Original Report. Percutaneous Radiofrequency Ablation of Hepatic Metastases for Symptomatic Relief of Neuroendocrine Syndromes

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1 Adam R. Henn 1 Edward A. Levine 2 William McNulty 3 Ronald J. Zagoria 1 Received July 16, 2002; accepted after revision April 8, Presented at the 2002 annual meeting of the American Roentgen Ray Society, Atlanta, April May Department of Radiology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC Address correspondence to R. J. Zagoria. 2 Department of Surgical Oncology, Wake Forest University School of Medicine, Winston-Salem, NC Hanover Medical Specialists, 1520 Physicians Dr., Wilmington, NC AJR 2003;181: X/03/ American Roentgen Ray Society Original Report Percutaneous Radiofrequency Ablation of Hepatic Metastases for Symptomatic Relief of Neuroendocrine Syndromes OBJECTIVE. The purpose of this study was to evaluate the efficacy of percutaneous radiofrequency ablation of hepatic neuroendocrine metastases for symptomatic relief of neuroendocrine syndromes. CONCLUSION. Percutaneous radiofrequency ablation, a minimally invasive technique, is an effective and safe way to reduce systemic symptoms in patients with hepatic metastases from neuroendocrine neoplasms. C arcinoid and islet cell tumors are a fascinating group of neuroendocrine tumors found throughout the body. These tumors have been described as cancers in slow motion [1] because survival, even with advanced disease, is frequently prolonged. However, neuroendocrine tumors often cause incapacitating symptoms because of the production of a wide variety of hormones. Although the growth rate of these tumors can be quite slow, death often results from the paraneoplastic syndromes associated with the excessive hormones released by these tumors. The treatment of hepatic metastases from neuroendocrine tumors can be a vexing problem for physicians because the metastases are usually multiple, unresectable, and unresponsive to chemotherapy and radiation therapy. Therapeutic options should focus on palliative care to improve the patient s quality of life, rather than attempting cure [2, 3]. Invasive techniques such as partial hepatectomy [1 3], laparoscopic cryoablation [4], and transarterial hepatic embolization [2, 5, 6] have all been shown to relieve symptoms in some patients. Hepatic resection can be used for curative treatment; however, the procedure has low but significant mortality and complication rates [2, 3]. Despite even aggressive surgical resections in this setting, tumors recur in most treated patients [3]. Alternatively, medical treatment with somatostatin analogues, such as octreotide, results in temporary symptomatic relief in most patients, but these drugs do not effectively stop tumor growth. Furthermore, even the long-acting somatostatin injections are extremely expensive, and effectiveness in controlling symptoms is often short-lived [6]. Radiofrequency ablation has been used for several years to treat hepatic neoplasms. Although radiofrequency ablation can be used via open or laparoscopic techniques, less invasive percutaneous radiofrequency ablation for treatment is also available. We evaluated the use of this minimally invasive technique, percutaneous radiofrequency ablation, for relief of symptoms from hepatic metastases of neuroendocrine tumors. Materials and Methods After obtaining institutional review board approval, we retrospectively collected data on seven consecutive patients (Table 1) with symptomatic hepatic metastases from neuroendocrine tumors (six AJR:181, October

2 Henn et al. TABLE 1 Patient Information Patient No. Sex Age (yr) Cell Type Surgical History Note. 5-HIAA = 5-hydroxyindoleacetic acid, NA = not available, tid = three times per day. a Long-acting octreotide, 30 mg every 3 weeks. No. Treated Hepatic Lesions Total No. Average Size (cm) Maximum Symptom Score Change (mo) with carcinoid tumors and one with an insulinoma) who were treated with percutaneous imaging-guided radiofrequency tumor ablation. The six women and one man were years old (average, 56 years). In each patient at least one of the hepatic metastases was a biopsy-proven metastatic neuroendocrine tumor. Four of the patients had previously undergone resection of the primary neuroendocrine tumor. Three of the primary tumors were located in the ileum; the fourth was a pancreatic islet cell tumor. Two patients had unresectable primary tumors (including a lower abdominal mass and a pancreatic mass), and one patient had an occult primary tumor (Table 1). Patients were referred for percutaneous radiofrequency tumor ablation by their medical oncologist. Each patient had previously been evaluated for possible surgical resection, and surgery was not thought to be a curative option in any of these patients. None of the patients had been previously treated for hepatic metastases with alternative invasive procedures or hepatic resection. In addition to these criteria, the pretreatment CT scan of each patient was reviewed, and a judgment was made that 50% or less of the hepatic volume was replaced by tumor and that the hepatic metastases would be accessible for percutaneous ablation. All patients suffered systemic symptoms attributable to their neuroendocrine tumors. The symptoms of each patient were scored using a standardized scoring system (Table 2) previously described for carcinoid syndrome [7]. This scoring system was also applied to the patient with insulinoma, another type of neuroendocrine tumor. Her symptoms were classified as to the degree of disability and frequency of symptoms similar to the classification of symptoms from carcinoid syndrome. Twenty-four-hour urine measurements of 5-hydroxyindoleacetic acid (5-HIAA) were taken before and after the radiofrequency ablation in all patients except one (Table 1). All patients were evaluated before the procedure by a radiologist with expertise in interventional procedures and imaging-guided radiofrequency tumor ablation. Written informed consent was obtained from each patient during an evaluation visit before the procedure. Each patient underwent CT of the abdomen before imaging-guided therapy. An anesthesiologist assessed each patient before the procedure. Patients with neuroendocrine tumor related cardiovascular symptoms were treated prophylactically with octreotide injection and were orally administered steroids for 24 hr before radiofrequency ablation. These two patients received generic octreotide in a 240-mg IV injection before the procedure and prednisone in 50-mg tablets every 6 hr for three doses. These precautionary measures were taken to decrease the possible risk 5-HIAA 24-hr Urine Change (mg) Octreotide Use Before Ablation After Ablation 1 M 66 Carcinoid None From 4 to 1 (7) From to 60.3 No No 21 2 F 54 Carcinoid Right hemicolectomy From 4 to 1 (28) From 33 to NA Yes No 28 3 F 52 Carcinoid None From 3 to 1 (10) From 40 to 5.2 No Yes 25 4 F 75 Carcinoid Ileocecal resection From 2 to 1 (35) From 37.4 to 90.3 No No 35 5 F 50 Carcinoid Right hemicolectomy and ileal resection From 2 to 2 (26) From 15.8 to 7.0 Yes, 150 µg tid Yes, 150 µg tid 6 F 38 Carcinoid None From 3 to 3 (8) From 69.9 to No No 8 7 F 60 Insulinoma Partial pancreatectomy and splenectomy TABLE 2 Neuroendocrine Symptom Grading System [7] Score Description Explanation 1 No symptoms Asymptomatic 2 Mild symptoms Symptoms include diarrhea, flushing, or asthma up to four times weekly 3 Symptoms impact daily life Daily symptoms of diarrhea, flushing, or asthma 4 Severe symptoms Daily symptoms of diarrhea, flushing, or asthma that require reorganization of daily activities 5 Disabling symptoms Disabled by numerous attacks, unable to leave home, or requires hospitalization Follow-Up (mo) From 1 to 1 (17) From 40.1 to 7.9 µu/ Yes a No 17 ml (fasting insulin) from the sudden release of vasoactive hormones during mechanical manipulation of the neuroendocrine tumors. In addition, every patient received 1 g of cefazolin IV 30 min before the procedure. Patients were placed in the CT scanner in a supine position. A staff member of the anesthesiology department administered general anesthesia. Patients were continuously monitored by the anesthesiologist throughout the procedure. Using CT guidance, we localized each of the hepatic tumors (Fig. 1). Once the tumor was seen on CT, a radiofrequency generator (CC-1 radiofrequency ablation device, Radionics, Burlington, MA) was connected to a radiofrequency electrode. A 17-gauge water-cooled cluster electrode with a 2.5-cm-long active tip was advanced into each tumor (Fig. 1). The tip of the electrode was advanced so that it was abutting the deepest segment of the tumor. Once the position was confirmed with repeated CT of the area of interest, the radiofrequency device was activated in conjunction with its water-cooling system. Radiofrequency ablation of every tumor in this series was completed using the automatic impedance control setting on this generator for the 12-min treatment period recommended by the manufacturer. The temperature after treatment in the area of ablation always exceeded 50 C, and the average posttreatment tumor temperature was 65 C. After the 12-min treatment, the electrode was either moved to another tumor or repositioned in the same tumor for further treatment. For tumors exceeding 2 cm in diameter, more than one treatment was performed in the tumor after repositioning the electrode to destroy another area of that lesion. A complete explanation of this radiofrequency tumor ablation technique has been previously published [8]. For patients with multiple hepatic metastases (6/7 patients) (Table 1), the procedure was repeated until all detectable and reachable metastases had been treated with at least one 12-min ablation. After the ablation procedure, each patient was observed in the recovery room for approximately 1 hr. Patients were admitted to a hospital room for over AJR:181, October 2003

3 Radiofrequency Ablation of Hepatic Metastases A B C D Fig year-old woman with insulinoma that was well controlled with octreotide, but who developed debilitating life-threatening symptoms when not receiving continuous octreotide therapy. Her fasting insulin dropped from preablation level of 40.1 µu/ml with octreotide therapy to 7.9 µu/ml without octreotide injections. A, Contrast-enhanced CT scan obtained 1 month before ablation procedure shows heterogeneous mass (arrows) in liver. B, CT scan obtained during radiofrequency ablation procedure shows cluster electrode (arrow) with its tip in insulinoma (arrowheads). C, Contrast-enhanced CT scan obtained immediately after radiofrequency ablation procedure, which included nine ablations, shows ablated tumor as sharply marginated nonenhancing area. Note small volume of persistent bright enhancement (arrows) at periphery that was believed to be untreated and viable tumor. D, Contrast-enhanced CT scan obtained 12 months after ablation shows sharply demarcated low-density area of ablated tissue surrounded by residual tumor that has grown since B and C. night observation and analgesia. The nursing staff checked vital signs during the hospitalization. Standard vital signs were checked and recorded every 15 min for the first hour after the ablation, every 30 min for the next 2 hr, once at the 4-hr mark, and then once per work shift for the remainder of the time in the hospital. In addition, hematocrit and hemoglobin levels were checked at least once before patient discharge to assess internal hemorrhage. All patients were discharged from the hospital in less than 24 hr without significant pain or complications. The referring physicians followed up their patients on an outpatient basis, and the time of the initial follow-up appointment was left to their discretion. Patients were assessed using a standardized scoring system, 24-hr urine 5-HIAA levels, and their need for further octreotide therapy. Clinical and laboratory documents were made available by the referring physicians. The final follow-up for each patient who had a symptomatic improvement af- AJR:181, October 2003 ter radiofrequency ablation was made by telephone. Four (80%) of the five responders were interviewed, and the fifth was assessed with a telephone contact with her referring physician, who continuously cared for this patient. Results Each radiofrequency tumor ablation was carried out successfully and no major procedural complications occurred. The number of hepatic metastases treated in each patient ranged from one to 13 (mean, 5.4 metastases). Each patient was treated in a single session, with each tumor being treated for at least 12 min. Tumors ranged in size from smaller than 1 cm to 12 cm in cross-sectional diameter. Thirty-eight tumors were treated with 57 abla- tions (mean, 1.5 ablations per tumor). Procedure duration times were not recorded for this study, but the time the patient was in the CT scanner for this procedure ranged from approximately 90 min to 270 min. Five (71%) of seven patients had symptomatic relief after percutaneous radiofrequency tumor ablation. Patient symptoms were assessed at 8 months or longer after the procedure. The average symptom reduction was 2.4 points on a 5-point symptom scale. Two of the three patients requiring octreotide injections for symptom control were able to completely discontinue their therapy after radiofrequency tumor ablation with no recurrence of symptoms. The insulinoma patient was closely followed up by her referring physician after the 1007

4 Henn et al. ablation and stopped the octreotide therapy less than 2 weeks after the procedure. The second patient had intermittently required octreotide and planned to restart the therapy before the ablation. This patient has not required octreotide in the 28 months since the ablation. One patient who did not experience symptomatic relief did have a reduction in her urinary 5-HIAA level (from 15.8 to 7.0 mg/24 hr), which normalized after radiofrequency tumor ablation treatment. The other patient who did not experience symptomatic relief had a large unresectable pancreatic carcinoid tumor in addition to the hepatic metastases, and she reported no progression of carcinoid symptoms during the period after radiofrequency ablation treatment. Two (40%) of the five patients who initially had symptomatic relief have had recurrence of their symptoms after a long period (mean, 27 months) of symptomatic relief. One patient was a 66-year-old man (Table 1) who had explosive diarrhea and flushing before the ablation. The diarrhea and flushing resolved after the ablation. He remained asymptomatic for 17 months, when the diarrhea started to return and new lesions were detected on cross-sectional imaging. This patient continues to be less symptomatic than he was before the ablation. A second patient was a 52-year-old woman with severe diarrhea, nausea, and vomiting before the ablation. Her symptoms were more confusing because she also has a diagnosis of Crohn s disease and erosive esophagitis. This patient was asymptomatic for 10 months after the ablation; her symptoms eventually returned and she began receiving octreotide therapy 23 months after her ablation procedure. No life-threatening complications occurred, and all patients were discharged within 24 hr. However, four patients experienced a minor procedural complication. One patient developed a superficial burn on her thigh at the site of a radiofrequency ablation grounding pad placement even though four grounding pads were used for each procedure. She was evaluated by a plastic surgeon and treated with a topical agent. This burn completely resolved without any significant sequela. Two patients developed tiny pneu- A mothoraces from transpleural placement of the radiofrequency electrode to treat lesions high in the dome of the liver. Each of these pneumothoraces was self-limited and did not require intervention. One patient complained of neuritis at a percutaneous puncture site, but it resolved spontaneously without treatment. Follow-up scans have shown well-demarcated, nonenhancing lesions in the liver (Figs. 1 and 2) corresponding to the sites of ablation. Residual or new metastases are seen as brightly enhancing areas (Fig. 1) that are distinctly different from the ablated tumor tissue. Follow-up of these patients ranged from 8 to 35 months (mean, 22.9 months) (Table 1) after treatment. All patients are alive as of the writing of this article. Discussion Neuroendocrine tumors have an indolent clinical course and often grow slowly. Survival for as many as 41 years [1] has been reported, even in patients with advanced disease. How- B Fig year-old woman with carcinoid syndrome and single metastasis in liver. Patient refused surgery and could not afford medical therapy for control of her worsening symptoms. A, Contrast-enhanced CT scan before ablation shows 5.6-cm metastasis in left lobe of liver. B, Contrast-enhanced CT scan obtained 2 weeks after ablation shows ablated tumor as sharply demarcated low-attenuation lesion with no visible enhancement. C, Contrast-enhanced CT scan obtained 8 months after ablation shows some shrinkage of ablated tumor and no evidence of local recurrence. New lesion (arrow) is visible in liver segment VIII. Note slight prominence of intrahepatic bile ducts not seen on earlier scans. Bile duct dilatation suggests partial obstruction from occult mass or ablation-induced stricture. C 1008 AJR:181, October 2003

5 Radiofrequency Ablation of Hepatic Metastases ever, the clinical course of patients with hepatic metastases from neuroendocrine tumors is not uniformly favorable. The 5-year survival rate for patients with untreated hepatic metastases from neuroendocrine tumors is 19 38% [2], with many of these patients succumbing to paraneoplastic syndromes. Such syndromes have varied presentations but can be associated with disabling diarrhea, flushing, nausea, cachexia, and cardiovascular disease caused by the release of metabolically active hormones. Cytoreduction of the hepatic metastases has been shown to increase survival and decrease symptoms in some patients. Unfortunately, in most patients treated by surgical resection with curative intent, additional hepatic metastases develop [9] that presumably were occult at the time of surgery. Repeated hepatic resections are not practical for most patients with metastatic neuroendocrine tumors. This fact, coupled with a surgical mortality rate of up to 6% [1] and morbidity associated with partial hepatectomy, has led researchers to evaluate less invasive treatment modalities that can be performed repeatedly as new lesions develop. Hepatic arterial embolization with or without chemotherapy is an option for palliative treatment of hepatic metastases from neuroendocrine tumors. Hepatic arterial embolization and chemoembolization have resulted in relief from symptoms for 4 18 months in most patients [3, 5, 6]. Embolization techniques are associated with a 4% mortality rate and an 86% rate of postembolic syndrome, which requires hospitalization [5]. In addition, serious complications have occurred in 11 12% of patients treated with hepatic embolization for neuroendocrine syndromes [5, 6]. Cryotherapy has been used for the treatment of hepatic neuroendocrine metastases in a small group of patients. However, one third of these patients develop potentially life-threatening coagulopathies after treatment [10], which has led most surgeons to abandon cryotherapy in favor of radiofrequency ablation. Medical therapy with octreotide is helpful; approximately 80% of patients experience some response to injected octreotide [6]. Unfortunately, this therapy is not curative and symptomatic relief is usually temporary, with resistance developing on average in 12 months for patients with carcinoid tumors and sooner in patients with islet cell tumors [6]. One study, which was performed in a porcine model and in six patients, has shown the possible efficacy of using radiofrequency energy to destroy hepatic neuroendocrine metastases in the liver [9]. In that study, procedures were performed laparoscopically and the results showed effective cytoreduction of the hepatic metastases. However, laparoscopic thermal ablation requires a more invasive and technically demanding technique than imaging-guided percutaneous procedures, in addition to the cost of an operating room. Laparoscopy is unnecessary for the delivery of radiofrequency energy to treat neuroendocrine metastases, and therefore we used a percutaneous approach. Percutaneous imaging-guided radiofrequency tumor ablation of various hepatic neoplasms has shown success rates comparable to those of surgical resection [11, 12]. In these series, fewer than 5% of patients experienced serious complications from imaging-guided radiofrequency tumor ablation of hepatic neoplasms. Mortality is rare for this percutaneous procedure. Clinical trials with radiofrequency ablation of hepatic neoplasms have shown that complete tumor eradication is more likely to occur with small tumors, particularly tumors of 4 cm in diameter or less, than with large tumors [11, 12]. Because of the small volume of tissue coagulated with each thermal ablation, complete necrosis of large tumors is difficult to achieve. Although this is a significant limitation for the curative treatment of aggressive hepatic malignancies, previous surgical studies have shown that the degree of clinical symptoms from neuroendocrine tumors parallels the tumor volume [1 3]. Cytoreduction of 90% or greater, rather than complete ablation, is adequate for durable symptomatic relief from neuroendocrine hepatic metastases [1]. In three patients in our study, complete hepatic tumor ablation could not be achieved with percutaneous imaging-guided radiofrequency tumor ablation because of the large number of lesions or the potentially dangerous location of the lesions (Fig. 1). One patient had at least 13 insulinoma metastatic lesions. A CT scan obtained immediately after treatment (Fig. 1) showed approximately 90% reduction in viable tumor volume. This patient, whose condition was well controlled with octreotide but who developed debilitating life-threatening symptoms without continuous octreotide therapy, was able to completely discontinue her octreotide injections. Her fasting insulin level decreased from a preprocedural level of 40.1 µu/ml with octreotide therapy to 7.9 µu/ml without octreotide injections. To our knowledge, two previous studies have addressed symptomatic control of malignant carcinoid with radiofrequency ablation [4, 7]. These studies showed decreased symptoms in some of the nine patients after ablation, but the procedures in these two studies were performed with surgical exploration or laparoscopy [4, 7]. In addition, one study reserved radiofrequency ablation as a salvage procedure for patients whose hepatic artery embolization was not successful [7]. Five of seven patients in our series showed excellent symptomatic response to a single percutaneous procedure. One patient who did not experience a clinical response did have a reduction in her urine 5- HIAA level. Before the procedure, her urinary 5-HIAA levels were elevated, but they returned to normal after radiofrequency ablation of her five hepatic metastases. However, this patient had previously undergone hemicolectomy and partial small-bowel resection. On the basis of her oncologist s assessment, it was thought that her symptoms, which consisted only of diarrhea, were due to short-bowel syndrome rather than to carcinoid syndrome. The other patient who did not experience symptomatic relief continues to have intermittent diarrhea and has a large unresectable pancreatic carcinoid tumor in addition to the hepatic metastases. Although her symptoms were not improved after the ablation, she reports no progression of carcinoid symptoms. Follow-up studies have shown enlargement of the primary pancreatic tumor and elevation of the 5- HIAA levels. The untreated pancreatic tumor is probably the cause of the failure of treatment to alleviate symptoms in this patient. That two of the patients developed recurrence of their symptoms provides an insight into the long-term effects of this treatment. One patient has developed new lesions but remains less symptomatic than he was before the ablation. The second patient has had complete recurrence of her symptoms and began receiving octreotide therapy 23 months after the ablation. Despite the recurrence of symptoms, the ablations were successful in providing a long period of symptomatic relief for both patients. Three patients remain stable, with no symptom recurrence, months (mean, 27 months) after radiofrequency ablation treatment. The results of this study should be viewed as preliminary because the study has limitations as a result of the retrospective data collection and the small number of patients. The patients in our study were referred for radiofrequency ablation treatment because of their clinical symptoms, their limited alternative treatment options, and the success in using radiofrequency ablation for treatment of hepatic neoplasms in general. Each patient was evaluated for radiofrequency ablation treatment on an individual basis; the potential risks and ben- AJR:181, October

6 Henn et al. efits of each treatment option were estimated. Because of the retrospective design of this study, the patient demographics and clinical follow-up are not uniform. Even so, these results support the idea that for patients with neuroendocrine syndromes and hepatic metastases, a single session of imaging-guided percutaneous radiofrequency tumor ablation can result in symptomatic relief. Unlike other therapies, morbidity is minimal and the anticipated mortality rate associated with this procedure is low. Patients can be treated on an outpatient basis and relief of symptoms is immediate. The potential exists for repeated percutaneous radiofrequency ablations in these patients should recurrence or new metastases develop. We are not currently advocating percutaneous radiofrequency ablation for patients who are good surgical candidates because no data suggest improved survival compared with surgical resection. However, on the basis of the results with other hepatic tumors, percutaneous radiofrequency ablation may become a less invasive alternative for primary treatment in the future. At this time, imaging-guided percutaneous radiofrequency tumor ablation may be the preferred treatment for symptomatic relief of neuroendocrine syndromes caused by unresectable hepatic metastases. References 1. Chamberlain RS, Canes D, Brown KT, et al. Hepatic neuroendocrine metastases: does intervention alter outcomes? J Am Coll Surg 2000;190: Que FG, Nagorney DM, Batts KP, et al. Hepatic resection for metastatic neuroendocrine carcinomas. Am J Surg 1995;169: Ahlman H, Westberg G, Wangberg B, et al. Treatment of hepatic metastases of carcinoid tumors. World J Surg 1996;20: Siperstein A, Rogers S, Hansen P, Gitomirsky A. Laparoscopic thermal ablation of hepatic neuroendocrine tumor metastases. Surgery 1997;122: Brown KT, Koh BY, Brody LA, et al. Particle embolization of hepatic neuroendocrine metastases for control of pain and hormonal symptoms. J Vasc Interv Radiol 1999;10: Moertel CG. Karnofsky memorial lecture: an odyssey in the land of small tumors. J Clin Oncol 1987;5: Wessels FJ, Schell SR. Radiofrequency ablation treatment of refractory carcinoid hepatic metastases. J Surg Res 2001;95: de Baere T, Denys A, Wood BJ, et al. Radiofrequency liver ablation: experimental comparative study of water-cooled versus expandable systems. AJR 2001;176: Que FG, Sarmiento JM, Nagorney DM. Hepatic surgery for metastatic gastrointestinal neuroendocrine tumors. Cancer Control 2002;9: Cozzi PJ, Englund R. Cryotherapy treatment of patients with hepatic metastases from neuroendocrine tumors. Cancer 1995;76: de Baere T, Elias D, Dromain C, et al. Radiofrequency ablation of 100 hepatic metastases with a mean follow-up of more than 1 year. AJR 2000;175: McGahan JP, Dodd GD III. Radiofrequency ablation of the liver: current status. AJR 2001;176: AJR:181, October 2003