REVIEW ARTICLE
Radiofrequency Ablation for Neuroendocrine Liver Metastases: A Systematic Review Helen Mohan, MRCSI, Patrick Nicholson, MRCSI, Des C. Winter, MD, Donal O’Shea, MD, Dermot O’Toole, MD, Justin Geoghegan, FRCSI, Donal Maguire, FRCSI, Emir Hoti, FRCSEd, Oscar Traynor, FRCSI, and Colin P. Cantwell, MD
ABSTRACT To determine the efficacy of radiofrequency (RF) ablation in neuroendocrine tumor (NET) liver metastases. A systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eight studies were included (N ¼ 301). Twenty-six percent of RF ablation procedures were percutaneous (n ¼ 156), with the remainder conducted at surgery. Forty-eight percent of patients had a concomitant liver resection. Fifty-four percent of patients presented with symptoms, with 92% reporting symptom improvement following RF ablation (alone or in combination with surgery). The median duration of symptom improvement was 14–27 months. However, recurrence was common (63%–87%). RF ablation can provide symptomatic relief in NET liver metastases alone or in combination with surgery.
ABBREVIATIONS NET = neuroendocrine tumor, PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses, RF = radiofrequency
Neuroendocrine tumors (NETs) often present with established liver metastases (1,2). NET liver metastases can give rise to troublesome symptoms because of their hormonal activity (3–6). Radiofrequency (RF) ablation has been well described as a therapeutic option for liver metastases from colorectal cancer and hepatocellular carcinoma (7–11). The present review examined the role of RF ablation in symptom control in NET liver metastases.
From the Departments of Surgery (H.M., P.N., D.C.W., J.G., D.M., E.H., O.T.), Radiology (C.P.C.), and Endocrinology (D.O’S.), St. Vincent’s University Hospital; and Department of Clinical Medicine and Gastroenterology (D.O’T.), Trinity Centre for Health Sciences, St. James Hospital and Trinity College Dublin, Dublin, Ireland. Received April 23, 2014; final revision received October 8, 2014; accepted December 8, 2014. Address correspondence to H.M., Department of Surgery, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland; E-mail: [email protected] H.M. and P.N. contributed equally as joint first co-authors. None of the authors have identified a conflict of interest. Tables E1 and E2 are available online at www.jvir.org. & SIR, 2014 J Vasc Interv Radiol 2014; XX:]]]–]]] http://dx.doi.org/10.1016/j.jvir.2014.12.009
Therapeutic strategies in NET liver metastases primarily focus on reducing tumor volume or functional secretory capacity (12). Surgical options include resection or rarely transplantation, but the majority of patients do not have resectable or “transplantable” disease at presentation, and surgery carries a high recurrence rate (13–16). Somatostatin analogues are the most effective pharmacologic therapy for symptom control, and traditional chemotherapy has limited efficacy (17,18). Given the lack of an ideal solution for NET liver metastases with surgery or pharmacotherapy and the tendency for recurrence of disease, a minimally invasive approach that is effective but well tolerated is needed for symptom control. Interventional radiologic options in liver tumors include embolization and ablative techniques (19–24). Data from studies on RF ablation in primary hepatocellular carcinoma suggest that RF ablation is effective in this disease and has several advantages, as it can be used repeatedly and has a low sideeffect profile (7,8,25). NETs have distinct and varied tumor biology, which provides a rationale to study them as a group separate from other tumors (26). The present study aimed to determine whether RF ablation provides symptom control in NET liver metastases.
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MATERIALS AND METHODS Search Strategy A systematic review was conducted with reference to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (27). The PRISMA statement was designed to promote accurate and clear reporting of systematic reviews and meta-analyses. Two reviewers independently performed a literature search by using MEDLINE and the Cochrane Central Register of Controlled Trials to identify articles relevant to RF ablation in NET liver metastases. Search terms used were “neuroendocrine,” “NET,” “carcinoid,” “hepatic,” “catheter ablation,” “thermal ablation,” “radiofrequency ablation,” and “RF ablation.” Abstracts were screened for relevance, and full-text articles were retrieved. These were independently analyzed and assessed for eligibility by both reviewers. The reference lists of these articles were studied to identify additional relevant papers.
Inclusion Criteria Only English-language articles were included. Individual case reports were excluded, as were animal studies. There were no date limitations and no other limitations on study type. Studies performed with curative and palliative intent were included. There was no restriction on the type of RF generators or electrode design used in the studies. In cases in which more than one study had been published from an individual center, only the most recent or relevant was included to avoid counting patients twice in cases in which patient populations overlapped.
Data Extraction Data extraction was performed independently by two reviewers with the use of a predefined data extraction template (Table E1 [28], available online at www.jvir. org). Data fields included complications, symptom relief, and survival.
Quality Assessment No randomized controlled trial was identified comparing RF ablation versus other treatment modalities for NET liver metastases. All studies were retrospective case series reporting single-center experiences with RF ablation for NET. The PRISMA statement makes inclusion of a quality assessment mandatory (27). Downs and Black (28) described a checklist for the assessment of quality of randomized and nonrandomized studies in 1998, with 27 checklist items. The Downs and Black checklist was modified by one of the present authors (H.M.) to allow it to be used to assess study quality for the present series of nonrandomized studies. With this modified score, a maximum score of 14 was possible, with higher scores reflecting higher quality of studies (Table E2 [14,15,29– 34], available online at www.jvir.org). In view of the low
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quality of studies in the present review, a meta-analysis was not performed. Instead, a systematic review was performed to present the data as they currently stand. There is a need for high-quality randomized controlled trials in this area.
Statistical Analysis Because of the heterogeneity of the data, meta-analysis was not performed. Means are given as weighted means unless stated otherwise.
RESULTS After removal of duplicates, the literature search retrieved 1,550 titles, of which 13 met the inclusion criteria. All were retrospective case series (Fig). These 12 studies were from eight centers in four countries (United States, Sweden, France, and United Kingdom) (14,15,29–39). When overlapping patient cohorts from the same center were excluded, eight studies were left in the final analysis (14,15,29–34). Of these, seven reported outcomes following RF ablation for NETs alone. Amersi et al (31) reported results following RF ablation for liver metastases from a variety of primary tumors, but it was possible to separate NET results from other tumors, which enabled the study’s inclusion. All studies were retrospective; no study scored higher than 11 of 14 on quality assessment per the modified Downs and Black checklist (Table E2).
Demographics A total of 301 patients (Table) with NET liver metastases underwent RF ablation from 1994 to 2009, with more than 595 ablation procedures performed for 978 tumors (14,15,29–34). “Carcinoid tumors” were the most common primary NET in included studies (59%), followed by nonfunctional pancreatic NETs (21%) and functional pancreatic NETs (13%). Other primary tumors included medullary thyroid cancer and adrenal carcinomas. The presence of extrahepatic disease was recorded in four studies (14,29,30,34), with a weighted mean of 22% with extrahepatic disease (range, 8%–29%). The number of tumors per patient was reported in five studies (14,29,31,32,34), with a mean of 4.5 tumors per patient. The range of tumors per patient was reported in five studies (15,29,30,32,34), with a range of one to 21 tumors. Elias et al (14) did not report a range, but all patients in this study had more than 15 liver metastases. Only four studies gave the mean size of the tumors (n ¼ 141), with a weighted mean size of 3.8 cm (range, o 1 to 8 cm).
Indications for RF Ablation and Patient Selection Patient selection criteria for RF ablation were heterogeneous among studies with palliative or curative intent. In
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Records idenfied through database searching (n = 3272)
Addional records idenfied through other sources (n = 2)
Titles Screened aer duplicates removed (n = 1550)
Abstracts Screened (n = 117)
Full-text arcles assessed for eligibility (n = 37)
Excluded Titles (n = 1433)
Excluded Abstracts (n = 80)
Full-text arcles excluded, with reasons (n = 29)
Studies included in qualitave synthesis (n = 8) Figure. Search strategy according to PRISMA template.
total, 124 patients underwent RF ablation as a palliative procedure, 101 procedures were performed with potential curative intent, and the intent of the remainder was not clear. There was considerable variability in patient selection criteria for RF ablation in the included studies (Table), such as in the number of tumors per patient. For example, Akylidiz et al (29) included patients with a maximum of 15 tumors whereas Elias et al (14) included patients with a minimum of 15 tumors. There were three main indications for RF ablation in the included studies: (a) as an adjunct to surgery for resected lesions, (b) for treatment for unresectable lesions, and (c) as a salvage therapy where other treatments have failed. As a mainstay of treatment for unresectable disease in those who had not undergone previous attempts at local control, for example, Henn et al (34) used RF ablation as a stand-alone treatment in patients with unresectable tumors who had not received treatment for liver metastases (n ¼ 7). As salvage therapy in patients in whom other local control attempts had failed, for example, Akyildiz et al (29) studied patients who showed no response to other therapies, including octreotide, systemic chemotherapy, chemoembolization, liver resection, interferon, and yttrium 90–labeled octreotide, and Wessels and Schell (32) included only patients with unresectable disease who had undergone failed selective hepatic artery embolization. RF ablation was also used as an adjunct to surgery, with remaining unresectable lesions treated with RF ablation, or as a stand-alone therapy for unresectable lesions (14,15,30,31,33). Taner et al (33) and Elias et al (14) used RF ablation as an
adjunct to surgery, whereas Amersi et al (31), Elvin et al (15), and Gillams et al (30) used RF ablation as an adjunct to surgery or as a stand-alone therapy for unresectable disease.
Pretreatment Imaging All patients underwent preoperative imaging to detect and characterize the liver lesions and detect extrahepatic disease. The most common methods were computed tomography (CT) of the thorax, abdomen, and pelvis for staging, and triphasic liver CT. Multiphase contrastenhanced magnetic resonance (MR) imaging of the liver (33), ultrasonography (US) of the liver (14), and somatostatin receptor scintigraphy (14) were also used. Only one study (15) specifically mentioned the use of contrast-enhanced US.
RF Ablation Technique The majority of studies in the present review used general anesthesia for RF ablation, even in cases of percutaneous RF ablation (of seven studies that reported anesthesia used [14,15,30,31,33–35], general anesthesia was used in 88% of procedures). One study (15) initially used local anesthesia, but switched to general anesthesia for improved pain control and because the investigators believed general anesthesia facilitated complete tumor ablation. RF ablation procedures in six of the eight studies were US-guided or intraoperative US–guided (14,29–33), one was contrast-enhanced US–guided (15), and Henn et al (34) used CT guidance.
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Study,
Local
Country
No. of
Mean
Sex
NET
Symptoms
Concomitant
Follow-up
Morbidity
Procedural 5-y Survival
Recurrence
after RF (mo)
(per Lesion)
of Origin
Pts.
Age (y)
(M/F)
Only
(%)
Resection
Technique
(mo)
(%)
Mortality
Akyildiz et al
89
56
54/35
Yes
44 (n ¼ 39)
No
119 Laparoscopic
30
6.0
1
(29), U.S. Gillams et al
25
56
13/12
Yes
56 (n ¼ 14)
Yes (1/25)
65 Percutaneous,
21
12
1
NR
OS 29
NR
(30), U.K.
(%)
Survival
5-y OS 57 DFS 15, OS 72
7.90%
1 open
Amersi et al (31), U.S.
25
NR
NR
No
NR
No
NR
NR
NR
NR
NR
OS 48.3
20% of 4 3 cm
Henn et al
7
56
1/6
Yes
100 (n ¼ 7)
No
7 Percutaneous
22.9*
57
0
NR
NR
NR
(34), U.S. Wessels and
3
39.6
1/2
Yes
100 (n ¼ 3)
No
2 Open, 1
6
NR
0
NR
NR
NR
Schell (32), U.S. Elias et al
Review: RF Ablation for Neuroendocrine Liver Metastases
Table . Demographics and Outcomes following RF Ablation for NETs (14,15,29–34)
laparoscopic 16
48
7/9
Yes
31 (n ¼ 5)
Yes (13/16)
197 Open
27
62.5
0
3-y OS 84
NR
NR
42
61.2
19/23
Yes
NR
Yes (23/42)
84 Percutaneous,
NR
NR
NR
NR
NR
NR
58*
1.06
0
5-y OS 80,
SFS 24
4.25%
(14), France Elvin et al (15), Sweden Taner et al (33), U.S.
25 open 94
53.7
41/53
Yes
62 (n ¼ 59)
Yes (all 94)
94 Open
SFS 16
Note.–Follow-up given as median unless denoted by *, where mean is given. DFS ¼ disease-free survival, NET ¼ neuroendocrine tumor, NR ¼ not reported, OS ¼ overall survival, RF ¼ radiofrequency, SFS ¼ symptom-free survival.
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Only two studies (32,34) reported that pre- or periprocedural infusions of octreotide were administered; in both cases, it was reserved for severely symptomatic patients or patients with cardiac carcinoid features. Prednisolone was also given with octreotide in one study (34). The majority of RF ablation procedures were conducted at surgery (73% at surgery [n ¼ 319 open, n ¼ 120 laparoscopic], 26% percutaneous [n ¼ 156]). Fortyeight percent of patients (131 of 276 recorded) had concomitant liver resection. RF ablation applicator insertion was guided by US in the majority of percutaneous and operative cases (Table). Henn et al (34) used a percutaneous approach with CT guidance, whereas Gillams et al (30) used CT for a subset of lesions not visualized on US. Intraprocedural treatment monitoring of therapy was not performed.
Procedural Morbidity and Mortality There were two deaths among the studies in the present series, yielding an overall mortality rate of 0.7% (two of 301). The deaths were caused by a carcinoid crisis in a patient with severe carcinoid heart disease (30) and abdominal sepsis from a colonic perforation in a patient who underwent laparoscopic RF ablation (29). The overall morbidity rate was 10% (Table). Complications reported included hemorrhage, abscess, viscus perforation, bile leak, biliopleural fistula, transient liver insufficiency, pneumothorax, grounding pad burn, urinary retention, pneumonia, and pleural effusions. As 48% of patients had a concomitant liver resection, the true rate of complications from RF ablation itself is difficult to deduce accurately from the included studies, and it is similarly difficult to separate results from percutaneous and surgical RF ablation. The study by Akyildiz et al (29) is a series of patients who did not undergo concomitant liver resection but had RF ablation via a laparoscopic approach, and they reported a morbidity rate of 6%, with one death caused by intraabdominal sepsis, and two cases of hemorrhage.
Symptom Relief Six studies with a total of 234 patients reported whether patients had symptoms before RF ablation. Overall, 54% of patients (127 of 234) were reported to have had symptoms. Following RF ablation, 92% of patients were reported to have experienced partial or complete symptom relief (117 of the 127 symptomatic patients). The median duration of symptom relief reported ranged from 14 to 27 months (29,34). There was a lack of clarity in studies regarding methods of symptom assessment. Only two studies actually reported a formal neuroendocrine symptom score (32,34). Wessels and Schell (32) used a scoring system they had devised specifically for malignant carcinoid syndrome symptoms, which consisted of
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a five-point Likert scale ranging from 1 (no symptoms) to 5 (disabling symptoms). Henn et al (34) used and referenced this symptom score Wessel and Schell (32) had previously described. These two studies also recorded whether somatostatin analogue requirements were altered (32,34). Similarly, the time at which symptoms were assessed varied widely among studies, with only three studies (29,32,34) specifying a time frame after the procedure. Among these three studies (29,32,34), timing varied from at 1 week to within 4 weeks to after 8 months. Data regarding alteration of somatostatin analogue dosing after RF ablation are incomplete. In two series that included only 10 patients in total (32,34), three patients were able to stop somatostatin analogue therapy and another two patients were able to reduce their dosage.
Follow-up and Recurrence Median follow-up ranged from 6 to 58 months (absolute range, 3 mo to 13 y). Most studies conducted early postprocedural CT within 1 week of RF ablation to establish a baseline for subsequent follow-up and detect incomplete ablation (14,15,29–32) (Table). Follow-up imaging varied among studies, as did reporting of recurrence rates. Elvin et al (15) demonstrated a 10% local recurrence rate on follow-up imaging, detected as an area of increased vascularity on CT or Doppler US, but did not report their overall recurrence rate. Their follow-up CT schedule was at 48 hours, every 3 months for 1 year, and then every 6 months, with positron emission tomography as required (15). Elias et al (14) reported a 67% overall recurrence rate and a 50% local recurrence rate at a median follow-up of 27 months. However, they used CT before discharge and then US, MR imaging, and somatostatin analogue scintigraphy every 6 months thereafter (14). This was also a high-risk patient cohort, as each patient had at least 15 tumors at baseline (14). Wessels and Schell (32) reported on a cohort of only three patients and did not report a local recurrence rate. Follow-up was with CT at 1 week, 4 weeks, and 12 weeks (32). Taner et al (33) reported a 4.2% local recurrence rate, with 22% undergoing further RF ablation for progressive metastases. The follow-up imaging method was not reported. Akyildiz et al (29) reported a 22% local recurrence rate and a 60% overall recurrence rate, and follow-up was performed with contrast-enhanced liver CT at 1 week, then CT of the thorax, abdomen, and pelvis every 3 months for 2 years and every 6 months thereafter, in addition to tumor marker assessments. Amersi et al (31) used an almost identical follow-up regimen to Akyildiz et al (29) and reported a similar local recurrence rate of 20% (31). Henn et al (34) did not report imaging follow-up or local recurrence rates, but, based on symptom assessment via telephone, two of the five patients who experienced
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symptom relief with RF ablation developed recurrence of their symptoms. Gillams et al (30) reported an 8% local recurrence rate and a 40% local recurrence rate. MR imaging and CT were used for follow-up, but the timing was not specified.
Survival Data were too heterogeneous to combine and analyze overall 5-year survival rates and factors predictive of outcomes. Reported 5-year survival rates ranged from 57% to 80%. Factors identified on analysis within individual studies as statistically significant predictors of poor survival were greater liver metastasis volume (4 70 mL) (29), presence of symptoms (29), male sex and extrahepatic disease (29), and high Ki-67 proliferative index (4 3.5) (33). No matched or unmatched historical or randomized comparison of survival without RF ablation was available.
DISCUSSION The present review demonstrates that RF ablation is a good option as a palliative treatment because it has a low side-effect profile and can provide symptom relief. RF ablation can yield sustained medium-term symptomatic relief by reducing the viable tumor burden in the liver. This may in turn reduce the dose of somatostatin analogue required. In the setting of a significant recurrence rate after attempted cure, RF ablation can be repeated for symptomatic palliation. The present study highlights that there is a paucity of high-quality data on RF ablation for NET liver metastases. This is in keeping with the findings of a previous Cochrane review (40) that was precluded from drawing any conclusion about surgery versus other treatments for neuroendocrine liver metastases as a result of the low quality of studies available. The low quality of included studies limited the ability of the present review to determine whether RF ablation has benefits versus surgery or conveys a survival advantage. However, this does not mean that the current literature on RF ablation for NET should be ignored; rather, it must be interpreted with caution and provides a rationale for future prospective studies. The principal advantage of RF ablation is that it is well tolerated, with low mortality and morbidity rates compared with surgery alone. In the present review, there were two deaths among a total cohort of 301 patients with NET liver metastases. This compares favorably with mortality rates reported with other locoregional therapies such as embolization (34,41,42). There was one death as a result of the hormonal nature of NET, as one patient died of a carcinoid crisis (29). Overall, the mortality rate of RF ablation for NET was similar to that reported for nonneuroendocrine tumors (41). The 10% complication rate in the present review
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was higher than in previous studies (41). However, 48% of patients in the present review underwent concomitant liver resection, making it difficult to assess the true complication rate from RF ablation alone, as many complications were surgical in nature. Indeed, a recent systematic review of surgical resection (43) reported a median complication rate of 23%. In addition, the number of liver metastases per patient was relatively high in some included studies; for example, Elias et al (14) reported a 62.5% complication rate, but used RF ablation and surgery in 13 of 16 patients and included only patients with a high tumor burden (4 15 liver metastases). Differences in complication rates may also result from variability in reporting between studies. For example, on first glance, Henn et al (34) appear to have a high complication rate of 57%, but this study includes only seven patients in total, and there were four minor complications and no major complications. Other studies with lower complication rates may indeed have low complication rates, or, alternatively, may have reported only major complications. From a practical perspective, RF ablation is timeconsuming and requires rigorous planning, with lesion identification, applicator insertion (under image guidance), and treatment delivery. This process can take an average of 30 minutes per lesion (44). The number of RF ablation applicator placements and treatment deliveries depends on the lesion diameter and selected ablation device. Examination of this process of planning and treatment delivery was beyond the scope of the present review. The present study is limited by the retrospective nature of the included studies, with heterogeneous patient selection, RF ablation methods, treatment algorithms, combinations with other therapies, follow-up imaging protocols, and nonstandardized terminology and reporting. Five of the eight articles in the review were published before the publication of the guidelines for standardization of terminology and reporting criteria in 2005 (19). Of the articles published since 2005 (14,29,33), only one—that of Elias et al (14)—complies with terminology and reporting criteria. A survival advantage after RF ablation of liver metastases cannot be confirmed on the basis of the available data, as studies are heterogeneous in patient selection, methodology, and reporting. Only two studies reported 5-year survival (29,33). Further studies are needed with standardized reporting of patient selection, complications, and outcomes with the use of scoring systems such as the Clavien–Dindo classification for surgical complications (45). To properly assess the impact of RF ablation on long-term symptom relief, tumor burden, and survival, prospective multicenter studies or registries with standardized reporting criteria are needed. In conclusion, RF ablation can provide symptomatic relief in NET liver metastases alone or in combination with surgery. However, there are insufficient data to
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determine whether RF ablation improves survival or recurrence. Prospectively gathered data are needed to guide treatment algorithms.
REFERENCES 1. Lewis MA, Hobday TJ. Treatment of neuroendocrine tumor liver metastases. International journal of hepatology 2012; 2012:973946. 2. Steinmuller T, Kianmanesh R, Falconi M, et al. Consensus guidelines for the management of patients with liver metastases from digestive (neuro)endocrine tumors: foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 2008; 87:47–62. 3. Pavel M, Baudin E, Couvelard A, et al. ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 2012; 95:157–176. 4. Panzuto F, Nasoni S, Falconi M, et al. Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocrine-related cancer 2005; 12:1083–1092. 5. Madeira I, Terris B, Voss M, et al. Prognostic factors in patients with endocrine tumours of the duodenopancreatic area. Gut 1998; 43: 422–427. 6. Tomassetti P, Campana D, Piscitelli L, et al. Endocrine pancreatic tumors: factors correlated with survival. Annals of oncology: official journal of the European Society for Medical Oncology / ESMO 2005; 16: 1806–1810. 7. Jansen MC, van Hillegersberg R, Chamuleau RA, van Delden OM, Gouma DJ, van Gulik TM. Outcome of regional and local ablative therapies for hepatocellular carcinoma: a collective review. European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 2005; 31:331–347. 8. Tiong L, Maddern GJ. Systematic review and meta-analysis of survival and disease recurrence after radiofrequency ablation for hepatocellular carcinoma. The British journal of surgery 2011; 98:1210–1224. 9. Boame N, Gresham G, Jonker D, Martel G, Balaa F, Asmis T. Use of chemotherapy and radiofrequency ablation to treat colorectal cancer metastases: a retrospective review of The Ottawa Hospital Cancer Centre over 7 years. Current oncology 2014; 21:e557–e563. 10. Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Annals of surgery 2004; 239:818–825, discussion 25-7. 11. Weng M, Zhang Y, Zhou D, et al. Radiofrequency ablation versus resection for colorectal cancer liver metastases: a meta-analysis. PloS one 2012; 7:e45493. 12. Horsch D, Grabowski P, Schneider CP, et al. Current treatment options for neuroendocrine tumors. Drugs of today 2011; 47:773–786. 13. Fan ST, Le Treut YP, Mazzaferro V, et al. Liver transplantation for neuroendocrine tumour liver metastases. HPB: the official journal of the International Hepato Pancreato Biliary Association 2014. 14. Elias D, Goere D, Leroux G, et al. Combined liver surgery and RFA for patients with gastroenteropancreatic endocrine tumors presenting with more than 15 metastases to the liver. European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 2009; 35:1092–1097. 15. Elvin A, Skogseid B, Hellman P. Radiofrequency ablation of neuroendocrine liver metastases. Abdominal imaging 2005; 30:427–434. 16. Kianmanesh R, Sauvanet A, Hentic O, et al. Two-step surgery for synchronous bilobar liver metastases from digestive endocrine tumors: a safe approach for radical resection. Annals of surgery 2008; 247: 659–665. 17. Madoff DC, Gupta S, Ahrar K, Murthy R, Yao JC. Update on the management of neuroendocrine hepatic metastases. Journal of vascular and interventional radiology: JVIR 2006; 17:1235–1249. 18. Kloppel G, Couvelard A, Perren A, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: towards a standardized approach to the diagnosis of gastroenteropancreatic neuroendocrine tumors and their prognostic stratification. Neuroendocrinology 2009; 90:162–166.
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19. Goldberg SN, Grassi CJ, Cardella JF, et al. Image-guided tumor ablation: standardization of terminology and reporting criteria. Journal of vascular and interventional radiology: JVIR 2005; 16:765–778. 20. Dodd GD 3rd, Soulen MC, Kane RA, et al. Minimally invasive treatment of malignant hepatic tumors: at the threshold of a major breakthrough. Radiographics: a review publication of the Radiological Society of North America, Inc 2000; 20:9–27. 21. Melodelima D, Vincenot J, Chen Y, Dupre A, Rivoire M, Chapelon JY. Thermal ablation by high-intensity-focused ultrasound using a toroidal transducer for the treatment of colorectal liver metastases during an open procedure. Clinical results. The Journal of the Acoustical Society of America 2013; 133:3410. 22. Goldberg SN, Grassi CJ, Cardella JF, et al. Image-guided tumor ablation: standardization of terminology and reporting criteria. Radiology 2005; 235:728–739. 23. McCarley JR, Soulen MC. Percutaneous ablation of hepatic tumors. Seminars in interventional radiology 2010; 27:255–260. 24. Yang TX, Chua TC, Morris DL. Radioembolization and chemoembolization for unresectable neuroendocrine liver metastases - a systematic review. Surgical oncology 2012; 21:299–308. 25. Eltawil KM, Boame N, Mimeault R, et al. Patterns of recurrence following selective intraoperative radiofrequency ablation as an adjunct to hepatic resection for colorectal liver metastases. Journal of surgical oncology 2014. 26. Schimmack S, Svejda B, Lawrence B, Kidd M, Modlin IM. The diversity and commonalities of gastroenteropancreatic neuroendocrine tumors. Langenbeck’s archives of surgery / Deutsche Gesellschaft fur Chirurgie 2011; 396:273–298. 27. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS medicine 2009; 6:e1000100. 28. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and nonrandomised studies of health care interventions. Journal of epidemiology and community health 1998; 52:377–384. 29. Akyildiz HY, Mitchell J, Milas M, Siperstein A, Berber E. Laparoscopic radiofrequency thermal ablation of neuroendocrine hepatic metastases: long-term follow-up. Surgery 2010; 148:1288–1293, discussion 93. 30. Gillams A, Cassoni A, Conway G, Lees W. Radiofrequency ablation of neuroendocrine liver metastases: the Middlesex experience. Abdominal imaging 2005; 30:435–441. 31. Amersi FF, McElrath-Garza A, Ahmad A, et al. Long-term survival after radiofrequency ablation of complex unresectable liver tumors. Arch Surg 2006; 141:581–587, discussion 7-8. 32. Wessels FJ, Schell SR. Radiofrequency ablation treatment of refractory carcinoid hepatic metastases. The Journal of surgical research 2001; 95: 8–12. 33. Taner T, Atwell TD, Zhang L, et al. Adjunctive radiofrequency ablation of metastatic neuroendocrine cancer to the liver complements surgical resection. HPB: the official journal of the International Hepato Pancreato Biliary Association 2013; 15:190–195. 34. Henn AR, Levine EA, McNulty W, Zagoria RJ. Percutaneous radiofrequency ablation of hepatic metastases for symptomatic relief of neuroendocrine syndromes. AJR American journal of roentgenology 2003; 181:1005–1010. 35. Mazzaglia PJ, Berber E, Milas M, Siperstein AE. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases: a 10-year experience evaluating predictors of survival. Surgery 2007; 142:10–19. 36. Berber E, Flesher N, Siperstein AE. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases. World journal of surgery 2002; 26:985–990. 37. Hellman P, Ladjevardi S, Skogseid B, Akerstrom G, Elvin A. Radiofrequency tissue ablation using cooled tip for liver metastases of endocrine tumors. World journal of surgery 2002; 26:1052–1056. 38. Eriksson J, Stalberg P, Nilsson A, et al. Surgery and radiofrequency ablation for treatment of liver metastases from midgut and foregut carcinoids and endocrine pancreatic tumors. World journal of surgery 2008; 32:930–938. 39. Karabulut K, Akyildiz HY, Lance C, et al. Multimodality treatment of neuroendocrine liver metastases. Surgery 2011; 150:316–325. 40. Gurusamy KS, Ramamoorthy R, Sharma D, Davidson BR. Liver resection versus other treatments for neuroendocrine tumours in patients with resectable liver metastases. The Cochrane database of systematic reviews 2009:CD007060.
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41. Livraghi T, Solbiati L, Meloni MF, Gazelle GS, Halpern EF, Goldberg SN. Treatment of focal liver tumors with percutaneous radio-frequency ablation: complications encountered in a multicenter study. Radiology 2003; 226:441–451. 42. Brown KT, Koh BY, Brody LA, et al. Particle embolization of hepatic neuroendocrine metastases for control of pain and hormonal symptoms. Journal of vascular and interventional radiology: JVIR 1999; 10:397–403.
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43. Saxena A, Chua TC, Perera M, Chu F, Morris DL. Surgical resection of hepatic metastases from neuroendocrine neoplasms: a systematic review. Surgical oncology 2012; 21:e131–e141. 44. de Jong KP, Wertenbroek MW. Liver resection combined with local ablation: where are the limits? Digestive surgery 2011; 28:127–133 45. Clavien PA, Sanabria JR, Strasberg SM. Proposed classification of complications of surgery with examples of utility in cholecystectomy. Surgery 1992; 111:518–526.
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Table E1 . Modified Downs and Black Quality Assessment Scoring System (28) Reporting 1. Is the hypothesis/aim/objective of the study clearly described? 2.
Are the main outcomes to be measured clearly described in the introduction or methods section?
3. 4.
Are the characteristics of the patients included in the study clearly described? Are the interventions of interest clearly described? (Ie, Is the type of RF ablation clearly described?)
5.
Are the main findings of the study clearly described?
6.
Have all the important adverse events that may be a consequence of the intervention been reported (ie, perioperative complications)?
7.
Have the characteristics of patients lost to follow-up been described?
External validity 8. Were the subjects asked to participate in the study representative of the entire population from which they were recruited? 9.
Were those subjects who were prepared to participate representative of the entire population from which they were recruited?
10.
Were the staff, places, and faculties where the patients were treated representative of the treatment the majority of patients receive? (Ie, are RF ablation methods in this study similar to in other studies included?)
Internal validity 11. 12.
Was an attempt made to blind those measuring the main outcomes of the intervention? If any of the results of the study were based on “data dredging,” was this made clear?
a.
Are all planned analyses in the methods section?
b. c.
Were the statistical tests used to assess the main outcomes appropriate? Were the main outcome measures used accurate (valid and reliable)?
Table E2 . Modified Downs and Black Checklist Scores for Each Included Study (12,13,29,35–39) Study Akyildiz et al (29) Gillams et al (30)
Score 11 10
Amersi et al (31)
5
Henn et al (34) Wessels and Schell (32)
9 8
Elias et al (14)
9
Elvin et al (15) Taner et al (33)
7 9
Maximum score
14
Radiofrequency Ablation for Neuroendocrine Liver Metastases: A Systematic Review Helen Mohan, MRCSI, Patrick Nicholson, MRCSI, Des C. Winter, MD, Donal O’Shea, MD, Dermot O’Toole, MD, Justin Geoghegan, FRCSI, Donal Maguire, FRCSI, Emir Hoti, FRCSEd, Oscar Traynor, FRCSI, and Colin P. Cantwell, MD
ABSTRACT To determine the efficacy of radiofrequency (RF) ablation in neuroendocrine tumor (NET) liver metastases. A systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eight studies were included (N ¼ 301). Twenty-six percent of RF ablation procedures were percutaneous (n ¼ 156), with the remainder conducted at surgery. Forty-eight percent of patients had a concomitant liver resection. Fifty-four percent of patients presented with symptoms, with 92% reporting symptom improvement following RF ablation (alone or in combination with surgery). The median duration of symptom improvement was 14–27 months. However, recurrence was common (63%–87%). RF ablation can provide symptomatic relief in NET liver metastases alone or in combination with surgery.
ABBREVIATIONS NET = neuroendocrine tumor, PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses, RF = radiofrequency
Neuroendocrine tumors (NETs) often present with established liver metastases (1,2). NET liver metastases can give rise to troublesome symptoms because of their hormonal activity (3–6). Radiofrequency (RF) ablation has been well described as a therapeutic option for liver metastases from colorectal cancer and hepatocellular carcinoma (7–11). The present review examined the role of RF ablation in symptom control in NET liver metastases.
From the Departments of Surgery (H.M., P.N., D.C.W., J.G., D.M., E.H., O.T.), Radiology (C.P.C.), and Endocrinology (D.O’S.), St. Vincent’s University Hospital; and Department of Clinical Medicine and Gastroenterology (D.O’T.), Trinity Centre for Health Sciences, St. James Hospital and Trinity College Dublin, Dublin, Ireland. Received April 23, 2014; final revision received October 8, 2014; accepted December 8, 2014. Address correspondence to H.M., Department of Surgery, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland; E-mail: [email protected] H.M. and P.N. contributed equally as joint first co-authors. None of the authors have identified a conflict of interest. Tables E1 and E2 are available online at www.jvir.org. & SIR, 2014 J Vasc Interv Radiol 2014; XX:]]]–]]] http://dx.doi.org/10.1016/j.jvir.2014.12.009
Therapeutic strategies in NET liver metastases primarily focus on reducing tumor volume or functional secretory capacity (12). Surgical options include resection or rarely transplantation, but the majority of patients do not have resectable or “transplantable” disease at presentation, and surgery carries a high recurrence rate (13–16). Somatostatin analogues are the most effective pharmacologic therapy for symptom control, and traditional chemotherapy has limited efficacy (17,18). Given the lack of an ideal solution for NET liver metastases with surgery or pharmacotherapy and the tendency for recurrence of disease, a minimally invasive approach that is effective but well tolerated is needed for symptom control. Interventional radiologic options in liver tumors include embolization and ablative techniques (19–24). Data from studies on RF ablation in primary hepatocellular carcinoma suggest that RF ablation is effective in this disease and has several advantages, as it can be used repeatedly and has a low sideeffect profile (7,8,25). NETs have distinct and varied tumor biology, which provides a rationale to study them as a group separate from other tumors (26). The present study aimed to determine whether RF ablation provides symptom control in NET liver metastases.
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MATERIALS AND METHODS Search Strategy A systematic review was conducted with reference to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (27). The PRISMA statement was designed to promote accurate and clear reporting of systematic reviews and meta-analyses. Two reviewers independently performed a literature search by using MEDLINE and the Cochrane Central Register of Controlled Trials to identify articles relevant to RF ablation in NET liver metastases. Search terms used were “neuroendocrine,” “NET,” “carcinoid,” “hepatic,” “catheter ablation,” “thermal ablation,” “radiofrequency ablation,” and “RF ablation.” Abstracts were screened for relevance, and full-text articles were retrieved. These were independently analyzed and assessed for eligibility by both reviewers. The reference lists of these articles were studied to identify additional relevant papers.
Inclusion Criteria Only English-language articles were included. Individual case reports were excluded, as were animal studies. There were no date limitations and no other limitations on study type. Studies performed with curative and palliative intent were included. There was no restriction on the type of RF generators or electrode design used in the studies. In cases in which more than one study had been published from an individual center, only the most recent or relevant was included to avoid counting patients twice in cases in which patient populations overlapped.
Data Extraction Data extraction was performed independently by two reviewers with the use of a predefined data extraction template (Table E1 [28], available online at www.jvir. org). Data fields included complications, symptom relief, and survival.
Quality Assessment No randomized controlled trial was identified comparing RF ablation versus other treatment modalities for NET liver metastases. All studies were retrospective case series reporting single-center experiences with RF ablation for NET. The PRISMA statement makes inclusion of a quality assessment mandatory (27). Downs and Black (28) described a checklist for the assessment of quality of randomized and nonrandomized studies in 1998, with 27 checklist items. The Downs and Black checklist was modified by one of the present authors (H.M.) to allow it to be used to assess study quality for the present series of nonrandomized studies. With this modified score, a maximum score of 14 was possible, with higher scores reflecting higher quality of studies (Table E2 [14,15,29– 34], available online at www.jvir.org). In view of the low
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quality of studies in the present review, a meta-analysis was not performed. Instead, a systematic review was performed to present the data as they currently stand. There is a need for high-quality randomized controlled trials in this area.
Statistical Analysis Because of the heterogeneity of the data, meta-analysis was not performed. Means are given as weighted means unless stated otherwise.
RESULTS After removal of duplicates, the literature search retrieved 1,550 titles, of which 13 met the inclusion criteria. All were retrospective case series (Fig). These 12 studies were from eight centers in four countries (United States, Sweden, France, and United Kingdom) (14,15,29–39). When overlapping patient cohorts from the same center were excluded, eight studies were left in the final analysis (14,15,29–34). Of these, seven reported outcomes following RF ablation for NETs alone. Amersi et al (31) reported results following RF ablation for liver metastases from a variety of primary tumors, but it was possible to separate NET results from other tumors, which enabled the study’s inclusion. All studies were retrospective; no study scored higher than 11 of 14 on quality assessment per the modified Downs and Black checklist (Table E2).
Demographics A total of 301 patients (Table) with NET liver metastases underwent RF ablation from 1994 to 2009, with more than 595 ablation procedures performed for 978 tumors (14,15,29–34). “Carcinoid tumors” were the most common primary NET in included studies (59%), followed by nonfunctional pancreatic NETs (21%) and functional pancreatic NETs (13%). Other primary tumors included medullary thyroid cancer and adrenal carcinomas. The presence of extrahepatic disease was recorded in four studies (14,29,30,34), with a weighted mean of 22% with extrahepatic disease (range, 8%–29%). The number of tumors per patient was reported in five studies (14,29,31,32,34), with a mean of 4.5 tumors per patient. The range of tumors per patient was reported in five studies (15,29,30,32,34), with a range of one to 21 tumors. Elias et al (14) did not report a range, but all patients in this study had more than 15 liver metastases. Only four studies gave the mean size of the tumors (n ¼ 141), with a weighted mean size of 3.8 cm (range, o 1 to 8 cm).
Indications for RF Ablation and Patient Selection Patient selection criteria for RF ablation were heterogeneous among studies with palliative or curative intent. In
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Records idenfied through database searching (n = 3272)
Addional records idenfied through other sources (n = 2)
Titles Screened aer duplicates removed (n = 1550)
Abstracts Screened (n = 117)
Full-text arcles assessed for eligibility (n = 37)
Excluded Titles (n = 1433)
Excluded Abstracts (n = 80)
Full-text arcles excluded, with reasons (n = 29)
Studies included in qualitave synthesis (n = 8) Figure. Search strategy according to PRISMA template.
total, 124 patients underwent RF ablation as a palliative procedure, 101 procedures were performed with potential curative intent, and the intent of the remainder was not clear. There was considerable variability in patient selection criteria for RF ablation in the included studies (Table), such as in the number of tumors per patient. For example, Akylidiz et al (29) included patients with a maximum of 15 tumors whereas Elias et al (14) included patients with a minimum of 15 tumors. There were three main indications for RF ablation in the included studies: (a) as an adjunct to surgery for resected lesions, (b) for treatment for unresectable lesions, and (c) as a salvage therapy where other treatments have failed. As a mainstay of treatment for unresectable disease in those who had not undergone previous attempts at local control, for example, Henn et al (34) used RF ablation as a stand-alone treatment in patients with unresectable tumors who had not received treatment for liver metastases (n ¼ 7). As salvage therapy in patients in whom other local control attempts had failed, for example, Akyildiz et al (29) studied patients who showed no response to other therapies, including octreotide, systemic chemotherapy, chemoembolization, liver resection, interferon, and yttrium 90–labeled octreotide, and Wessels and Schell (32) included only patients with unresectable disease who had undergone failed selective hepatic artery embolization. RF ablation was also used as an adjunct to surgery, with remaining unresectable lesions treated with RF ablation, or as a stand-alone therapy for unresectable lesions (14,15,30,31,33). Taner et al (33) and Elias et al (14) used RF ablation as an
adjunct to surgery, whereas Amersi et al (31), Elvin et al (15), and Gillams et al (30) used RF ablation as an adjunct to surgery or as a stand-alone therapy for unresectable disease.
Pretreatment Imaging All patients underwent preoperative imaging to detect and characterize the liver lesions and detect extrahepatic disease. The most common methods were computed tomography (CT) of the thorax, abdomen, and pelvis for staging, and triphasic liver CT. Multiphase contrastenhanced magnetic resonance (MR) imaging of the liver (33), ultrasonography (US) of the liver (14), and somatostatin receptor scintigraphy (14) were also used. Only one study (15) specifically mentioned the use of contrast-enhanced US.
RF Ablation Technique The majority of studies in the present review used general anesthesia for RF ablation, even in cases of percutaneous RF ablation (of seven studies that reported anesthesia used [14,15,30,31,33–35], general anesthesia was used in 88% of procedures). One study (15) initially used local anesthesia, but switched to general anesthesia for improved pain control and because the investigators believed general anesthesia facilitated complete tumor ablation. RF ablation procedures in six of the eight studies were US-guided or intraoperative US–guided (14,29–33), one was contrast-enhanced US–guided (15), and Henn et al (34) used CT guidance.
4 ’
Study,
Local
Country
No. of
Mean
Sex
NET
Symptoms
Concomitant
Follow-up
Morbidity
Procedural 5-y Survival
Recurrence
after RF (mo)
(per Lesion)
of Origin
Pts.
Age (y)
(M/F)
Only
(%)
Resection
Technique
(mo)
(%)
Mortality
Akyildiz et al
89
56
54/35
Yes
44 (n ¼ 39)
No
119 Laparoscopic
30
6.0
1
(29), U.S. Gillams et al
25
56
13/12
Yes
56 (n ¼ 14)
Yes (1/25)
65 Percutaneous,
21
12
1
NR
OS 29
NR
(30), U.K.
(%)
Survival
5-y OS 57 DFS 15, OS 72
7.90%
1 open
Amersi et al (31), U.S.
25
NR
NR
No
NR
No
NR
NR
NR
NR
NR
OS 48.3
20% of 4 3 cm
Henn et al
7
56
1/6
Yes
100 (n ¼ 7)
No
7 Percutaneous
22.9*
57
0
NR
NR
NR
(34), U.S. Wessels and
3
39.6
1/2
Yes
100 (n ¼ 3)
No
2 Open, 1
6
NR
0
NR
NR
NR
Schell (32), U.S. Elias et al
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Table . Demographics and Outcomes following RF Ablation for NETs (14,15,29–34)
laparoscopic 16
48
7/9
Yes
31 (n ¼ 5)
Yes (13/16)
197 Open
27
62.5
0
3-y OS 84
NR
NR
42
61.2
19/23
Yes
NR
Yes (23/42)
84 Percutaneous,
NR
NR
NR
NR
NR
NR
58*
1.06
0
5-y OS 80,
SFS 24
4.25%
(14), France Elvin et al (15), Sweden Taner et al (33), U.S.
25 open 94
53.7
41/53
Yes
62 (n ¼ 59)
Yes (all 94)
94 Open
SFS 16
Note.–Follow-up given as median unless denoted by *, where mean is given. DFS ¼ disease-free survival, NET ¼ neuroendocrine tumor, NR ¼ not reported, OS ¼ overall survival, RF ¼ radiofrequency, SFS ¼ symptom-free survival.
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Only two studies (32,34) reported that pre- or periprocedural infusions of octreotide were administered; in both cases, it was reserved for severely symptomatic patients or patients with cardiac carcinoid features. Prednisolone was also given with octreotide in one study (34). The majority of RF ablation procedures were conducted at surgery (73% at surgery [n ¼ 319 open, n ¼ 120 laparoscopic], 26% percutaneous [n ¼ 156]). Fortyeight percent of patients (131 of 276 recorded) had concomitant liver resection. RF ablation applicator insertion was guided by US in the majority of percutaneous and operative cases (Table). Henn et al (34) used a percutaneous approach with CT guidance, whereas Gillams et al (30) used CT for a subset of lesions not visualized on US. Intraprocedural treatment monitoring of therapy was not performed.
Procedural Morbidity and Mortality There were two deaths among the studies in the present series, yielding an overall mortality rate of 0.7% (two of 301). The deaths were caused by a carcinoid crisis in a patient with severe carcinoid heart disease (30) and abdominal sepsis from a colonic perforation in a patient who underwent laparoscopic RF ablation (29). The overall morbidity rate was 10% (Table). Complications reported included hemorrhage, abscess, viscus perforation, bile leak, biliopleural fistula, transient liver insufficiency, pneumothorax, grounding pad burn, urinary retention, pneumonia, and pleural effusions. As 48% of patients had a concomitant liver resection, the true rate of complications from RF ablation itself is difficult to deduce accurately from the included studies, and it is similarly difficult to separate results from percutaneous and surgical RF ablation. The study by Akyildiz et al (29) is a series of patients who did not undergo concomitant liver resection but had RF ablation via a laparoscopic approach, and they reported a morbidity rate of 6%, with one death caused by intraabdominal sepsis, and two cases of hemorrhage.
Symptom Relief Six studies with a total of 234 patients reported whether patients had symptoms before RF ablation. Overall, 54% of patients (127 of 234) were reported to have had symptoms. Following RF ablation, 92% of patients were reported to have experienced partial or complete symptom relief (117 of the 127 symptomatic patients). The median duration of symptom relief reported ranged from 14 to 27 months (29,34). There was a lack of clarity in studies regarding methods of symptom assessment. Only two studies actually reported a formal neuroendocrine symptom score (32,34). Wessels and Schell (32) used a scoring system they had devised specifically for malignant carcinoid syndrome symptoms, which consisted of
5
a five-point Likert scale ranging from 1 (no symptoms) to 5 (disabling symptoms). Henn et al (34) used and referenced this symptom score Wessel and Schell (32) had previously described. These two studies also recorded whether somatostatin analogue requirements were altered (32,34). Similarly, the time at which symptoms were assessed varied widely among studies, with only three studies (29,32,34) specifying a time frame after the procedure. Among these three studies (29,32,34), timing varied from at 1 week to within 4 weeks to after 8 months. Data regarding alteration of somatostatin analogue dosing after RF ablation are incomplete. In two series that included only 10 patients in total (32,34), three patients were able to stop somatostatin analogue therapy and another two patients were able to reduce their dosage.
Follow-up and Recurrence Median follow-up ranged from 6 to 58 months (absolute range, 3 mo to 13 y). Most studies conducted early postprocedural CT within 1 week of RF ablation to establish a baseline for subsequent follow-up and detect incomplete ablation (14,15,29–32) (Table). Follow-up imaging varied among studies, as did reporting of recurrence rates. Elvin et al (15) demonstrated a 10% local recurrence rate on follow-up imaging, detected as an area of increased vascularity on CT or Doppler US, but did not report their overall recurrence rate. Their follow-up CT schedule was at 48 hours, every 3 months for 1 year, and then every 6 months, with positron emission tomography as required (15). Elias et al (14) reported a 67% overall recurrence rate and a 50% local recurrence rate at a median follow-up of 27 months. However, they used CT before discharge and then US, MR imaging, and somatostatin analogue scintigraphy every 6 months thereafter (14). This was also a high-risk patient cohort, as each patient had at least 15 tumors at baseline (14). Wessels and Schell (32) reported on a cohort of only three patients and did not report a local recurrence rate. Follow-up was with CT at 1 week, 4 weeks, and 12 weeks (32). Taner et al (33) reported a 4.2% local recurrence rate, with 22% undergoing further RF ablation for progressive metastases. The follow-up imaging method was not reported. Akyildiz et al (29) reported a 22% local recurrence rate and a 60% overall recurrence rate, and follow-up was performed with contrast-enhanced liver CT at 1 week, then CT of the thorax, abdomen, and pelvis every 3 months for 2 years and every 6 months thereafter, in addition to tumor marker assessments. Amersi et al (31) used an almost identical follow-up regimen to Akyildiz et al (29) and reported a similar local recurrence rate of 20% (31). Henn et al (34) did not report imaging follow-up or local recurrence rates, but, based on symptom assessment via telephone, two of the five patients who experienced
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symptom relief with RF ablation developed recurrence of their symptoms. Gillams et al (30) reported an 8% local recurrence rate and a 40% local recurrence rate. MR imaging and CT were used for follow-up, but the timing was not specified.
Survival Data were too heterogeneous to combine and analyze overall 5-year survival rates and factors predictive of outcomes. Reported 5-year survival rates ranged from 57% to 80%. Factors identified on analysis within individual studies as statistically significant predictors of poor survival were greater liver metastasis volume (4 70 mL) (29), presence of symptoms (29), male sex and extrahepatic disease (29), and high Ki-67 proliferative index (4 3.5) (33). No matched or unmatched historical or randomized comparison of survival without RF ablation was available.
DISCUSSION The present review demonstrates that RF ablation is a good option as a palliative treatment because it has a low side-effect profile and can provide symptom relief. RF ablation can yield sustained medium-term symptomatic relief by reducing the viable tumor burden in the liver. This may in turn reduce the dose of somatostatin analogue required. In the setting of a significant recurrence rate after attempted cure, RF ablation can be repeated for symptomatic palliation. The present study highlights that there is a paucity of high-quality data on RF ablation for NET liver metastases. This is in keeping with the findings of a previous Cochrane review (40) that was precluded from drawing any conclusion about surgery versus other treatments for neuroendocrine liver metastases as a result of the low quality of studies available. The low quality of included studies limited the ability of the present review to determine whether RF ablation has benefits versus surgery or conveys a survival advantage. However, this does not mean that the current literature on RF ablation for NET should be ignored; rather, it must be interpreted with caution and provides a rationale for future prospective studies. The principal advantage of RF ablation is that it is well tolerated, with low mortality and morbidity rates compared with surgery alone. In the present review, there were two deaths among a total cohort of 301 patients with NET liver metastases. This compares favorably with mortality rates reported with other locoregional therapies such as embolization (34,41,42). There was one death as a result of the hormonal nature of NET, as one patient died of a carcinoid crisis (29). Overall, the mortality rate of RF ablation for NET was similar to that reported for nonneuroendocrine tumors (41). The 10% complication rate in the present review
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was higher than in previous studies (41). However, 48% of patients in the present review underwent concomitant liver resection, making it difficult to assess the true complication rate from RF ablation alone, as many complications were surgical in nature. Indeed, a recent systematic review of surgical resection (43) reported a median complication rate of 23%. In addition, the number of liver metastases per patient was relatively high in some included studies; for example, Elias et al (14) reported a 62.5% complication rate, but used RF ablation and surgery in 13 of 16 patients and included only patients with a high tumor burden (4 15 liver metastases). Differences in complication rates may also result from variability in reporting between studies. For example, on first glance, Henn et al (34) appear to have a high complication rate of 57%, but this study includes only seven patients in total, and there were four minor complications and no major complications. Other studies with lower complication rates may indeed have low complication rates, or, alternatively, may have reported only major complications. From a practical perspective, RF ablation is timeconsuming and requires rigorous planning, with lesion identification, applicator insertion (under image guidance), and treatment delivery. This process can take an average of 30 minutes per lesion (44). The number of RF ablation applicator placements and treatment deliveries depends on the lesion diameter and selected ablation device. Examination of this process of planning and treatment delivery was beyond the scope of the present review. The present study is limited by the retrospective nature of the included studies, with heterogeneous patient selection, RF ablation methods, treatment algorithms, combinations with other therapies, follow-up imaging protocols, and nonstandardized terminology and reporting. Five of the eight articles in the review were published before the publication of the guidelines for standardization of terminology and reporting criteria in 2005 (19). Of the articles published since 2005 (14,29,33), only one—that of Elias et al (14)—complies with terminology and reporting criteria. A survival advantage after RF ablation of liver metastases cannot be confirmed on the basis of the available data, as studies are heterogeneous in patient selection, methodology, and reporting. Only two studies reported 5-year survival (29,33). Further studies are needed with standardized reporting of patient selection, complications, and outcomes with the use of scoring systems such as the Clavien–Dindo classification for surgical complications (45). To properly assess the impact of RF ablation on long-term symptom relief, tumor burden, and survival, prospective multicenter studies or registries with standardized reporting criteria are needed. In conclusion, RF ablation can provide symptomatic relief in NET liver metastases alone or in combination with surgery. However, there are insufficient data to
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determine whether RF ablation improves survival or recurrence. Prospectively gathered data are needed to guide treatment algorithms.
REFERENCES 1. Lewis MA, Hobday TJ. Treatment of neuroendocrine tumor liver metastases. International journal of hepatology 2012; 2012:973946. 2. Steinmuller T, Kianmanesh R, Falconi M, et al. Consensus guidelines for the management of patients with liver metastases from digestive (neuro)endocrine tumors: foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 2008; 87:47–62. 3. Pavel M, Baudin E, Couvelard A, et al. ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 2012; 95:157–176. 4. Panzuto F, Nasoni S, Falconi M, et al. Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocrine-related cancer 2005; 12:1083–1092. 5. Madeira I, Terris B, Voss M, et al. Prognostic factors in patients with endocrine tumours of the duodenopancreatic area. Gut 1998; 43: 422–427. 6. Tomassetti P, Campana D, Piscitelli L, et al. Endocrine pancreatic tumors: factors correlated with survival. Annals of oncology: official journal of the European Society for Medical Oncology / ESMO 2005; 16: 1806–1810. 7. Jansen MC, van Hillegersberg R, Chamuleau RA, van Delden OM, Gouma DJ, van Gulik TM. Outcome of regional and local ablative therapies for hepatocellular carcinoma: a collective review. European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 2005; 31:331–347. 8. Tiong L, Maddern GJ. Systematic review and meta-analysis of survival and disease recurrence after radiofrequency ablation for hepatocellular carcinoma. The British journal of surgery 2011; 98:1210–1224. 9. Boame N, Gresham G, Jonker D, Martel G, Balaa F, Asmis T. Use of chemotherapy and radiofrequency ablation to treat colorectal cancer metastases: a retrospective review of The Ottawa Hospital Cancer Centre over 7 years. Current oncology 2014; 21:e557–e563. 10. Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Annals of surgery 2004; 239:818–825, discussion 25-7. 11. Weng M, Zhang Y, Zhou D, et al. Radiofrequency ablation versus resection for colorectal cancer liver metastases: a meta-analysis. PloS one 2012; 7:e45493. 12. Horsch D, Grabowski P, Schneider CP, et al. Current treatment options for neuroendocrine tumors. Drugs of today 2011; 47:773–786. 13. Fan ST, Le Treut YP, Mazzaferro V, et al. Liver transplantation for neuroendocrine tumour liver metastases. HPB: the official journal of the International Hepato Pancreato Biliary Association 2014. 14. Elias D, Goere D, Leroux G, et al. Combined liver surgery and RFA for patients with gastroenteropancreatic endocrine tumors presenting with more than 15 metastases to the liver. European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 2009; 35:1092–1097. 15. Elvin A, Skogseid B, Hellman P. Radiofrequency ablation of neuroendocrine liver metastases. Abdominal imaging 2005; 30:427–434. 16. Kianmanesh R, Sauvanet A, Hentic O, et al. Two-step surgery for synchronous bilobar liver metastases from digestive endocrine tumors: a safe approach for radical resection. Annals of surgery 2008; 247: 659–665. 17. Madoff DC, Gupta S, Ahrar K, Murthy R, Yao JC. Update on the management of neuroendocrine hepatic metastases. Journal of vascular and interventional radiology: JVIR 2006; 17:1235–1249. 18. Kloppel G, Couvelard A, Perren A, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: towards a standardized approach to the diagnosis of gastroenteropancreatic neuroendocrine tumors and their prognostic stratification. Neuroendocrinology 2009; 90:162–166.
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19. Goldberg SN, Grassi CJ, Cardella JF, et al. Image-guided tumor ablation: standardization of terminology and reporting criteria. Journal of vascular and interventional radiology: JVIR 2005; 16:765–778. 20. Dodd GD 3rd, Soulen MC, Kane RA, et al. Minimally invasive treatment of malignant hepatic tumors: at the threshold of a major breakthrough. Radiographics: a review publication of the Radiological Society of North America, Inc 2000; 20:9–27. 21. Melodelima D, Vincenot J, Chen Y, Dupre A, Rivoire M, Chapelon JY. Thermal ablation by high-intensity-focused ultrasound using a toroidal transducer for the treatment of colorectal liver metastases during an open procedure. Clinical results. The Journal of the Acoustical Society of America 2013; 133:3410. 22. Goldberg SN, Grassi CJ, Cardella JF, et al. Image-guided tumor ablation: standardization of terminology and reporting criteria. Radiology 2005; 235:728–739. 23. McCarley JR, Soulen MC. Percutaneous ablation of hepatic tumors. Seminars in interventional radiology 2010; 27:255–260. 24. Yang TX, Chua TC, Morris DL. Radioembolization and chemoembolization for unresectable neuroendocrine liver metastases - a systematic review. Surgical oncology 2012; 21:299–308. 25. Eltawil KM, Boame N, Mimeault R, et al. Patterns of recurrence following selective intraoperative radiofrequency ablation as an adjunct to hepatic resection for colorectal liver metastases. Journal of surgical oncology 2014. 26. Schimmack S, Svejda B, Lawrence B, Kidd M, Modlin IM. The diversity and commonalities of gastroenteropancreatic neuroendocrine tumors. Langenbeck’s archives of surgery / Deutsche Gesellschaft fur Chirurgie 2011; 396:273–298. 27. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS medicine 2009; 6:e1000100. 28. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and nonrandomised studies of health care interventions. Journal of epidemiology and community health 1998; 52:377–384. 29. Akyildiz HY, Mitchell J, Milas M, Siperstein A, Berber E. Laparoscopic radiofrequency thermal ablation of neuroendocrine hepatic metastases: long-term follow-up. Surgery 2010; 148:1288–1293, discussion 93. 30. Gillams A, Cassoni A, Conway G, Lees W. Radiofrequency ablation of neuroendocrine liver metastases: the Middlesex experience. Abdominal imaging 2005; 30:435–441. 31. Amersi FF, McElrath-Garza A, Ahmad A, et al. Long-term survival after radiofrequency ablation of complex unresectable liver tumors. Arch Surg 2006; 141:581–587, discussion 7-8. 32. Wessels FJ, Schell SR. Radiofrequency ablation treatment of refractory carcinoid hepatic metastases. The Journal of surgical research 2001; 95: 8–12. 33. Taner T, Atwell TD, Zhang L, et al. Adjunctive radiofrequency ablation of metastatic neuroendocrine cancer to the liver complements surgical resection. HPB: the official journal of the International Hepato Pancreato Biliary Association 2013; 15:190–195. 34. Henn AR, Levine EA, McNulty W, Zagoria RJ. Percutaneous radiofrequency ablation of hepatic metastases for symptomatic relief of neuroendocrine syndromes. AJR American journal of roentgenology 2003; 181:1005–1010. 35. Mazzaglia PJ, Berber E, Milas M, Siperstein AE. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases: a 10-year experience evaluating predictors of survival. Surgery 2007; 142:10–19. 36. Berber E, Flesher N, Siperstein AE. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases. World journal of surgery 2002; 26:985–990. 37. Hellman P, Ladjevardi S, Skogseid B, Akerstrom G, Elvin A. Radiofrequency tissue ablation using cooled tip for liver metastases of endocrine tumors. World journal of surgery 2002; 26:1052–1056. 38. Eriksson J, Stalberg P, Nilsson A, et al. Surgery and radiofrequency ablation for treatment of liver metastases from midgut and foregut carcinoids and endocrine pancreatic tumors. World journal of surgery 2008; 32:930–938. 39. Karabulut K, Akyildiz HY, Lance C, et al. Multimodality treatment of neuroendocrine liver metastases. Surgery 2011; 150:316–325. 40. Gurusamy KS, Ramamoorthy R, Sharma D, Davidson BR. Liver resection versus other treatments for neuroendocrine tumours in patients with resectable liver metastases. The Cochrane database of systematic reviews 2009:CD007060.
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41. Livraghi T, Solbiati L, Meloni MF, Gazelle GS, Halpern EF, Goldberg SN. Treatment of focal liver tumors with percutaneous radio-frequency ablation: complications encountered in a multicenter study. Radiology 2003; 226:441–451. 42. Brown KT, Koh BY, Brody LA, et al. Particle embolization of hepatic neuroendocrine metastases for control of pain and hormonal symptoms. Journal of vascular and interventional radiology: JVIR 1999; 10:397–403.
Mohan et al
’
JVIR
43. Saxena A, Chua TC, Perera M, Chu F, Morris DL. Surgical resection of hepatic metastases from neuroendocrine neoplasms: a systematic review. Surgical oncology 2012; 21:e131–e141. 44. de Jong KP, Wertenbroek MW. Liver resection combined with local ablation: where are the limits? Digestive surgery 2011; 28:127–133 45. Clavien PA, Sanabria JR, Strasberg SM. Proposed classification of complications of surgery with examples of utility in cholecystectomy. Surgery 1992; 111:518–526.
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Table E1 . Modified Downs and Black Quality Assessment Scoring System (28) Reporting 1. Is the hypothesis/aim/objective of the study clearly described? 2.
Are the main outcomes to be measured clearly described in the introduction or methods section?
3. 4.
Are the characteristics of the patients included in the study clearly described? Are the interventions of interest clearly described? (Ie, Is the type of RF ablation clearly described?)
5.
Are the main findings of the study clearly described?
6.
Have all the important adverse events that may be a consequence of the intervention been reported (ie, perioperative complications)?
7.
Have the characteristics of patients lost to follow-up been described?
External validity 8. Were the subjects asked to participate in the study representative of the entire population from which they were recruited? 9.
Were those subjects who were prepared to participate representative of the entire population from which they were recruited?
10.
Were the staff, places, and faculties where the patients were treated representative of the treatment the majority of patients receive? (Ie, are RF ablation methods in this study similar to in other studies included?)
Internal validity 11. 12.
Was an attempt made to blind those measuring the main outcomes of the intervention? If any of the results of the study were based on “data dredging,” was this made clear?
a.
Are all planned analyses in the methods section?
b. c.
Were the statistical tests used to assess the main outcomes appropriate? Were the main outcome measures used accurate (valid and reliable)?
Table E2 . Modified Downs and Black Checklist Scores for Each Included Study (12,13,29,35–39) Study Akyildiz et al (29) Gillams et al (30)
Score 11 10
Amersi et al (31)
5
Henn et al (34) Wessels and Schell (32)
9 8
Elias et al (14)
9
Elvin et al (15) Taner et al (33)
7 9
Maximum score
14
