 10 patients had resolve of carcinoid syndrome symptoms. The 5- and 10-year survival rates from diagnosis were 83% and 56%, respectively. Three patients were palliated with no further treatment for 55, 69, and 100 months, respectively. In another recent series from Germany, 26 patients who had progressive neuroendocrine tumors were treated with doxorubicin, lipiodol, and contrast followed by Gelfoam embolization [45]. Overall, these patients underwent 62 chemoembolization procedures with successful completion of the procedure in 57 cases. The reason for unsuccessful completion was hepatic artery spasm. The liver tumor burden was greater than 50% in 12 patients. Five patients died within 6 months, all of whom had greater than 75% tumor burden in the liver. Two patients died within 30 days from hepatic failure. The objective morphologic response rate was poor; only 14 patients demonstrated stable disease and 2 patients had regression of disease. The responses were correlated with the degree of lipiodol uptake (>50%) and tumor burden (<50%) of liver parenchyma. In no patients who had >75% of liver involvement was there a response, and survival was worse. This case series included a significant number of very ill patients who had high disease burden and helps to demonstrate the value of selecting patients who will benefit from the procedure. A recent report has been published with retrospective survival data from patients who had undergone aggressive treatment with surgical resection, cryoablation, or chemoembolization, compared with others who received no aggressive treatment (medical therapy) [46]. From 1990 until 2004, 60 patients were documented to have malignant disease with hepatic metastasis. Of these patients, 23 received no aggressive interventional treatment of liver metastases. Resection or cryoablation were used to treat another 19 patients, whereas another 18 patients received chemoembolization with or without resection or cryoablation. The median ages of the groups were comparable. The group receiving chemoembolization had a higher percentage of pancreatic islet cell tumors. The median survival for the cohort receiving medical therapy was 20 months, but was 96 months and 50 months for the groups receiving resection/cryoablation and chemoembolization, respectively. The 5-year survival was 25% for the group receiving medical therapy, but was 72% and 50% for those patients receiving resection/cryoablation or chemoembolization, respectively. Overall, the data are difficult to interpret because of the types of treatments given, but it is clear that those patients opting for aggressive therapy did have a survival advantage. That the group receiving chemoembolization did not have as great a survival likely reflects a selection bias, because this was a retrospective analysis of patients treated over a period of 14 years. In
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addition, there were more pancreatic islet cell tumors in the group receiving chemoembolization. This may have worsened the outcome because of the poor response and survival of this tumor type compared with carcinoid tumors, a trend also noted in the M.D. Anderson Cancer Center data discussed elsewhere in this article. The investigators do report that symptom improvement was noted in 88% of patients treated with chemoembolization, 95% in those treated with surgery/cryoablation and only 42% in patients treated medically. It was also found that >50% liver involvement correlated with a poor outcome and decreased survival (P < .001). The largest and most recent report of patients treated with embolization techniques for metastatic neuroendocrine tumors comes from the M.D. Anderson Cancer Center [47]. In this latest update of this cohort, patients treated with either hepatic artery embolization or hepatic artery chemoembolization were retrospectively analyzed for response rate and survival. A total of 123 patients were included in the study; 69 of these patients had carcinoid tumors and 54 patients had pancreatic islet cell tumors. Outcomes were compiled by tumor type and treatment type. The carcinoid tumors had a higher overall response rate (66% versus 35%, P ¼ .001) and a longer progression-free survival (23 months versus 16 months, P ¼ .046). Overall survival was also significantly longer for the patients who had carcinoid tumors (33.8 months versus 23.2 months, P ¼ .012) compared with patients who had pancreatic islet cell tumors. When outcomes were analyzed by the type of treatment rendered, some differences were noted. Patients who had carcinoid tumors treated with hepatic arterial embolization had a higher response rate than those who had hepatic arterial chemoembolization (81% versus 44%, P ¼ .003). In patients who had pancreatic islet cell tumors the response rate was higher in the chemoembolization group but did not reach statistical significance (50% versus 25%, P ¼ .06). The overall survival and the progression-free survival of patients who had carcinoid or pancreatic islet cell tumors were not significantly different between the two treatment types, although there was a trend favoring slightly longer overall survival and progression-free survival in the groups treated with chemoembolization. The M.D. Anderson data, summarized in Table 2, suggest that carcinoid tumors have improved outcomes compared with pancreatic islet cell tumors. The addition of chemotherapy to embolization did not alter treatment effects in patients who had carcinoid tumors but did result in higher response rates in the patients who had pancreatic islet cell tumors. In each tumor type neither chemoembolization nor simple embolization conferred a significant overall survival or progression-free survival advantage over the other. Personal Experience We have been performing chemoembolization for appropriate patients at our institution since 1988. Patients are carefully selected to include those most likely to benefit. These are generally patients who have liver-predominant disease and symptomatic or rapidly growing tumors who are neither surgical nor
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Table 2 Summary of the M.D. Anderson Cancer Center retrospective data for HAE and HACE by tumor type Response rate Carcinoid
Progression-free survival (mo) Overall survival (mo) Islet cell tumor
Carcinoid
HAE 81% 25% 20.9 HACE 44% 50% 23.9 (P ¼ .003) (P ¼ .06) (P ¼ .99)
Islet cell tumor
Carcinoid
Islet cell tumor
14.1 33.2 18 18.9 33.8 31.5 (P ¼ .49) (P ¼ .35) (P ¼ .84)
Abbreviations: HACE, hepatic artery chemoembolization; HAE, hepatic artery embolization.
RFA candidates. Any potentially resectable lesions are treated with surgery. If the patient understands the risks, has a good performance status, has a patent portal vein, a bilirubin <3.0, an albumin >2.8, and a creatinine <2.0, then chemoembolization is recommended. All patients receive hydration with normal saline and prophylactic medication with lactulose, furosemide, antibiotics, ranitidine, and narcotic analgesics. Most patients are hospitalized for a single night after the procedure for pain control, hydration, and monitoring of hepatic function. We always perform single-lobe embolizations because of the additional morbidity of whole-liver procedures. Patients undergo a noncontrast CT of the abdomen the day after the procedure to identify the location of the lipiodol in the tumor indicating successful devascularization. The scan is repeated 1 month after the procedure. Beginning at 3 months, triphasic scans are obtained to look for evidence of new lesions. Both the presence of necrosis and any diminution in tumor size are interpreted as partial responses to chemoembolization. Approximately 90 patients who have neuroendocrine metastases have been treated successfully with chemoembolization in our institution over the last 15 years. Most recently, 28 patients harboring hepatic neuroendocrine metastases underwent 71 total procedures. Several of them (13) underwent tandem TACE of right and left lobes of the liver treated 4 to 6 weeks apart. Some of this cohort had undergone TACE many years previously and had not needed further procedures until tumor growth was evident. Many patients had thus been diagnosed 5 to 10 years previously. Three patients had first undergone TACE in the mid-1990s. All patients reviewed here have had at least one TACE performed since 2002. Most patients had multiple procedures; only 8 patients had a single TACE. One patient had seven procedures over the years, and another patient had six procedures. Overall, however, 18 patients had 2 to 4 procedures each. Twenty-one patients had carcinoid disease and 7 had other neuroendocrine tumors (VIPoma, glucagonoma, pancreatic islet cell tumor). Symptoms attributable to tumor burden (pain, early satiety, fatigue) or carcinoid syndrome were noted to be present in 22 patients (78%). These symptoms were decreased in severity after treatment with TACE in 15 of these patients (68%). In
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addition, 18 of 26 (69%) evaluable patients demonstrated an objective radiographic response to TACE treatment. Of the 21 patients evaluable for survival, median survival after first TACE procedure was 28 months (range 8 to 158 months) and median survival since diagnosis was 66 months (range 15 to 158 months). Most patients suffered the immediate common adverse effects of fever, chills, fatigue, and abnormal liver function tests and these resolved. Severe adverse effects encountered included thyrotoxicosis/severe fatigue in one patient, portal vein thrombosis and prolonged hepatic failure (eventually resolved) in one patient, hepatic abscess in one patient, and pleural effusions and severe hypoxia in another patient. We continue to recommend TACE to appropriate patients for neuroendocrine hepatic metastases and we work in conjunction with our hepatic surgical specialists and interventional radiology to make this a multidisciplinary approach to each patient. In addition, we frequently use other local therapies, such as RFA and hepatic resection, as they become indicated for patients either before or after chemoembolization. RADIOFREQUENCY ABLATION Given the indolent natural history of neuroendocrine metastases, most of these tumors are discovered only when they are very large or are multiple and symptomatic, limiting the patients’ options to systemic therapy or chemoembolization. There are certainly patients who have more limited disease, however, and these may be suitable for new local modalities such as RFA. In this technique, an electrode is inserted into the tumor percutaneously under ultrasound or CT guidance. It can also be done by laparoscopic or laparotomy means with the use of intraoperative ultrasound. The electrode is placed into the tumor and emits high-frequency radio waves that cause frictional heat generation because of the ionic vibration of tissue particles. Thermal energy is generated, producing temperatures of greater than 60 C that result in tumor destruction. Lesions as large as 5 to 6 cm can be ablated using multi-tipped electrodes, although success may be limited by the anatomic location and neighboring vascular supply of the lesion. Large vessels in close proximity to a lesion treated with RFA may cause inadequate heating of a tumor edge and may result in local relapse. In general, candidate lesions must be fewer than four in number, smaller than 5 cm, accessible percutaneously, and not in contiguity to vascular structures, bowel, or the gall bladder. Although introduced initially for hepatocellular and colorectal cancers, neuroendocrine metastases have recently been evaluated also. The radiofrequency literature is somewhat fraught with anecdotes and descriptive experiences. Any survival conclusions are as tentative as those in the chemoembolization papers, given the long natural history of the disease and the inability to perform randomized trials. Nonetheless, there are several good reports of success in individual patients. Henn and colleagues [48] describe successful relief of
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symptoms in five of seven treated patients, although one patient developed new lesions. Berber described 34 patients treated with laparoscopic RFA: 80% had ‘‘significant’’ symptom control, and 65% had some decrease in their tumor marker [49]. New hepatic lesions developed in 28%, whereas 41% showed no progression of cancer at all. In another recent study of 15 patients, 43 tumors were treated with RFA and at a median follow-up of 2.1 years only two local failures were noted [50]. All these studies report only minimal toxicity that is substantially less than that associated with chemoembolization. Often RFA is used adjunctively with hepatic tumor resection or chemoembolization. CRYOTHERAPY AND PERCUTANEOUS ALCOHOL INJECTION Cryotherapy is yet another means for treating primary or secondary liver tumors. It is not commonly used and there are few published reports detailing outcomes of large numbers of patients. There have been fewer than 50 patients reported in the literature. The procedure is similar to RFA with placement of the cryoprobe into the tumor percutaneously or intraoperatively under ultrasound guidance. The temperature of the cryoprobe is lowered by passage of liquid nitrogen though the uninsulated tip of the cryoprobe. Multiple freeze– thaw cycles are performed and a characteristic ‘‘ice ball’’ is formed. When the size of the ice ball is made larger than the tumor then an adequate treatment margin is assumed. This degree of freezing leads to tumor destruction. The few reports of this procedure indicate it does have efficacy. One study of 19 patients who had neuroendocrine liver metastases revealed a reduction in tumor markers of 80% and dramatically relieved symptoms [51]. In another study of 13 patients, 2 patients have had recurrence at a median follow-up of 13.5 months [52]. Of the 7 patients who had symptoms, a complete response was seen in 5 patients and a partial response was seen in the other 2 patients. Toxicity was minimal except in 2 patients who developed a coagulopathy and had to go back to the operating room; 1 patient developed renal failure and another patient had a pulmonary embolism. There was no in-hospital mortality. Percutaneous ethanol injection has been used to treat hepatocellular carcinoma, but there are few data on its use in neuroendocrine tumor metastases. FUTURE POSSIBILITIES IN LIVER-DIRECTED THERAPY Stereotactic radiosurgery, although previously used for central nervous system tumors, is evolving and beginning to be used for various visceral tumors, including liver tumors. This type of focused radiotherapy may afford the opportunity to deliver tumoricidal doses of radiation while sparing normal liver and avoiding hepatoxicity. Other techniques combining radiation and intra-arterial delivery, such as the use of yttrium-90 glass microspheres or iodine-131 lipiodol, have been reported for hepatocellular cancers but not yet for neuroendocrine tumors. SUMMARY Neuroendocrine tumors, despite being indolent, frequently cause significant morbidity and mortality from hepatic metastatic lesions. It is possible to
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directly target these liver lesions with embolization/chemoembolization, RFA, or other therapies. The observational studies that exist seem to indicate a prolongation of survival. But, more importantly, the liver-directed therapies are able to decrease symptoms in most patients. The value of these therapeutic interventions therefore lies mainly in their palliative capabilities. Coupled with aggressive use of octreotide, local ablative techniques may frequently control symptoms of hormone excess and tumor bulk. Because of the possible adverse effects of these interventions, however, careful patient selection is essential to minimize the morbidity and mortality of the procedures. Malignant neuroendocrine tumors are a rare group of cancers and are probably best cared for in a multidisciplinary fashion with surgery, medical oncology, and interventional radiology. Appropriate timely use of surgical resection, embolization/chemoembolization, RFA, or even chemotherapy may provide many patients with improved quality of life and possibly prolonged survival also. References [1] Breedis C, Young G. The blood supply of neoplasms in the liver. Am J Pathol 1954;30:969. [2] Lein WM, Ackerman NB. The blood supply of experimental liver metastasis. II. A microcirculatory study of the normal and tumor vessels of the liver with the use of perfused silicone rubber. Surgery 1970;68:334. [3] Ackerman NB, Lein WM, Silverman NA. The blood supply of experimental liver metastatses. III. The effects of acute ligation of hepatic artery and portal vein. Surgery 1972;71:636. [4] Ridge JA, Bading JR, et al. Perfision of colorectal hepatic metastasis. Relative distribution of flow from hepatic artery and portal vein. Cancer 1987;59:1547. [5] Sigurdson ER, et al. Tumor and liver drug uptake following hepatic artery and portal vein infusion. J Clin Orthod 1987;5:1836. [6] Ensminger WD, Gvyes JW. Clinical pharmacology of hepatic arterial chemotherapy. Semin Oncol 1983;10:176. [7] Collins JM. Pharmacologic rationale for regional drug delivery. J Clin Orthod 1984;2:498. [8] Eksborg S, Cedermark BJ, Standler HS. Intrahepatic and intravenous administration of Adriamycin—a comparative pharmacokinetic study in patients with malignant liver tumors. Med Oncol Tumor Pharmacother 1985;2:47. [9] Markowitz J. The hepatic artery. Surg Gynecol Obstet 1952;52:644. [10] McDermott WV, Hensle TW. Metastatic carcinoid to the liver treated by hepatic dearterialization. Ann Surg 1974;180:305. [11] Cady B, Oberfield RA. Arterial infusion chemotherapy of hepatoma. Surg Gynecol Obstet 1974;138:381. [12] Claouse ME, Ahmed R, et al. Complications of long-term transbrachial hepatic artery infusion chemotherapy. AJR Am J Roentgenol 1977;129:799. [13] Ramming KP. The effectiveness of hepatic artery infusion in treatment of primary hepatobiliary tumors. Semin Oncol 1983;10:199. [14] Boyse M for the Meta-analysis Group in Cancer. Reappraisal of hepatic arterial infusion in the treatment of non-resectable liver metastasis from colorectal cancer. Meta-analysis Group in Cancer. J Natl Cancer Inst 1996;88:252. [15] Bern MM, McDermott W, Cady B, et al. Intraarterial hepatic infusion and intravenous Adriamycin for treatment of hepatocellular carcinoma: a clinical and pharmacological report. Cancer 1978;42:399. [16] Shepherd FA, Evans WK, Blackstein ME, et al. Hepatic arterial infusion of mitoxantrone in the treatment of primary hepatocellular carcinoma. J Clin Oncol 1987;5:635.
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[17] Lansfield FJ, Ramirez G, Davos HL, et al. Further clinical studies with intrahepatic arterial infusion of 5-fluorouracil. Cancer 1975;36(Suppl 6):2413. [18] Campbell KA, Burns RC, Sitzman JV, et al. Regional chemotherapy devices: effect of experience and anatomy on complications. J Clin Oncol 1993;11:822. [19] Patt YZ, Mavligit GM. Arterial chemotherapy in the management of colorectal cancer: an overview. Semin Oncol 1991;18:478. [20] Moertel CG, Johnston CM, McKusick MA, et al. The management of patients with advanced carcinoid tumors and islet cell carcinomas. Ann Intern Med 1994;120:302. [21] Moertel CG. Karnosfsky Memorial Lecture. An odyssey in a land of small tumors. J Clin Oncol 1987;5:1502. [22] Patt YZ, Chuang VO, Wallace S, et al. Hepatic arterial chemotherapy and occlusion for palliation of primary hepatocellular and unknown primary neoplasms in the liver. Cancer 1983;51:1359. [23] Takayasu K, Shima Y, Muramatsu Y, et al. Hepatocellular carcinoma treatment with intraarterial iodized oil with and without chemotherapeutic agents. Radiology 1987;163:345. [24] Kanematsu T, Inokuchi K, Sugimachi K, et al. Selective effects of lipiodolized antitumor agents. J Surg Oncol 1984;25:218. [25] Okamura J, Horikawa S, Fujiyama T, et al. An appraisal of transcatheter arterial embolization combined with transcatheter artial infusion of chemotherapeutic agents for hepatic malignancies. World J Surg 1982;6:352. [26] Takayasu K, Moriyama N, Muramatsu Y, et al. Hepatic arterial embolization for hepatocellular carcinoma: comparison of CT scans and resected specimens. Radiology 1984;15: 661. [27] Shamamura Y, Gunven P, Takenaka Y, et al. Combined peripheral and central chemoembolization for liver tumors. Experience with lipiodol-doxorubicin and gelatin sponge. Cancer 1988;61:238. [28] Saski Y, Imaoka S, Kasgaih, et al. A new approach to chemoembolization therapy for hepatoma using ethidized oil, cisplatin and gelatin sponge. Cancer 1987;60:1194. [29] Nakamura H, Hashimoto T, Taguchi T, et al [Chemoembolization]. Gan To Kagaku Ryoho 1987;14:1656 [in Japanese]. [30] Kanematsu T, Furuta T, Takenaka K, et al. A 5-year experience of lipiodolization: selective regional chemotherapy for 200 patients with hepatocellular carcinoma. Hepatology 1989;10(1):98–102. [31] Shibata J, Fufiyama S, Sato T, et al. Hepatic arterial injection chemotherapy with cisplatin suspended in an oily lymphographic agent for hepatocellular carcinoma. Cancer 1989;64:1586. [32] Perry LJ, Stuart KE. Hepatic chemoembolization. In: Saini S, Gazelle GS, Mueller PR, editors. Hepatobiliary and pancreatic radiology. New York: Thieme; 1998. p. 448–69. [33] Kruskal JB, Hlatkly L, Hahnfield P, et al. In vivo and in vitro analysis of the effectiveness of doxorubicin combined with temporary arterial occlusion in liver tumors. J Vasc Interv Radiol 1993;4:741. [34] Konno T. Targeting cancer chemotherapeutic agents by use of lipiodol contrast medium. Cancer 1990;66:1897. [35] Kan Z, Ivancev K, Hagerstrand I, et al. In vivo microscopy of the liver after injection of lipiodol into the hepatic artery and portal vein in the rat. Acta Radiol 1989;30:419. [36] Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2002;2(1):48–58. [37] Krishna R, Mayer LD. Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci 2000;11(4):265–83. [38] Stuart K, Perry L, Lewis WD, et al. Prognostic features among patients with hepatocellular carcinoma treated with chemoembolization. Proc Am Soc Clin Oncol 1997;16: 1089a.
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[39] Llado L, Virgili J, Figueras J, et al. A prognostic index of the survival of patients with unresectable hepatocellular carcinoma after trans-catheter arterial chemoembolization. Cancer 2000;88:50. [40] Lopez RR, Pan SH, Hoffman AL, et al. Comparison of transarterial chemoembolization in patients with unresectable diffuse verses focal hepatocellular carcinoma. Arch Surg 2002;137:653. [41] Hayek E, Speakman E, Rehmus E. Acute doxorubicin cardiotoxicity. N Engl J Med 2005;352:2456. [42] Perry L, Stuart K, Stokes K, et al. Hepatic arterial chemoembolization for metastatic neuroendocrine tumors. Surgery 1994;116:1111. [43] Schell S, Camp E, Caridi J, et al. Hepatic artery embolization for control of symptoms, octreotide requirements and tumor progression in metastatic carcinoid tumors. J Gastrointest Surg 2002;6:664. [44] Roche A, Girish A, de Baere T, et al. Trans-catheter arterial chemoembolization as first line treatment for hepatic metastasis from endocrine tumors. Eur Radiol 2003;13:136. [45] Kress O, Wagner H, Wied M, et al. Transarterial chemoembolization of advanced liver metastasis of neuroendocrine tumors—a retrospective single-center analysis. Digestion 2003;68:94. [46] Touzios J, Kiely J, Pitt S, et al. Neuroendocrine hepatic metastasis—does aggressive management improve survival? Ann Surg 2005;241:776. [47] Gupta S, Johnson M, Murthy R, et al. Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors: variables affecting response rates and survival. Cancer 2005;104:1590. [48] Henn AR, Levine EA, McNulty W, Zagoria RJ. Radiofrequency ablation of hepatic metastases for symptomatic relief of neuroendocrine syndromes. Am J Roentgenol 2003;181: 1005–10. [49] Berber E, Flesher N, Siperstein AE. Laparoscopic ablation of neuroendocrine liver metastases. World J Surg 2002;26:985–90. [50] Hellman P, Ladjevardi S, Skogseid B, et al. Radiofrequency tissue ablation using cooled tip for liver metastasis of endocrine tumors. World J Surg 2002;26:1052. [51] Bilichik A, Sarantou T, Foshag L, et al. Cryosurgical palliation of metastatic neuroendocrine tumors resistant to conventional therapy. Surgery 1997;122:1040. [52] Siefert J, Cozzi P, Morris D, et al. Cryotherapy for neuroendocrine liver metastatsis. Semin Surg Oncol 1998;14:175.
HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA
Liver-Directed Therapies for Metastatic Neuroendocrine Tumors Crain Garrot, MDa,b, Keith Stuart, MDb,c,* a
Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, MA 01805, USA b Harvard Medical School, Boston, MA, USA c Department of Hematology and Oncology, Lahey Clinic, 41 Mall Road, Burlington, MA 01805, USA
N
euroendocrine tumors are a broad group of neoplasms that are believed to derive from primitive neuroectodermal cells that are dispersed throughout the body during embryonic development. As a result, the sites of origin of these tumors are diverse. The biologic behavior of these neoplasms can be variable but they are generally low grade and indolent, such as pancreatic islet cell tumors and carcinoid tumors. These cancers usually arise in the gastrointestinal tract, although bronchopulmonary, ovarian, or thyroid carcinoid tumors are also encountered on occasion. Neuroendocrine malignancies typically have metastasized to the liver by the time of diagnosis and are usually detected because of local symptoms caused by tumor bulk (pain, early satiety, or palpable mass). Ninety-five percent of patients who have carcinoid syndrome already have liver metastases. These masses tend to grow slowly and patients may present with massive tumors causing vague, subclinical symptoms that in retrospect have been present for some time (Fig. 1). Treatment options for neuroendocrine tumors have historically centered around surgical resection. Hepatic metastatic lesions can be resected even if the primary is not identified. Surgical treatment of neuroendocrine tumors is covered elsewhere in this issue. Systemic or biologic therapies are of limited value and are often ineffective, although there is some degree of optimism with recent antiangiogenic approaches. Because hepatic metastases are responsible for most of the morbidity and mortality of these diseases, liver-directed therapies can be of great benefit for those in whom resection is not indicated. Alleviation of symptoms and prolongation of survival are the main goals, although the latter has been more difficult to quantitate.
*Corresponding author. Department of Hematology and Oncology, Lahey Clinic, 41 Mall Road, Burlington, MA 01805. E-mail address: [email protected] (K. Stuart). 0889-8588/07/$ – see front matter doi:10.1016/j.hoc.2007.04.003
ª 2007 Elsevier Inc. All rights reserved. hemonc.theclinics.com
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Fig. 1. CT of a patient who had a large carcinoid tumor who presented with mild vague pain in right upper quadrant and mild fatigue.
Hepatic metastases of neuroendocrine tumors are known to be highly hypervascular. This has led to the development of transarterial hepatic chemoembolization (TACE) as a means of treating this disease with palliative intent. Because of the hypervascularity of these lesions, reported response rates are as high as 70% to 90%. Morbidity is generally tolerable although significant adverse effects are encountered on occasion. Median survival of patients who have neuroendocrine tumors is variable but is generally about 2 years after diagnosis of hepatic metastatic lesions. Because of the extended natural history of these tumors and the lack of an appropriate control group, it is unclear whether there is any significant prolongation of survival. For this reason TACE is often reserved for patients whose tumors are already symptomatic or beginning to grow at a faster rate. Radiofrequency ablation (RFA) is another form of liver-directed therapy used as a means of treating smaller tumors. The growing experience with RFA in hepatocellular carcinoma and colorectal cancer metastases has led to its use in neuroendocrine tumors also. For those patients who present with more limited disease, RFA may be an extremely effective maneuver. In addition, for those lesions previously treated with resection or TACE, RFA may provide adjunctive treatment after regrowth or recurrence. Many alternative therapies may be considered for patients who have liverpredominant disease as noted in Table 1. A partial list of liver-directed treatments includes cryotherapy and percutaneous ethanol injection. There is little published experience of each of these lesser-used modalities and the use of any one of them is generally restricted to a small subset of patients who have hepatic malignancies. Radiation therapy and chemotherapy are used in selected cases but are not discussed here. Liver-directed therapies have a unique role in this class of neoplasms. They afford the ability to target the areas of disease leading to most morbidity and mortality. In the absence of effective systemic therapy, much investigation has focused on developing and testing means of local control to reduce hepatic
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Table 1 Available treatment options for hepatic metastatic neuroendocrine tumors Treatment modality
Limitations
Hepatic lobar resection
Three or fewer lesions, geographically restricted to one lobe Adequate hepatic function, patent portal vein Considerable local toxicity Three or fewer lesions, each <5 cm
Chemoembolization
Thermal ablation (radiofrequency, microwave, laser) Cryotherapy Intralesional ethanol
Conformal radiation Systemic or intra-arterial chemotherapy
Small lesions Rarely done percutaneously Few, small lesions Difficulty viewing during injections Requires multiple sessions Solitary lesion Toxicity, lack of efficacy
deaths. As a result, liver-directed therapies have become paramount in the treatment of neuroendocrine tumors over the last 2 decades and are now widely used procedures to cytoreduce intrahepatic tumor burden, alleviate systemic and local symptoms, and possibly improve survival. CHEMOEMBOLIZATION Rationale Chemoembolization developed conceptually from experience with intra-arterial chemotherapy and embolic therapy. It is well established that primary and secondary liver tumors derive their blood supply from the hepatic artery [1], whereas approximately 50% of the oxygen supply to normal liver is from the portal system [2,3]. In addition, nutrient flow from the hepatic artery to a tumor is twice that from the portal vein [4]. Experiments that gave chemotherapy during surgery demonstrated a 10 times higher intratumoral concentration when given through the hepatic artery rather than the portal vein [5]. This makes arterially directed treatment especially attractive from a delivery and a safety perspective because the tumor can be targeted while the uninvolved liver is spared. Moreover, the pharmacokinetic advantage of locoregional drug administration enhances the theoretic benefit [6–8]. Many drugs exhibit preferential extraction when delivered intrahepatically and they can achieve favorable liver/systemic drug concentration ratios, thus minimizing the systemic toxicities associated with chemotherapy. For instance, hepatic drug exposure has been estimated to be double for doxorubicin, sevenfold greater for cisplatin, eightfold higher for mitomycin, 10 times greater for 5-fluorouracil, and up to 400-fold higher for 5-fluorodeoxyuridine when delivered intrahepatically rather than intravenously [6].
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History and Development More than 50 years ago the vascular characteristics of liver metastases began to be elucidated. This knowledge led to investigation of alternative therapies for liver tumors based on the physiologic and theoretic advantages of a dual blood supply. Markowitz [9] first suggested in 1952 that disruption of the blood supply to hepatic tumors might be a palliative maneuver. Interest in this form of therapy grew in the 1960s when hepatic artery ligation was first attempted in humans and resulted in significant tumor necrosis [10–12]. Carcinoid metastases in particular seemed to respond especially well because of their reliably hypervascular nature. Despite the potential palliative effect, however, this procedure was not commonly performed, perhaps because of the reported operative mortality that ranged between 10% and 40%. Regional arterial infusion chemotherapy using surgically placed catheters was first attempted in the early 1960s [9]. The development of advanced interventional radiologic techniques enabled this idea to advance more rapidly. Percutaneous placement of intra-arterial catheters was subsequently developed and used for patients who had hepatocellular carcinoma and for metastatic lesions [13–15]. The addition of chemotherapy to the embolization mixture also began to evolve [16–19]. Moertel [20] did much to popularize this form of therapy and published the results of 111 patients who had neuroendocrine metastatic lesions treated with hepatic arterial occlusion either by surgical ligation or percutaneous catheter embolization. Hormonal and tumor responses were substantial, with about 80% showing some improvement. Toxicity was daunting, however, and in fact from this cohort Moertel documented a seminal case of a patient who had severe carcinoid crisis induced by hepatic artery ligation. The patient suffered distributive shock attributable to release of massive amounts of vasodilatory substances from the tumor and did not respond to any standard resuscitation measures. Within 2 minutes of receiving a single dose of a somatostatin analog, however, her blood pressure normalized [21]. Octreotide is now administered prophylactically in arterial or surgical procedures for carcinoid tumors to prevent this event. It is still encountered on rare occasion, however, despite prophylactic octreotide. Chemoembolization represents a combination of two partially effective therapies with the aim of improving on both. There are multiple variations on the technique and ingredients, but it has evolved into a common procedure in many institutions worldwide. Early studies demonstrated that extensive tumor necrosis could be produced and radiographic responses were reported as high as 83% [22–27]. Tissue levels of chemotherapy were found to be up to 40 times higher in tumor cells than in the surrounding liver and shown to persist for months [28–31]. Moreover, there is reason to believe that the ischemia and resulting hypoxia induced by the embolization component might actually enhance the cytotoxic action of the chemotherapy. As more reports were published it became clear that despite considerable side effects in the immediate time period surrounding the procedure, chemoembolization was relatively well
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tolerated, it led to significant symptom control, and there was hope that survival might be prolonged. Technique Chemoembolization is performed percutaneously in the angiography suite with the patient under conscious sedation. After infiltrating local anesthesia to the skin and subcutaneous tissues of the vascular access site, the Seldinger technique is used to gain access to the arterial vasculature. An initial diagnostic mesenteric and hepatic arteriography is performed with digital subtraction technique. A superior mesenteric artery injection reveals any hepatic arterial supply originating from this vessel and any problems with patency of the portal vein. The celiac artery is then studied and followed by selective arteriography to the common hepatic artery, then left or right hepatic arteries. It should be noted that larger tumors near the periphery of the liver can recruit arterial supply from the adjacent parietal arteries, such as the phrenic, internal mammary, or intercostal arteries. This may allow recurrence in parts of a previously embolized tumor. It is not possible to evaluate for this at the time of chemoembolization, however, and it is only noted several months or years later when the supplied portion of the tumor begins to grow. It is also noted on occasion that the gastroduodenal artery arises uncomfortably close to the origin of the middle or left hepatic arteries, or that the right gastric artery may arise from the right or common hepatic artery. Coil embolization of these vessels may then be performed to protect the stomach and duodenum from any reflux of the chemoembolic agents [32]. Once the catheter is lodged in the appropriate vessel supplying the tumor, the chemotherapy mixture is injected into the tumor. Many centers use a single agent, such as doxorubicin, whereas others add or substitute other chemotherapy agents, such as cisplatin, mitomycin, or 5-fluorouracil. Lipiodol (ethiodized oil) is a cottonseed oil–based contrast material that is commonly added to the mixture to form a chemoemulsion. This helps to increase the dwell time of the chemotherapy by slowing the arterial flow as the oily chemotherapy mixture flows though the vessels. In addition, it forms tiny micelles that serve to embolize small vessels and capillaries with diameters as small as 5 to 10 microns [33–36]. The chemotherapeutic agents are dissolved in a water-based contrast agent that has a high iodine content and therefore a high specific gravity (about 1.6) that is similar to the oil, allowing easy miscibility. Some centers mix larger embolic particles with the chemotherapy solution to deliver all agents simultaneously. It may produce a better result to perform the particulate embolization separately, however, immediately following delivery of chemoembolization. This allows more control over the arterial flow after complete delivery of chemotherapy is ensured. In this way multiple lesions may be treated simultaneously. The specific agent used for embolization varies by center; plastic particles cause a permanent thrombosis, whereas gelatin foam particles may allow for recanalization of the vessels and retreatment if necessary.
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In most centers patients are admitted to the hospital the day of the procedure for premedication and are hospitalized for a single day. Occasionally patients need an additional night of hospitalization, but this is rare. Patients are usually followed radiographically with a noncontrast CT scan the day after the procedure and subsequently at 1 month to evaluate lipiodol remaining in the treated lesion, which when present indicates successful devascularization of the tumor. Either the presence of necrosis or any diminution in tumor size can be interpreted as a partial response to chemoembolization (Fig. 2). The Benefit of Hypoxia The antitumor effects of intra-arterial chemotherapy and embolization are additive. The mechanism for this is unclear but may revolve around the metabolic changes induced in tumor cells under hypoxic conditions. These metabolic changes may interact with one mechanism by which tumor cells develop resistance to chemotherapy drugs. Many drugs, especially doxorubicin, are actively expelled from tumor cells because of the action of the transmembrane pump P-glycoprotein, the product of the multidrug resistance gene
Fig. 2. CT image of a patient who had large left lobe metastatic carcinoid lesions (A) before chemoembolism, (B) the day after the chemoembolization, and (C) one month after the procedure.
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[36–40]. P-glycoprotein is an ATP-dependent pump, and it is probable that the tissue hypoxia caused by the embolic portion of the procedure causes decreased ATP because of altered cellular metabolism. The likely result is an inhibitory effect on the efflux pump and increased levels of chemotherapy inside the cell. This is considerably important for the population of cells that may have an alternate blood supply (and would survive an ischemic insult) but still suffer hypoxia during and for a short time after the procedure. Higher chemotherapy levels will likely result in enhanced cell kill. This may explain the additive effects of embolization and intra-arterial chemotherapy. Patient Selection and Eligibility for the Procedure Because of the potential toxicity of chemoembolization, especially the local effects caused by hepatic ischemia, strict criteria for eligibility for appropriate patients must be met (Box 1). Generally, adequate hematologic and renal function must be present, and hepatic function should be relatively well preserved. In our center, we have found that patients who have a serum bilirubin greater than 3.0 mg/dL and an albumin less than 2.8 mg/dL have a significantly higher mortality rate. In addition, a patent portal vein is also essential. There are situations, such as a focal tumor with a discrete partial portal thrombosis, that still benefit from chemoembolization in a nonprotocol situation. Adverse Events Given the combination of chemotherapy and hepatic ischemia, side effects are common. There is a postembolization syndrome characterized by abdominal pain, fever, and malaise attributable to hepatocyte and tumor necrosis. Transaminases commonly increase as much as 100-fold, and a leukemoid reaction is commonly seen also. Rarely, patients may develop bacteremia, pneumonia, ascites, renal dysfunction, pleural effusions, arterial desaturations, or encephalopathy. Symptomatic hypothyroidism may occur as a result of the excess iodine load. Intrahepatic abscess or gallbladder ischemia is extremely rare but has been described. An increasing bilirubin level is a sign of irreversible hepatic Box 1: Chemoembolization for metastatic neuroendocrine tumors Indications Rapid enlargement of tumor mass Increasing symptoms of tumor bulk Patient preference for the procedure in lieu of other treatments Criteria Radiographically appropriate tumor Patent portal vein Total bilirubin <3 mg/dL Albumin >2.8 mg/dL Adequate hematologic and renal function
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necrosis and generally occurs in the setting of cirrhosis. In an effort to reduce hepatic toxicity, chemoembolization should be restricted to a single lobe or major branch of the hepatic artery at one time. In addition, acute doxorubicin cardiotoxicity has been described after chemoembolization in a recent case report [41] but this is likely a very rare if not idiosyncratic event. Patients can be brought back after 1 month once toxicities and abnormal chemistries have resolved to complete the procedure in the opposite lobe. Any new lesions can be treated subsequently if patients fulfill the original eligibility criteria. Clinical Experience with Chemoembolization in Neuroendocrine Tumors Neuroendocrine tumors with hepatic metastasis are uncommon in the general population, yet are a common indication for chemoembolization. Because of their slow growth and general hypervascularity, this type of metastasis is ideal for the use of TACE treatment to decrease tumor bulk and palliate symptoms. Morbidity is generally less than in the hepatocellular carcinoma population, because cirrhosis is rarely a complicating factor. As previously noted, median survival in many of these series is at least 2 years, although given the extended natural history of these tumors it is unclear whether this represents a significant prolongation of survival. For this reason, TACE is generally reserved for patients whose tumors are already symptomatic or are beginning to grow at a significant rate. There have been no randomized trials involving chemoembolization for neuroendocrine tumors. The existing literature consists mainly of single center reports of small numbers of patients. Over the last 2 decades many medical centers from around the world have demonstrated some success in treating neuroendocrine tumors with chemoembolization. Our group reported the results of 30 patients in 1994 [42]. All were treated with intra-arterial injection of an emulsification of doxorubicin, lipiodol, and water-soluble contrast followed by embolization with absorbable gelatin powder (Gelfoam). Twentyseven patients exhibited subjective improvement in clinical symptoms. Hormone markers and tumor size were reduced by at least 50% in 79% of patients. After minor responses were included the overall response rate was 92%. The median survival was 24 months. The treatment was tolerated well although the postembolization syndrome occurred in most patients. Some institutions continue to use embolization-only techniques as was reported by Schell and colleagues [43] in 2002. This group treated 24 patients who had metastatic carcinoid disease by giving lipiodol/Gelfoam by way of hepatic intra-arterial embolization. Fourteen patients suffered from carcinoid syndrome with symptoms qualified by a symptom severity score. Endpoints of the study included tumor response, symptom severity, and octreotide dose. Overall 19 patients demonstrated a decrement in tumor size and 4 others achieved stable disease. The mean symptom severity score decreased from 3.8 to 1.4 (P < .0001) and 64% of patients became asymptomatic. Forty-six percent of patients were able to discontinue octreotide. There were no treatment-related serious adverse events or deaths.
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Another report in 2003 from Austria described a small cohort of 14 patients treated with chemoembolization for metastatic neuroendocrine tumors as a first-line therapy [44]. These investigators used doxorubicin emulsified in lipiodol intra-arterial infusion followed by gelatin sponge particle embolization. Liver involvement was less than 50% in most patients and 10 patients had symptoms of carcinoid syndrome. An objective morphologic response was seen in 12 of 14 cases and 7 of 10 patients had resolve of carcinoid syndrome symptoms. The 5- and 10-year survival rates from diagnosis were 83% and 56%, respectively. Three patients were palliated with no further treatment for 55, 69, and 100 months, respectively. In another recent series from Germany, 26 patients who had progressive neuroendocrine tumors were treated with doxorubicin, lipiodol, and contrast followed by Gelfoam embolization [45]. Overall, these patients underwent 62 chemoembolization procedures with successful completion of the procedure in 57 cases. The reason for unsuccessful completion was hepatic artery spasm. The liver tumor burden was greater than 50% in 12 patients. Five patients died within 6 months, all of whom had greater than 75% tumor burden in the liver. Two patients died within 30 days from hepatic failure. The objective morphologic response rate was poor; only 14 patients demonstrated stable disease and 2 patients had regression of disease. The responses were correlated with the degree of lipiodol uptake (>50%) and tumor burden (<50%) of liver parenchyma. In no patients who had >75% of liver involvement was there a response, and survival was worse. This case series included a significant number of very ill patients who had high disease burden and helps to demonstrate the value of selecting patients who will benefit from the procedure. A recent report has been published with retrospective survival data from patients who had undergone aggressive treatment with surgical resection, cryoablation, or chemoembolization, compared with others who received no aggressive treatment (medical therapy) [46]. From 1990 until 2004, 60 patients were documented to have malignant disease with hepatic metastasis. Of these patients, 23 received no aggressive interventional treatment of liver metastases. Resection or cryoablation were used to treat another 19 patients, whereas another 18 patients received chemoembolization with or without resection or cryoablation. The median ages of the groups were comparable. The group receiving chemoembolization had a higher percentage of pancreatic islet cell tumors. The median survival for the cohort receiving medical therapy was 20 months, but was 96 months and 50 months for the groups receiving resection/cryoablation and chemoembolization, respectively. The 5-year survival was 25% for the group receiving medical therapy, but was 72% and 50% for those patients receiving resection/cryoablation or chemoembolization, respectively. Overall, the data are difficult to interpret because of the types of treatments given, but it is clear that those patients opting for aggressive therapy did have a survival advantage. That the group receiving chemoembolization did not have as great a survival likely reflects a selection bias, because this was a retrospective analysis of patients treated over a period of 14 years. In
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addition, there were more pancreatic islet cell tumors in the group receiving chemoembolization. This may have worsened the outcome because of the poor response and survival of this tumor type compared with carcinoid tumors, a trend also noted in the M.D. Anderson Cancer Center data discussed elsewhere in this article. The investigators do report that symptom improvement was noted in 88% of patients treated with chemoembolization, 95% in those treated with surgery/cryoablation and only 42% in patients treated medically. It was also found that >50% liver involvement correlated with a poor outcome and decreased survival (P < .001). The largest and most recent report of patients treated with embolization techniques for metastatic neuroendocrine tumors comes from the M.D. Anderson Cancer Center [47]. In this latest update of this cohort, patients treated with either hepatic artery embolization or hepatic artery chemoembolization were retrospectively analyzed for response rate and survival. A total of 123 patients were included in the study; 69 of these patients had carcinoid tumors and 54 patients had pancreatic islet cell tumors. Outcomes were compiled by tumor type and treatment type. The carcinoid tumors had a higher overall response rate (66% versus 35%, P ¼ .001) and a longer progression-free survival (23 months versus 16 months, P ¼ .046). Overall survival was also significantly longer for the patients who had carcinoid tumors (33.8 months versus 23.2 months, P ¼ .012) compared with patients who had pancreatic islet cell tumors. When outcomes were analyzed by the type of treatment rendered, some differences were noted. Patients who had carcinoid tumors treated with hepatic arterial embolization had a higher response rate than those who had hepatic arterial chemoembolization (81% versus 44%, P ¼ .003). In patients who had pancreatic islet cell tumors the response rate was higher in the chemoembolization group but did not reach statistical significance (50% versus 25%, P ¼ .06). The overall survival and the progression-free survival of patients who had carcinoid or pancreatic islet cell tumors were not significantly different between the two treatment types, although there was a trend favoring slightly longer overall survival and progression-free survival in the groups treated with chemoembolization. The M.D. Anderson data, summarized in Table 2, suggest that carcinoid tumors have improved outcomes compared with pancreatic islet cell tumors. The addition of chemotherapy to embolization did not alter treatment effects in patients who had carcinoid tumors but did result in higher response rates in the patients who had pancreatic islet cell tumors. In each tumor type neither chemoembolization nor simple embolization conferred a significant overall survival or progression-free survival advantage over the other. Personal Experience We have been performing chemoembolization for appropriate patients at our institution since 1988. Patients are carefully selected to include those most likely to benefit. These are generally patients who have liver-predominant disease and symptomatic or rapidly growing tumors who are neither surgical nor
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Table 2 Summary of the M.D. Anderson Cancer Center retrospective data for HAE and HACE by tumor type Response rate Carcinoid
Progression-free survival (mo) Overall survival (mo) Islet cell tumor
Carcinoid
HAE 81% 25% 20.9 HACE 44% 50% 23.9 (P ¼ .003) (P ¼ .06) (P ¼ .99)
Islet cell tumor
Carcinoid
Islet cell tumor
14.1 33.2 18 18.9 33.8 31.5 (P ¼ .49) (P ¼ .35) (P ¼ .84)
Abbreviations: HACE, hepatic artery chemoembolization; HAE, hepatic artery embolization.
RFA candidates. Any potentially resectable lesions are treated with surgery. If the patient understands the risks, has a good performance status, has a patent portal vein, a bilirubin <3.0, an albumin >2.8, and a creatinine <2.0, then chemoembolization is recommended. All patients receive hydration with normal saline and prophylactic medication with lactulose, furosemide, antibiotics, ranitidine, and narcotic analgesics. Most patients are hospitalized for a single night after the procedure for pain control, hydration, and monitoring of hepatic function. We always perform single-lobe embolizations because of the additional morbidity of whole-liver procedures. Patients undergo a noncontrast CT of the abdomen the day after the procedure to identify the location of the lipiodol in the tumor indicating successful devascularization. The scan is repeated 1 month after the procedure. Beginning at 3 months, triphasic scans are obtained to look for evidence of new lesions. Both the presence of necrosis and any diminution in tumor size are interpreted as partial responses to chemoembolization. Approximately 90 patients who have neuroendocrine metastases have been treated successfully with chemoembolization in our institution over the last 15 years. Most recently, 28 patients harboring hepatic neuroendocrine metastases underwent 71 total procedures. Several of them (13) underwent tandem TACE of right and left lobes of the liver treated 4 to 6 weeks apart. Some of this cohort had undergone TACE many years previously and had not needed further procedures until tumor growth was evident. Many patients had thus been diagnosed 5 to 10 years previously. Three patients had first undergone TACE in the mid-1990s. All patients reviewed here have had at least one TACE performed since 2002. Most patients had multiple procedures; only 8 patients had a single TACE. One patient had seven procedures over the years, and another patient had six procedures. Overall, however, 18 patients had 2 to 4 procedures each. Twenty-one patients had carcinoid disease and 7 had other neuroendocrine tumors (VIPoma, glucagonoma, pancreatic islet cell tumor). Symptoms attributable to tumor burden (pain, early satiety, fatigue) or carcinoid syndrome were noted to be present in 22 patients (78%). These symptoms were decreased in severity after treatment with TACE in 15 of these patients (68%). In
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addition, 18 of 26 (69%) evaluable patients demonstrated an objective radiographic response to TACE treatment. Of the 21 patients evaluable for survival, median survival after first TACE procedure was 28 months (range 8 to 158 months) and median survival since diagnosis was 66 months (range 15 to 158 months). Most patients suffered the immediate common adverse effects of fever, chills, fatigue, and abnormal liver function tests and these resolved. Severe adverse effects encountered included thyrotoxicosis/severe fatigue in one patient, portal vein thrombosis and prolonged hepatic failure (eventually resolved) in one patient, hepatic abscess in one patient, and pleural effusions and severe hypoxia in another patient. We continue to recommend TACE to appropriate patients for neuroendocrine hepatic metastases and we work in conjunction with our hepatic surgical specialists and interventional radiology to make this a multidisciplinary approach to each patient. In addition, we frequently use other local therapies, such as RFA and hepatic resection, as they become indicated for patients either before or after chemoembolization. RADIOFREQUENCY ABLATION Given the indolent natural history of neuroendocrine metastases, most of these tumors are discovered only when they are very large or are multiple and symptomatic, limiting the patients’ options to systemic therapy or chemoembolization. There are certainly patients who have more limited disease, however, and these may be suitable for new local modalities such as RFA. In this technique, an electrode is inserted into the tumor percutaneously under ultrasound or CT guidance. It can also be done by laparoscopic or laparotomy means with the use of intraoperative ultrasound. The electrode is placed into the tumor and emits high-frequency radio waves that cause frictional heat generation because of the ionic vibration of tissue particles. Thermal energy is generated, producing temperatures of greater than 60 C that result in tumor destruction. Lesions as large as 5 to 6 cm can be ablated using multi-tipped electrodes, although success may be limited by the anatomic location and neighboring vascular supply of the lesion. Large vessels in close proximity to a lesion treated with RFA may cause inadequate heating of a tumor edge and may result in local relapse. In general, candidate lesions must be fewer than four in number, smaller than 5 cm, accessible percutaneously, and not in contiguity to vascular structures, bowel, or the gall bladder. Although introduced initially for hepatocellular and colorectal cancers, neuroendocrine metastases have recently been evaluated also. The radiofrequency literature is somewhat fraught with anecdotes and descriptive experiences. Any survival conclusions are as tentative as those in the chemoembolization papers, given the long natural history of the disease and the inability to perform randomized trials. Nonetheless, there are several good reports of success in individual patients. Henn and colleagues [48] describe successful relief of
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symptoms in five of seven treated patients, although one patient developed new lesions. Berber described 34 patients treated with laparoscopic RFA: 80% had ‘‘significant’’ symptom control, and 65% had some decrease in their tumor marker [49]. New hepatic lesions developed in 28%, whereas 41% showed no progression of cancer at all. In another recent study of 15 patients, 43 tumors were treated with RFA and at a median follow-up of 2.1 years only two local failures were noted [50]. All these studies report only minimal toxicity that is substantially less than that associated with chemoembolization. Often RFA is used adjunctively with hepatic tumor resection or chemoembolization. CRYOTHERAPY AND PERCUTANEOUS ALCOHOL INJECTION Cryotherapy is yet another means for treating primary or secondary liver tumors. It is not commonly used and there are few published reports detailing outcomes of large numbers of patients. There have been fewer than 50 patients reported in the literature. The procedure is similar to RFA with placement of the cryoprobe into the tumor percutaneously or intraoperatively under ultrasound guidance. The temperature of the cryoprobe is lowered by passage of liquid nitrogen though the uninsulated tip of the cryoprobe. Multiple freeze– thaw cycles are performed and a characteristic ‘‘ice ball’’ is formed. When the size of the ice ball is made larger than the tumor then an adequate treatment margin is assumed. This degree of freezing leads to tumor destruction. The few reports of this procedure indicate it does have efficacy. One study of 19 patients who had neuroendocrine liver metastases revealed a reduction in tumor markers of 80% and dramatically relieved symptoms [51]. In another study of 13 patients, 2 patients have had recurrence at a median follow-up of 13.5 months [52]. Of the 7 patients who had symptoms, a complete response was seen in 5 patients and a partial response was seen in the other 2 patients. Toxicity was minimal except in 2 patients who developed a coagulopathy and had to go back to the operating room; 1 patient developed renal failure and another patient had a pulmonary embolism. There was no in-hospital mortality. Percutaneous ethanol injection has been used to treat hepatocellular carcinoma, but there are few data on its use in neuroendocrine tumor metastases. FUTURE POSSIBILITIES IN LIVER-DIRECTED THERAPY Stereotactic radiosurgery, although previously used for central nervous system tumors, is evolving and beginning to be used for various visceral tumors, including liver tumors. This type of focused radiotherapy may afford the opportunity to deliver tumoricidal doses of radiation while sparing normal liver and avoiding hepatoxicity. Other techniques combining radiation and intra-arterial delivery, such as the use of yttrium-90 glass microspheres or iodine-131 lipiodol, have been reported for hepatocellular cancers but not yet for neuroendocrine tumors. SUMMARY Neuroendocrine tumors, despite being indolent, frequently cause significant morbidity and mortality from hepatic metastatic lesions. It is possible to
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directly target these liver lesions with embolization/chemoembolization, RFA, or other therapies. The observational studies that exist seem to indicate a prolongation of survival. But, more importantly, the liver-directed therapies are able to decrease symptoms in most patients. The value of these therapeutic interventions therefore lies mainly in their palliative capabilities. Coupled with aggressive use of octreotide, local ablative techniques may frequently control symptoms of hormone excess and tumor bulk. Because of the possible adverse effects of these interventions, however, careful patient selection is essential to minimize the morbidity and mortality of the procedures. Malignant neuroendocrine tumors are a rare group of cancers and are probably best cared for in a multidisciplinary fashion with surgery, medical oncology, and interventional radiology. Appropriate timely use of surgical resection, embolization/chemoembolization, RFA, or even chemotherapy may provide many patients with improved quality of life and possibly prolonged survival also. References [1] Breedis C, Young G. The blood supply of neoplasms in the liver. Am J Pathol 1954;30:969. [2] Lein WM, Ackerman NB. The blood supply of experimental liver metastasis. II. A microcirculatory study of the normal and tumor vessels of the liver with the use of perfused silicone rubber. Surgery 1970;68:334. [3] Ackerman NB, Lein WM, Silverman NA. The blood supply of experimental liver metastatses. III. The effects of acute ligation of hepatic artery and portal vein. Surgery 1972;71:636. [4] Ridge JA, Bading JR, et al. Perfision of colorectal hepatic metastasis. Relative distribution of flow from hepatic artery and portal vein. Cancer 1987;59:1547. [5] Sigurdson ER, et al. Tumor and liver drug uptake following hepatic artery and portal vein infusion. J Clin Orthod 1987;5:1836. [6] Ensminger WD, Gvyes JW. Clinical pharmacology of hepatic arterial chemotherapy. Semin Oncol 1983;10:176. [7] Collins JM. Pharmacologic rationale for regional drug delivery. J Clin Orthod 1984;2:498. [8] Eksborg S, Cedermark BJ, Standler HS. Intrahepatic and intravenous administration of Adriamycin—a comparative pharmacokinetic study in patients with malignant liver tumors. Med Oncol Tumor Pharmacother 1985;2:47. [9] Markowitz J. The hepatic artery. Surg Gynecol Obstet 1952;52:644. [10] McDermott WV, Hensle TW. Metastatic carcinoid to the liver treated by hepatic dearterialization. Ann Surg 1974;180:305. [11] Cady B, Oberfield RA. Arterial infusion chemotherapy of hepatoma. Surg Gynecol Obstet 1974;138:381. [12] Claouse ME, Ahmed R, et al. Complications of long-term transbrachial hepatic artery infusion chemotherapy. AJR Am J Roentgenol 1977;129:799. [13] Ramming KP. The effectiveness of hepatic artery infusion in treatment of primary hepatobiliary tumors. Semin Oncol 1983;10:199. [14] Boyse M for the Meta-analysis Group in Cancer. Reappraisal of hepatic arterial infusion in the treatment of non-resectable liver metastasis from colorectal cancer. Meta-analysis Group in Cancer. J Natl Cancer Inst 1996;88:252. [15] Bern MM, McDermott W, Cady B, et al. Intraarterial hepatic infusion and intravenous Adriamycin for treatment of hepatocellular carcinoma: a clinical and pharmacological report. Cancer 1978;42:399. [16] Shepherd FA, Evans WK, Blackstein ME, et al. Hepatic arterial infusion of mitoxantrone in the treatment of primary hepatocellular carcinoma. J Clin Oncol 1987;5:635.
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