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Radiofrequency ablation for recurrent intrahepatic cholangiocarcinoma after curative resection
European Journal of Radiology 80 (2011) e221–e225
Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Radiofrequency ablation for recurrent intrahepatic cholangiocarcinoma after curative resection Jin Hyoung Kim a,∗ , Hyung Jin Won a , Yong Moon Shin a , Pyo Nyun Kim a , Sung-Gyu Lee b , Shin Hwang b a b
Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 28 July 2010 Accepted 20 September 2010 Keywords: Intrahepatic cholangiocarcinoma Hepatectomy Radiofrequency ablation CT
a b s t r a c t Objective: Percutaneous radiofrequency ablation (RFA) has shown efficacy in patients with recurrent hepatocellular carcinoma, but has not been well documented in patients with recurrent intrahepatic cholangiocarcinoma (ICC). We therefore evaluated the long-term survival and safety of percutaneous RFA for patients with recurrent ICC after curative resection. Materials and methods: A total of 20 patients with 29 recurrent ICCs underwent ultrasound-guided percutaneous RFA. All patients had undergone curative resection of the primary ICC. Tumor size ranged from 0.7 cm to 4.4 cm in maximum dimension (mean, 1.9 cm; median, 1.5 cm). Results: The technical effectiveness rate of RFA was 97% (28/29) of recurrent ICCs. Mean local tumor progression-free survival was 39.8 months, and the cumulative local tumor progression-free 6 month and 1, 2, and 4 year survival rates were 93%, 74%, 74%, and 74%, respectively. Median overall survival after RFA was 27.4 months and the cumulative overall 6 month and 1, 2, and 4 year survival rates were 95%, 70%, 60%, and 21%, respectively. There were two major complications (one liver abscess and one biliary stricture, 7% per treatment) during the follow-up, but no procedure-related deaths. Conclusion: RFA is safe and provides successful local tumor control in patients with recurrent ICC after curative resection. RFA for recurrent ICC resulted in a median overall survival rate of 27.4 months after RFA in the present series. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy after hepatocellular carcinoma (10% vs 90%, respectively), and its global incidence and mortality are increasing [1–4]. Although surgical resection currently represents the only form of curative therapy, there is frequent recurrence after curative resection. This has kept patient survival rates after surgical resection remain low, ranging from 20% to 43% at 5 years [5–8]. Repeat surgery for recurrent ICC after curative resection is frequently limited by poor remnant liver function or multifocal recurrence. Therefore, most patients with recurrent ICC receive palliative therapy, including systemic chemotherapy and/or radiation therapy. However, such options are usually only of limited benefit since ICCs generally respond poorly [9].
∗ Corresponding author at: Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Poongnap-2dong, Songpa-gu, Seoul 138-736, Republic of Korea. Tel.: +82 2 3010 4384; fax: +82 2 476 0090. E-mail address: [email protected] (J.H. Kim). 0720-048X/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2010.09.019
Percutaneous radiofrequency ablation (RFA) has been shown to be a safe and successful method for local tumor control in patients with recurrent hepatocellular carcinoma after surgery and has become increasingly used in these patients [10–12]. To our knowledge, however, study focusing on RFA for recurrent ICC after hepatic resection has been scarce [13,14]. We therefore evaluated the longterm survival results and complications of percutaneous RFA in 20 patients with 29 recurrent ICCs after curative resection. 2. Materials and methods 2.1. Patient population Our institutional review board approved this retrospective review of the patients’ medical and imaging records. Inclusion criteria of RFA were recurrent ICC ≤5 cm in maximum diameter, three or fewer recurrent ICCs, no imaging evidence of vascular invasion by the tumor, and no evidence of extrahepatic disease. Exclusion criteria included recurrent ICCs >5 cm in maximum diameter, multiple (>3) ICCs, poor performance status (Eastern Cooperative Oncology Group performance status rating grade 2–4), presence of vascular invasion, extrahepatic metastases, and coagulopathy (platelet count < 50 × 103 /L; international normalized ratio > 1.5).
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We identified a total of 20 patients with 29 recurrent ICCs who underwent RFA between October 1999 and March 2009. All patients had undergone curative resection of the primary ICC. Surgical resection consisted of right or left lobectomy in 12 patients, extended right or left lobectomy in 4 patients, segmentectomy in 2 patients, and bisegmentectomy in 2 patients. None of these patients had underlying liver cirrhosis. Six patients (30%) were positive for hepatitis B virus, and 1 (5%) was positive for hepatitis C virus. The diagnosis of recurrent ICC was based on the histologic results of image-guided percutaneous needle biopsy in 7 patients and the identification of newly presenting tumors on contrast-enhanced CT and/or whole-body PET (F-18 FDG) in the remaining 13 patients. The median time to recurrence was 7.4 months (range: 1.4–95.7 months), with 14 patients (60%) showing intrahepatic recurrence within 1 year after curative resection. Tumor sizes ranged from 0.7 cm to 4.4 cm in maximum dimension (mean, 1.9 cm; median, 1.5 cm). Of the 29 tumors, 25 had diameters ≤3 cm, and four had diameters of 3–5 cm. 2.2. Radiofrequency ablation technique RFA was performed percutaneously under ultrasonographic guidance, with the patient under conscious sedation and local anesthesia. A single or a cluster needle, internally cooled electrode (ValleyLab, Burlington, MA) was used, depending on tumor size, and radiofrequency current was emitted for 12 or 15 min by a 200 W generator set to deliver maximum power with the automatic impedance control method. Each tumor received one to five ablations (mean, 1.6 ablations) per session, based on tumor size and shape. 2.3. Follow-up Immediately after RFA, a contrast-enhanced CT scan was performed to evaluate possible complications such as bleeding or fluid collection. The efficacy of RFA was evaluated by contrast-enhanced CT 1 month after the procedure. Patients with residual tumor in the ablated area underwent an additional session of RFA for the residual lesion. In cases of complete ablation of the tumor, with no appearance of a new tumor in other liver sites on 1-month follow-up CT, subsequent follow-up contrast-enhanced CT scans were repeated every 2–3 months. All new tumors in the ablated lesion or in other liver sites that emerged during follow-up were treated with RFA if the patient still met the requirement for RFA. 2.4. Definition and evaluation of data Using the Society of Interventional Radiology reporting standards [15], technical effectiveness was defined as complete ablation of the tumor, as shown on imaging follow-up 1 month after the procedure. An irregular or nodular peripheral enhancement of the ablated area was considered a residual tumor at the ablation margin and a treatment failure. Local tumor progression was considered when nodular or irregular enhancement was seen during follow-up imaging (after 1 month). Major complications were defined as any event that resulted in additional treatment, including an increased level of care, hospital stay beyond observation status (including readmission after initial discharge), and permanent adverse sequelae, including substantial morbidity and disability, and death. All other complications were classified as minor. The local tumor progression-free survival period was calculated using the Kaplan–Meier method. Tumor size was dichotomized relative to the median (1.5 cm) and the local tumor progression-free survival curves of patients with tumors ≥1.5 cm and <1.5 cm were
Fig. 1. Contrast-enhanced axial computed tomography (CT) images of a 62-year-old patient with hepatic recurrence after segmentectomy for intrahepatic cholangiocarcinoma. (a) Image in the portal phase 1 month before radiofrequency ablation (RFA), showing a recurrent tumor (arrowhead) (1.2 cm in largest diameter) in segment V. (b) Image obtained 1 month after RFA, showing good local tumor control (arrowhead).
compared using the log-rank test. The local tumor progression-free survival period was measured in months from the date of initial RFA treatment and defined as the time interval between the initial RFA treatment and follow-up imaging showing local tumor progression. The overall survival and event-free survival periods were calculated using the Kaplan–Meier method on a patient-by-patient basis. The overall survival periods were measured in months from the date of diagnosis of hepatic recurrence and from the time of initial RFA. The overall survival period was defined as the time interval between initial RFA and patient death, and between diagnosis of recurrence and patient death. The event-free survival was defined as the time interval, in months, from the initial RFA to local tumor progression, occurrence of new ICC in the liver, distant metastasis, or death. 3. Results 3.1. Local tumor control Technical effectiveness was achieved in 28 of 29 tumors (97%) in 19 of 20 patients (95%) (Fig. 1). One patient showed a residual unablated tumor on 1-month follow-up CT. This patient underwent a secondary RFA, resulting in the complete ablation of the residual
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Fig. 3. Overall and event-free survival of 20 patients who underwent percutaneous radiofrequency ablation for recurrent intrahepatic cholangiocarcinoma after hepatectomy.
3.2. Overall and event-free survival periods after radiofrequency ablation
Fig. 2. Cumulative local tumor progression-free survival rates after radiofrequency ablation of (a) of all 29 tumors and (b) tumors <1.5 cm and ≥1.5 cm in diameter.
tumor; however new lesions in the liver and in the extrahepatic area occurred 2 months later, and this patient died of disease progression 9.5 months after initial RFA. Of the 28 tumors in which RFA showed technical effectiveness, six showed local tumor progression from 4 to 10.2 months (median, 8.1 months; mean, 7.6 months) after RFA. Three of these 6 tumors underwent repeat RFA, while the remaining three received supportive treatment only because of both intrahepatic and extrahepatic metastases. The mean local tumor progression-free survival period was 39.8 months (Fig. 2). The cumulative local tumor progression-free survival rates at 6 months and at 1, 2, and 4 years were 93%, 74%, 74%, and 74%, respectively. The local tumor progression-free survival period was significantly longer in patients with <1.5 cm than in those ≥1.5 cm (Fig. 2B) (P = 0.041).
The study period ended in April 2010, at which time, the patients had been followed up for 3.3–53.7 months (mean, 18 months; median, 12.8 months). Of the 20 patients, 7 were still alive while 13 had died, 11 of disease progression, one of pneumonia, and one of an infection related to a refractory biliary obstruction. No patient was lost-to follow up. The median overall survival periods after RFA and from the time of diagnosis of hepatic recurrence were 27.4 months and 28.4 months, respectively. The overall survival rates at 6 months and at 1, 2, 3 and 4 years after RFA were 95%, 70%, 60%, 21%, and 21%, respectively (Fig. 3). During the follow-up period, 12 of the 20 patients (60%) showed new lesions at other liver sites and/or in distant areas. Of these patients, 3 were treated with systemic chemotherapy and radiation therapy, 2 with surgery (one each for an intrahepatic tumor and a lung metastasis), and 1 with transarterial chemoembolization. The remaining 6 patients received supportive treatment only, including pain control, ascites control, and biliary drainage. The median event-free survival period after RFA was 6.1 months (Fig. 3). The event-free survival rates at 6 months and at 1, 2, and 4 years after RFA were 55%, 20%, 20%, and 20%. 3.3. Complications During the 29 radiofrequency ablation sessions, two major complications occurred (7%). Liver abscess developed at one ablated area 8 days after RFA in one patient. This patient was successfully treated with percutaneous drainage of the liver abscess and antibiotic therapy. One patient developed a biliary stricture after RFA requiring percutaneous transhepatic biliary drainage. There were no procedure-related deaths. Minor complications were also observed, including small amounts of pleural effusion around the ablated area in 8 patients and small hematomas in three. Follow-up CT scans showed that all of these disappeared 1 month after the procedure.
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4. Discussion Although surgical resection may provide only the curative option for ICC, patient prognosis after surgery is poor because of the high rate of recurrence [5–8]. Predictors of poor outcomes include positive resection margins, lymphatic and vascular invasion and periductal infiltrating disease, and preoperative CA 19-9 level [8,16,17]. The liver remnant is the most common single site of recurrence [8,16–18]. Survival from the time of recurrence is severely limited [7,19]. Repeat hepatectomy results in the complete resection of recurrent intrahepatic tumors, as well as providing the opportunity to explore the abdominal cavity for extrahepatic lesions. There are only few data regarding repeat hepatectomy for intrahepatic recurrence of ICC [20,21]. Among 7 patients with solitary ICC recurrence, Konstadoulakis et al. reported that the median survival time was 20 months in the 6 patients who received repeated hepatectomy [20]. However, repeat hepatectomy is frequently limited by poor remnant liver function or multifocal recurrence. In addition, technical and anatomic difficulties make repeat hepatectomy less feasible and more difficult to perform than initial hepatectomy. Furthermore, the liver remnant after initial hepatectomy frequently undergoes cirrhotic changes because of the parenchymal loss of the liver [11]. For these reasons, repeat hepatectomy may not be performed in most patients with recurrent ICC. Since 1990, when RFA was first used to treat hepatic tumors [22,23], it has been used more frequently because it can generate a well-controlled focal thermal injury with minimal morbidity and mortality [24]. Most recurrent ICC tumors are small, making percutaneous RF ablation feasible. In addition, percutaneous RFA is considered superior to repeat hepatectomy, both for safety and convenience, if survival results are approximately equal [11]. To our knowledge, this study is the first to evaluate long-term survival results and complications of percutaneous RFA in patients with recurrent ICC after curative resection. We found that RFA was technically effective in 97% of recurrent ICCs with no procedurerelated mortality. The mean local tumor progression-free period after RFA for recurrent ICC was 39.8 months and the cumulative 4-year local tumor progression-free survival rate was 74%. In agreement with previous findings, showing that tumor size was significantly associated with the local tumor progression-free survival after RFA for hepatic metastases from colorectal cancers [25], we found that tumors <1.5 cm showed significantly longer local tumor progression-free survival than tumors ≥1.5 cm after RFA for recurrent ICC (P = 0.041). In a recent series of 74 resected patients with ICC, Tamandl et al. stated that the median time between tumor recurrence and death was 16.4 months, and suggested that it might be increased by the use of a palliative treatment schedule [26]. During follow-up in the current study, we found that the median overall survival periods after RFA and from the time of diagnosis of hepatic recurrence were 27.4 months and 28.4 months, respectively. The median survival period (28.4 months) from tumor recurrence in the current study was longer than the reported survival length of 20 months [20] in patients who underwent repeat resection for hepatic recurrence of ICC. We observed 2 major complications after RFA for 29 recurrent ICCs (7%), comprising one liver abscess and one biliary stricture. RFA can thermally injure the bile ducts, resulting in bile duct strictures, as well as making an inadvertent connection between the biliary tree and the ablation zone. These ablation zones may become contaminated with enteric bacteria through the bilioenteric anastomosis, resulting in liver abscess [10].
The principal limitations of this study were its retrospective study design and the lack of a control group (especially, patients who underwent repeat hepatectomy). Nevertheless, we believe that results indicate that RFA may have a potential role in the treatment of recurrent ICC and provides support for prospective investigation. In conclusion, RFA is safe and provides successful local tumor control in patients with recurrent ICC after curative resection. RFA for recurrent ICC resulted in a median overall survival rate of 27.4 months after RFA in the current study. Further studies comparing the clinical outcomes of RFA and repeat hepatectomy in the treatment of recurrent ICC after curative resection are warranted. Conflict of interest The authors have no conflicts of interest and nothing to disclose. References [1] Shaib YH, El-Serag HB, Davila JA, et al. Risk factors of intrahepatic cholangiocarcinoma in the United States: a case–control study. Gastroenterology 2005;128(3):620–6. [2] Kim JH, Yoon HK, Sung KB, et al. Transcatheter arterial chemoembolization of chemoinfusion for unresectable intrahepatic cholangiocarcinoma: clinical efficacy and factors influencing outcomes. Cancer 2008;113(7):1614–22. [3] Khan S, Howard CT, Davidson BR, Taylor-Robinson SD. Cholangiocarcinoma. Lancet 2005;366(9493):1303–14. [4] Singal AG, Rakoski MO, Salgia R, et al. The clinical presentation and prognostic factors for intrahepatic and extrahepatic cholangiocarcinoma in a tertiary care centre. Aliment Pharmacol Ther 2010;31(6):625–33. [5] Jan YY, Yeh CN, Yeh TS, Hwang TL, Chen MF. Clinicopathological factors predicting long-term overall survival after hepatectomy for peripheral cholangiocarcinoma. World J Surg 2005;29(7):894–8. [6] Ohtsuka M, Ito H, Kimura F, et al. Extended hepatic resection and outcomes in intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg 2003;10(4):259–64. [7] Inoue K, Makuuchi M, Takayama T, et al. Long-term survival and prognostic factors in the surgical treatment of mass-forming type cholangiocarcinoma. Surgery 2000;127(5):498–505. [8] Cho SY, Park SJ, Kim SH, et al. Survival analysis of intrahepatic cholangiocarcinoma after resection. Ann Surg Oncol 2010;17(7):1823–30. [9] Malhi H, Gores GJ. Cholangiocarcinoma: modern advances in understanding a deadly old disease. J Hepatol 2006;45(6):856–67. [10] Choi D, Lim HK, Rhim H, et al. Percutaneous radiofrequency ablation for recurrent hepatocellular carcinoma after hepatectomy: long-term results and prognostic factors. Ann Surg Oncol 2007;14(8):2319–29. [11] Choi D, Lim HK, Kim MJ, et al. Recurrent hepatocellular carcinoma: percutaneous radiofrequency ablation after hepatectomy. Radiology 2004;230(1):135–41. [12] Yang W, Chen MH, Yin SS, et al. Radiofrequency ablation of recurrent hepatocellular carcinoma after hepatectomy: therapeutic efficacy on early- and late-phase recurrence. AJR (Am J Roentgenol) 2006;186(5 Suppl.):S275–83. [13] Oshima S, Takaishi K, Kurokawa E, et al. A case of successful management of recurrent intrahepatic cholangiocarcinoma by repeated radiofrequency ablations. Gan To Kagaku Ryoho 2009;36(12):2404–6 (in Japanese). [14] Park HS, Kim YJ, Park SW, et al. Hepatic vein pseudoaneurysm after radiofrequency ablation of recurrent intrahepatic cholangiocarcinoma managed with stent-graft placement. J Vasc Interv Radiol 2010;21(2):306–7. [15] Goldberg SN, Grassi CJ, Cardella JF, et al. Image-guided tumor ablation: standardization of terminology and reporting criteria. J Vasc Interv Radiol 2009;20(7 Suppl.):S377–90. [16] Endo I, Gonen M, Yopp AC, et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg 2008;248(1):84–96. [17] Aljiffry M, Walsh MJ, Molinari M. Advances in diagnosis, treatment and palliation of cholangiocarcinoma: 1990–2009. World J Gastroenterol 2009;15(34):4240–62. [18] Ercolani G, Vetrone G, Grazi GL, et al. Intrahepatic cholangiocarcinoma: primary liver resection and aggressive multimodal treatment of recurrence significantly prolong survival. Ann Surg 2010;252(1):107–14. [19] Yamamoto J, Kosuge T, Takayama T, et al. Surgical treatment of intrahepatic cholangiocarcinoma: four patients surviving more than five years. Surgery 1992;111(6):617–22. [20] Konstadoulakis M, Roayaie S, Gomatos IP, et al. Fifteen-year, single-center experience with the surgical management of intrahepatic cholangiocarcinoma: operative results and long-term outcome. Surgery 2008;143(3):366–74. [21] Kurosaki I, Hatakeyama K. Repeated hepatectomy for recurrent intrahepatic cholangiocarcinoma: report of two cases. Eur J Gastroenteraol Hepatol 2005;17(1):125–30.
J.H. Kim et al. / European Journal of Radiology 80 (2011) e221–e225 [22] McGahan JP, Browning PD, Brock JM, Teslik H. Hepatic ablation using radiofrequency electrocautery. Invest Radiol 1990;25(3):267–70. [23] Rossi S, Fornari F, Pathies C, Buscarini L. Thermal lesions induced by 480 kHz localized current field in guinea pig and pig liver. Tumori 1990;76(1):54–7. [24] Dodd GD, Soulen MC, Kane RA, et al. Minimally invasive treatment of malignant hepatic tumors: at the threshold of a major breakthrough. Radiographics 2000;20(1):9–27.
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[25] Stang A, Fischbach R, Teichmann W, Bokemeyer C, Braumann D. A systematic review on the clinical benefit and role of radiofrequency ablation as treatment of colorectal liver metastases. Eur J Cancer 2009;45(10):1748–56. [26] Tamandl D, Herberger B, Gruenberger B, Puhalla H, Klinger M, Gruenberger T. Influence of hepatic resection margin on recurrence and survival in intrahepatic cholangiocarcinoma. Ann Surg Oncol 2008;15(10):2787–94.
Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Radiofrequency ablation for recurrent intrahepatic cholangiocarcinoma after curative resection Jin Hyoung Kim a,∗ , Hyung Jin Won a , Yong Moon Shin a , Pyo Nyun Kim a , Sung-Gyu Lee b , Shin Hwang b a b
Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 28 July 2010 Accepted 20 September 2010 Keywords: Intrahepatic cholangiocarcinoma Hepatectomy Radiofrequency ablation CT
a b s t r a c t Objective: Percutaneous radiofrequency ablation (RFA) has shown efficacy in patients with recurrent hepatocellular carcinoma, but has not been well documented in patients with recurrent intrahepatic cholangiocarcinoma (ICC). We therefore evaluated the long-term survival and safety of percutaneous RFA for patients with recurrent ICC after curative resection. Materials and methods: A total of 20 patients with 29 recurrent ICCs underwent ultrasound-guided percutaneous RFA. All patients had undergone curative resection of the primary ICC. Tumor size ranged from 0.7 cm to 4.4 cm in maximum dimension (mean, 1.9 cm; median, 1.5 cm). Results: The technical effectiveness rate of RFA was 97% (28/29) of recurrent ICCs. Mean local tumor progression-free survival was 39.8 months, and the cumulative local tumor progression-free 6 month and 1, 2, and 4 year survival rates were 93%, 74%, 74%, and 74%, respectively. Median overall survival after RFA was 27.4 months and the cumulative overall 6 month and 1, 2, and 4 year survival rates were 95%, 70%, 60%, and 21%, respectively. There were two major complications (one liver abscess and one biliary stricture, 7% per treatment) during the follow-up, but no procedure-related deaths. Conclusion: RFA is safe and provides successful local tumor control in patients with recurrent ICC after curative resection. RFA for recurrent ICC resulted in a median overall survival rate of 27.4 months after RFA in the present series. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy after hepatocellular carcinoma (10% vs 90%, respectively), and its global incidence and mortality are increasing [1–4]. Although surgical resection currently represents the only form of curative therapy, there is frequent recurrence after curative resection. This has kept patient survival rates after surgical resection remain low, ranging from 20% to 43% at 5 years [5–8]. Repeat surgery for recurrent ICC after curative resection is frequently limited by poor remnant liver function or multifocal recurrence. Therefore, most patients with recurrent ICC receive palliative therapy, including systemic chemotherapy and/or radiation therapy. However, such options are usually only of limited benefit since ICCs generally respond poorly [9].
∗ Corresponding author at: Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Poongnap-2dong, Songpa-gu, Seoul 138-736, Republic of Korea. Tel.: +82 2 3010 4384; fax: +82 2 476 0090. E-mail address: [email protected] (J.H. Kim). 0720-048X/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2010.09.019
Percutaneous radiofrequency ablation (RFA) has been shown to be a safe and successful method for local tumor control in patients with recurrent hepatocellular carcinoma after surgery and has become increasingly used in these patients [10–12]. To our knowledge, however, study focusing on RFA for recurrent ICC after hepatic resection has been scarce [13,14]. We therefore evaluated the longterm survival results and complications of percutaneous RFA in 20 patients with 29 recurrent ICCs after curative resection. 2. Materials and methods 2.1. Patient population Our institutional review board approved this retrospective review of the patients’ medical and imaging records. Inclusion criteria of RFA were recurrent ICC ≤5 cm in maximum diameter, three or fewer recurrent ICCs, no imaging evidence of vascular invasion by the tumor, and no evidence of extrahepatic disease. Exclusion criteria included recurrent ICCs >5 cm in maximum diameter, multiple (>3) ICCs, poor performance status (Eastern Cooperative Oncology Group performance status rating grade 2–4), presence of vascular invasion, extrahepatic metastases, and coagulopathy (platelet count < 50 × 103 /L; international normalized ratio > 1.5).
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We identified a total of 20 patients with 29 recurrent ICCs who underwent RFA between October 1999 and March 2009. All patients had undergone curative resection of the primary ICC. Surgical resection consisted of right or left lobectomy in 12 patients, extended right or left lobectomy in 4 patients, segmentectomy in 2 patients, and bisegmentectomy in 2 patients. None of these patients had underlying liver cirrhosis. Six patients (30%) were positive for hepatitis B virus, and 1 (5%) was positive for hepatitis C virus. The diagnosis of recurrent ICC was based on the histologic results of image-guided percutaneous needle biopsy in 7 patients and the identification of newly presenting tumors on contrast-enhanced CT and/or whole-body PET (F-18 FDG) in the remaining 13 patients. The median time to recurrence was 7.4 months (range: 1.4–95.7 months), with 14 patients (60%) showing intrahepatic recurrence within 1 year after curative resection. Tumor sizes ranged from 0.7 cm to 4.4 cm in maximum dimension (mean, 1.9 cm; median, 1.5 cm). Of the 29 tumors, 25 had diameters ≤3 cm, and four had diameters of 3–5 cm. 2.2. Radiofrequency ablation technique RFA was performed percutaneously under ultrasonographic guidance, with the patient under conscious sedation and local anesthesia. A single or a cluster needle, internally cooled electrode (ValleyLab, Burlington, MA) was used, depending on tumor size, and radiofrequency current was emitted for 12 or 15 min by a 200 W generator set to deliver maximum power with the automatic impedance control method. Each tumor received one to five ablations (mean, 1.6 ablations) per session, based on tumor size and shape. 2.3. Follow-up Immediately after RFA, a contrast-enhanced CT scan was performed to evaluate possible complications such as bleeding or fluid collection. The efficacy of RFA was evaluated by contrast-enhanced CT 1 month after the procedure. Patients with residual tumor in the ablated area underwent an additional session of RFA for the residual lesion. In cases of complete ablation of the tumor, with no appearance of a new tumor in other liver sites on 1-month follow-up CT, subsequent follow-up contrast-enhanced CT scans were repeated every 2–3 months. All new tumors in the ablated lesion or in other liver sites that emerged during follow-up were treated with RFA if the patient still met the requirement for RFA. 2.4. Definition and evaluation of data Using the Society of Interventional Radiology reporting standards [15], technical effectiveness was defined as complete ablation of the tumor, as shown on imaging follow-up 1 month after the procedure. An irregular or nodular peripheral enhancement of the ablated area was considered a residual tumor at the ablation margin and a treatment failure. Local tumor progression was considered when nodular or irregular enhancement was seen during follow-up imaging (after 1 month). Major complications were defined as any event that resulted in additional treatment, including an increased level of care, hospital stay beyond observation status (including readmission after initial discharge), and permanent adverse sequelae, including substantial morbidity and disability, and death. All other complications were classified as minor. The local tumor progression-free survival period was calculated using the Kaplan–Meier method. Tumor size was dichotomized relative to the median (1.5 cm) and the local tumor progression-free survival curves of patients with tumors ≥1.5 cm and <1.5 cm were
Fig. 1. Contrast-enhanced axial computed tomography (CT) images of a 62-year-old patient with hepatic recurrence after segmentectomy for intrahepatic cholangiocarcinoma. (a) Image in the portal phase 1 month before radiofrequency ablation (RFA), showing a recurrent tumor (arrowhead) (1.2 cm in largest diameter) in segment V. (b) Image obtained 1 month after RFA, showing good local tumor control (arrowhead).
compared using the log-rank test. The local tumor progression-free survival period was measured in months from the date of initial RFA treatment and defined as the time interval between the initial RFA treatment and follow-up imaging showing local tumor progression. The overall survival and event-free survival periods were calculated using the Kaplan–Meier method on a patient-by-patient basis. The overall survival periods were measured in months from the date of diagnosis of hepatic recurrence and from the time of initial RFA. The overall survival period was defined as the time interval between initial RFA and patient death, and between diagnosis of recurrence and patient death. The event-free survival was defined as the time interval, in months, from the initial RFA to local tumor progression, occurrence of new ICC in the liver, distant metastasis, or death. 3. Results 3.1. Local tumor control Technical effectiveness was achieved in 28 of 29 tumors (97%) in 19 of 20 patients (95%) (Fig. 1). One patient showed a residual unablated tumor on 1-month follow-up CT. This patient underwent a secondary RFA, resulting in the complete ablation of the residual
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Fig. 3. Overall and event-free survival of 20 patients who underwent percutaneous radiofrequency ablation for recurrent intrahepatic cholangiocarcinoma after hepatectomy.
3.2. Overall and event-free survival periods after radiofrequency ablation
Fig. 2. Cumulative local tumor progression-free survival rates after radiofrequency ablation of (a) of all 29 tumors and (b) tumors <1.5 cm and ≥1.5 cm in diameter.
tumor; however new lesions in the liver and in the extrahepatic area occurred 2 months later, and this patient died of disease progression 9.5 months after initial RFA. Of the 28 tumors in which RFA showed technical effectiveness, six showed local tumor progression from 4 to 10.2 months (median, 8.1 months; mean, 7.6 months) after RFA. Three of these 6 tumors underwent repeat RFA, while the remaining three received supportive treatment only because of both intrahepatic and extrahepatic metastases. The mean local tumor progression-free survival period was 39.8 months (Fig. 2). The cumulative local tumor progression-free survival rates at 6 months and at 1, 2, and 4 years were 93%, 74%, 74%, and 74%, respectively. The local tumor progression-free survival period was significantly longer in patients with <1.5 cm than in those ≥1.5 cm (Fig. 2B) (P = 0.041).
The study period ended in April 2010, at which time, the patients had been followed up for 3.3–53.7 months (mean, 18 months; median, 12.8 months). Of the 20 patients, 7 were still alive while 13 had died, 11 of disease progression, one of pneumonia, and one of an infection related to a refractory biliary obstruction. No patient was lost-to follow up. The median overall survival periods after RFA and from the time of diagnosis of hepatic recurrence were 27.4 months and 28.4 months, respectively. The overall survival rates at 6 months and at 1, 2, 3 and 4 years after RFA were 95%, 70%, 60%, 21%, and 21%, respectively (Fig. 3). During the follow-up period, 12 of the 20 patients (60%) showed new lesions at other liver sites and/or in distant areas. Of these patients, 3 were treated with systemic chemotherapy and radiation therapy, 2 with surgery (one each for an intrahepatic tumor and a lung metastasis), and 1 with transarterial chemoembolization. The remaining 6 patients received supportive treatment only, including pain control, ascites control, and biliary drainage. The median event-free survival period after RFA was 6.1 months (Fig. 3). The event-free survival rates at 6 months and at 1, 2, and 4 years after RFA were 55%, 20%, 20%, and 20%. 3.3. Complications During the 29 radiofrequency ablation sessions, two major complications occurred (7%). Liver abscess developed at one ablated area 8 days after RFA in one patient. This patient was successfully treated with percutaneous drainage of the liver abscess and antibiotic therapy. One patient developed a biliary stricture after RFA requiring percutaneous transhepatic biliary drainage. There were no procedure-related deaths. Minor complications were also observed, including small amounts of pleural effusion around the ablated area in 8 patients and small hematomas in three. Follow-up CT scans showed that all of these disappeared 1 month after the procedure.
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4. Discussion Although surgical resection may provide only the curative option for ICC, patient prognosis after surgery is poor because of the high rate of recurrence [5–8]. Predictors of poor outcomes include positive resection margins, lymphatic and vascular invasion and periductal infiltrating disease, and preoperative CA 19-9 level [8,16,17]. The liver remnant is the most common single site of recurrence [8,16–18]. Survival from the time of recurrence is severely limited [7,19]. Repeat hepatectomy results in the complete resection of recurrent intrahepatic tumors, as well as providing the opportunity to explore the abdominal cavity for extrahepatic lesions. There are only few data regarding repeat hepatectomy for intrahepatic recurrence of ICC [20,21]. Among 7 patients with solitary ICC recurrence, Konstadoulakis et al. reported that the median survival time was 20 months in the 6 patients who received repeated hepatectomy [20]. However, repeat hepatectomy is frequently limited by poor remnant liver function or multifocal recurrence. In addition, technical and anatomic difficulties make repeat hepatectomy less feasible and more difficult to perform than initial hepatectomy. Furthermore, the liver remnant after initial hepatectomy frequently undergoes cirrhotic changes because of the parenchymal loss of the liver [11]. For these reasons, repeat hepatectomy may not be performed in most patients with recurrent ICC. Since 1990, when RFA was first used to treat hepatic tumors [22,23], it has been used more frequently because it can generate a well-controlled focal thermal injury with minimal morbidity and mortality [24]. Most recurrent ICC tumors are small, making percutaneous RF ablation feasible. In addition, percutaneous RFA is considered superior to repeat hepatectomy, both for safety and convenience, if survival results are approximately equal [11]. To our knowledge, this study is the first to evaluate long-term survival results and complications of percutaneous RFA in patients with recurrent ICC after curative resection. We found that RFA was technically effective in 97% of recurrent ICCs with no procedurerelated mortality. The mean local tumor progression-free period after RFA for recurrent ICC was 39.8 months and the cumulative 4-year local tumor progression-free survival rate was 74%. In agreement with previous findings, showing that tumor size was significantly associated with the local tumor progression-free survival after RFA for hepatic metastases from colorectal cancers [25], we found that tumors <1.5 cm showed significantly longer local tumor progression-free survival than tumors ≥1.5 cm after RFA for recurrent ICC (P = 0.041). In a recent series of 74 resected patients with ICC, Tamandl et al. stated that the median time between tumor recurrence and death was 16.4 months, and suggested that it might be increased by the use of a palliative treatment schedule [26]. During follow-up in the current study, we found that the median overall survival periods after RFA and from the time of diagnosis of hepatic recurrence were 27.4 months and 28.4 months, respectively. The median survival period (28.4 months) from tumor recurrence in the current study was longer than the reported survival length of 20 months [20] in patients who underwent repeat resection for hepatic recurrence of ICC. We observed 2 major complications after RFA for 29 recurrent ICCs (7%), comprising one liver abscess and one biliary stricture. RFA can thermally injure the bile ducts, resulting in bile duct strictures, as well as making an inadvertent connection between the biliary tree and the ablation zone. These ablation zones may become contaminated with enteric bacteria through the bilioenteric anastomosis, resulting in liver abscess [10].
The principal limitations of this study were its retrospective study design and the lack of a control group (especially, patients who underwent repeat hepatectomy). Nevertheless, we believe that results indicate that RFA may have a potential role in the treatment of recurrent ICC and provides support for prospective investigation. In conclusion, RFA is safe and provides successful local tumor control in patients with recurrent ICC after curative resection. RFA for recurrent ICC resulted in a median overall survival rate of 27.4 months after RFA in the current study. Further studies comparing the clinical outcomes of RFA and repeat hepatectomy in the treatment of recurrent ICC after curative resection are warranted. Conflict of interest The authors have no conflicts of interest and nothing to disclose. References [1] Shaib YH, El-Serag HB, Davila JA, et al. Risk factors of intrahepatic cholangiocarcinoma in the United States: a case–control study. Gastroenterology 2005;128(3):620–6. [2] Kim JH, Yoon HK, Sung KB, et al. Transcatheter arterial chemoembolization of chemoinfusion for unresectable intrahepatic cholangiocarcinoma: clinical efficacy and factors influencing outcomes. Cancer 2008;113(7):1614–22. [3] Khan S, Howard CT, Davidson BR, Taylor-Robinson SD. Cholangiocarcinoma. Lancet 2005;366(9493):1303–14. [4] Singal AG, Rakoski MO, Salgia R, et al. The clinical presentation and prognostic factors for intrahepatic and extrahepatic cholangiocarcinoma in a tertiary care centre. Aliment Pharmacol Ther 2010;31(6):625–33. [5] Jan YY, Yeh CN, Yeh TS, Hwang TL, Chen MF. Clinicopathological factors predicting long-term overall survival after hepatectomy for peripheral cholangiocarcinoma. World J Surg 2005;29(7):894–8. [6] Ohtsuka M, Ito H, Kimura F, et al. Extended hepatic resection and outcomes in intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg 2003;10(4):259–64. [7] Inoue K, Makuuchi M, Takayama T, et al. Long-term survival and prognostic factors in the surgical treatment of mass-forming type cholangiocarcinoma. Surgery 2000;127(5):498–505. [8] Cho SY, Park SJ, Kim SH, et al. Survival analysis of intrahepatic cholangiocarcinoma after resection. Ann Surg Oncol 2010;17(7):1823–30. [9] Malhi H, Gores GJ. Cholangiocarcinoma: modern advances in understanding a deadly old disease. J Hepatol 2006;45(6):856–67. [10] Choi D, Lim HK, Rhim H, et al. Percutaneous radiofrequency ablation for recurrent hepatocellular carcinoma after hepatectomy: long-term results and prognostic factors. Ann Surg Oncol 2007;14(8):2319–29. [11] Choi D, Lim HK, Kim MJ, et al. Recurrent hepatocellular carcinoma: percutaneous radiofrequency ablation after hepatectomy. Radiology 2004;230(1):135–41. [12] Yang W, Chen MH, Yin SS, et al. Radiofrequency ablation of recurrent hepatocellular carcinoma after hepatectomy: therapeutic efficacy on early- and late-phase recurrence. AJR (Am J Roentgenol) 2006;186(5 Suppl.):S275–83. [13] Oshima S, Takaishi K, Kurokawa E, et al. A case of successful management of recurrent intrahepatic cholangiocarcinoma by repeated radiofrequency ablations. Gan To Kagaku Ryoho 2009;36(12):2404–6 (in Japanese). [14] Park HS, Kim YJ, Park SW, et al. Hepatic vein pseudoaneurysm after radiofrequency ablation of recurrent intrahepatic cholangiocarcinoma managed with stent-graft placement. J Vasc Interv Radiol 2010;21(2):306–7. [15] Goldberg SN, Grassi CJ, Cardella JF, et al. Image-guided tumor ablation: standardization of terminology and reporting criteria. J Vasc Interv Radiol 2009;20(7 Suppl.):S377–90. [16] Endo I, Gonen M, Yopp AC, et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg 2008;248(1):84–96. [17] Aljiffry M, Walsh MJ, Molinari M. Advances in diagnosis, treatment and palliation of cholangiocarcinoma: 1990–2009. World J Gastroenterol 2009;15(34):4240–62. [18] Ercolani G, Vetrone G, Grazi GL, et al. Intrahepatic cholangiocarcinoma: primary liver resection and aggressive multimodal treatment of recurrence significantly prolong survival. Ann Surg 2010;252(1):107–14. [19] Yamamoto J, Kosuge T, Takayama T, et al. Surgical treatment of intrahepatic cholangiocarcinoma: four patients surviving more than five years. Surgery 1992;111(6):617–22. [20] Konstadoulakis M, Roayaie S, Gomatos IP, et al. Fifteen-year, single-center experience with the surgical management of intrahepatic cholangiocarcinoma: operative results and long-term outcome. Surgery 2008;143(3):366–74. [21] Kurosaki I, Hatakeyama K. Repeated hepatectomy for recurrent intrahepatic cholangiocarcinoma: report of two cases. Eur J Gastroenteraol Hepatol 2005;17(1):125–30.
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