Five-year Survival following Radiofrequency Ablation of Small, Solitary, Hepatic Colorectal Metastases

Transcription

1 Five-year Survival following Radiofrequency Ablation of Small, Solitary, Hepatic Colorectal Metastases Alice R. Gillams, MBChB, MRCP, FRCR, and William R. Lees, MBBS, FRCR, FRCS PURPOSE: Radiofrequency (RF) ablation is an increasingly accepted treatment for nonsurgical candidates with a limited number of colorectal hepatic metastases. RF ablation is most effective in tumors smaller than 4.0 cm. This report describes 5-year survival in patients with single tumors with a maximum diameter of 4 cm. MATERIALS AND METHODS: Forty of 291 patients (14%; 24 men, 16 women; mean age, 67 years; age range, 34 y) with no or treated extrahepatic disease were identified who were not candidates for resection and who had minimum follow-up of 6 months. Sixteen had undergone hepatic resection and two had undergone lung resection and lung ablation. Thirty-two (80%) received chemotherapy. Thirty-five were treated under general anesthesia and five under conscious sedation. Our standard ablation protocol used internally water-cooled electrodes introduced percutaneously with ultrasonography and computed tomography guidance and monitoring. Follow-up data were obtained from primary care physicians or oncologists. RESULTS: Mean tumor diameter was 2.3 cm (range, cm). There were two successfully treated systemic complications: a chest infection and an exacerbation of asthma. There were no local complications. Mean follow-up was 38 months (range, months). The median survival duration and 1-, 3-, and 5-year survival rates were 5 months and 97%, 84%, 40%, respectively, after ablation; and 63 months, 100%, 88%, and 54%, respectively, from the diagnosis of liver metastases. History of liver resection did not impact survival. CONCLUSIONS: RF ablation of solitary liver metastases 4 cm or smaller can be performed with minimal morbidity and results in excellent long-term survival, approaching that of surgical resection, even in patients who are not surgica candidates. J Vasc Interv Radiol 2008; 19: Abbreviation: RF radiofrequency COLORECTAL cancer is the third portion, approximately 15%, can undergo hepatic resection. Five-year sur- most common malignancy worldwide and the second most common cause ofvival after liver resection in carefully cancer death in developed countries selected patients ranges between 31% (1). Fifty percent of patients developand 58% (2 4). For the remainder of liver metastases but only a small pro-patients there is chemotherapy and/or local tumor ablation. Chemotherapy regimens have improved in recent From the Centre for Medical Imaging, University College Hospital, 235 Euston Road, Special X-Ray, Podium 2, London NW1 2BU, United Kingdom. Received September 5, 2007; final revision received January 18, 2008; accepted January 20, Address correspondence to A.G.; a.gillams@medphys.ucl.ac.uk A.R.G has received a single honorarium, for a lecture, from Covidien. SIR, 2008 DOI: /j.jvir vival times of months, 3-year survival rates of 46% 68%, and 5-year survival rates of 29% 44% have been reported (6 9). RF ablation is most effective in small-volume disease, ie, small numbers of tumors with a maximum diameter of 4 cm. We report our results in a cohort of patients with sol- tumors no larger than 4 cm in years but, even with the latest antian-itargiogenic agents, median survival diameter who had no or treated extrahepatic disease and who could not un- times are still less than 24 months 5). ( Radiofrequency (RF) ablation is an dergo liver resection. effective technique for the local destruction of tumor. Currently RF ablation is indicated in patients who can-materialnot undergo liver resection, most ofpatient Data AND METHODS whom have fewer than five tumors, but with an unfavorable distribution All patients gave written informed for resection. Despite this, median sur-consent. The institutional review board 712

2 Volume 19 Number 5 Gillams and Lees 713 waived the need for formal review because tissue ablation is approved by the United States Food and Drug Administration and the United Kingdom s National Institute of Clinical Excellence and the data review was retrospective. Data management was conducted within the requirements of the Data Protection Act (UK equivalent of the Health Insurance Portability and Accountability Act). From our database of 291 patients with colorectal liver metastases treated with RF ablation between 1997 and 2007, we identified 40 patients (14%) who had a solitary metastasis no larger than 4 cm in diameter, with no or treated extrahepatic disease and a minimum of 6 months follow-up. There were 24 men and 16 women with a mean age of 67 years (range, y). All patients were deemed to have inoperable disease because of inadequate residual liver volume resulting from previous resection, concomitant comorbidity, inability to achieve margins because of tumor location adjacent to the vena cava and hepatic venous confluence, or poor tumor biology. Three patients had treated extrahepatic disease, one had a peritoneal deposit removed at the time of primary resection, and two had had lung metastases resected and subsequent lung metastases ablated. There were 15 rectal tumors, four rectosigmoid tumors, 10 sigmoid tumors, nine ascending colon or hepatic flexure tumors, one transverse tumor, and one descending colonic carcinoma. Primary staging data were available in 35 cases, of which 21 were Dukes stage C, 12 were Dukes stage B, and two were Dukes stage A. The timing of liver metastases relative to primary resection was known in 39 cases. Eighteen patients had synchronous liver metastases and 21 had metachronous metastases. Median time to the development of liver metastases in the metachronous metastasis group was 16 months (range, 3 48 months). Nine of 21 developed liver metastases within 12 months of primary resection; therefore, a total of 27 of 39 cases (69%) were in the poorer prognostic group of synchronous or early metachronous liver metastases. Thirty-two of 40 patients received chemotherapy at initial diagnosis of liver metastases and/or after progression following resection or ablation. The chemotherapy regimen varied during the period of the study. In the early and mid-1990s, standard chemotherapy regimens included 5-fluorouracil and leucovorin (ie, folinic acid). Irinotecan and oxaliplatin were introduced in the late 1990s, and in the past three years, the monoclonal antibodies cetuximab and bevacizumab have been available for some patients. Eight patients did not receive chemotherapy because of significant comorbidity, advanced age, or patient choice; six received a 5-fluorouracil based regimen, 21 received oxaliplatin- or irinotecan-based regimens, and five received cetuximab. All patients underwent contrast agent enhanced computed tomography (CT) of the chest, abdomen, and pelvis to assess the number and location of metastases. The technique varied with the evolution in CT technology during the study period. In the early part of the study, scans were obtained during the portal venous phase with 2.5-mm collimation and ml of intravenous contrast medium pump-injected at a rate of 5 ml/sec. Since 2000, multislice CT has been used, and the liver was routinely assessed with biphasic scans during the late arterial and portal venous phase. With the introduction of 64-detector CT in 2005, 1-mm collimation became routine. Tumors were measured with electronic calipers on a Picture Archiving and Communication System. CT/ positron emission tomography imaging was used if there was any doubt about the interpretation of the CT findings, and was particularly useful if there was a question as to whether extrahepatic disease was present. RF Ablation Technique Thirty-seven treatments were performed percutaneously with ultrasonography (US) guidance alone (n 1) or with a combination of US and magnetic resonance (MR) imaging (n 4) or US and CT (n 32). Procedures were performed under conscious sedation with intravenous fentanyl and midazolam (n 5) or general anesthesia (n 32). The other three patients were treated at open laparotomy with US guidance, one in conjunction with bowel surgery and two in conjunction with liver resection. Thirty-seven patients were treated with a triple cluster (n 7) or a single (n 30) internally water-cooled electrode powered by a 200-W generator (Covidien, Boulder, Colorado). Treatment was performed at maximum power and continued until impedance change reduced power deposition to less than 50 W or for 6 minutes, whichever was shorter. For all tumors larger than 1 cm in diameter, multiple electrode positions were required to achieve overlapping ablations such that the whole tumor and a 1-cm margin of normal liver were ablated. Three patients were treated with an expandable electrode (RITA Medical Systems; Mountain View, California): two with a 3-cm electrode and one with a 5-cm electrode. Treatment with the expandable electrode was performed per manufacturer protocol, with the length of treatment dictated by the time taken to reach target temperatures. The choice of electrode design depended on availability at the time of treatment. When possible, scans were obtained during treatment to assess the efficacy of ablation. The zone of ablation was identified as an area of absent enhancement on images obtained after contrast medium administration. After ablation, patients were followed with CT scans at 3-month intervals. Successful ablation was identified as an area of absent enhancement that completely encompassed the tumor. Over time, the successful ablation zone becomes better defined and slowly shrinks. Enlargement of the ablation zone, a change in shape indicating enlargement in one area, and the development of intermediate enhancement were used to diagnose recurrence. Recurrent or new sites of disease were recorded. When new but limited disease developed, further ablation was offered. For those who developed more extensive liver metastases or extrahepatic disease such that further ablation was not possible or not appropriate, systemic chemotherapy was considered. Follow-up data were obtained from primary care physicians and oncologists. Kaplan-Meier plots of survival were performed with standard statistical analysis software (version 10; SPSS, Chicago, Illinois). Survival factors were compared with log-rank analysis, and a P value less than.05 was considered significant.

3 714 Five-year Survival after RF Ablation of Small, Solitary Liver Metastases May 2008 JVIR RESULTS The mean tumor size was 2.3 cm (range, cm). Fifteen tumors measured 3 4 cm, 24 tumors cm, and one was smaller than 1 cm. Thirteen patients were treated between 1997 and 2001, 12 in 2002 and 2003, and 15 from 2004 to Twentythree tumors were located in the right lobe, 15 in the left lobe, and two straddled the right and left lobes. Eight tumors were located in segment 8, eight in segment 7, six in segment 4a, five each in segments 2 and 5, three in segment 3, two in segment 6, two each straddling the border of segments 8 and 4a, and one in segment 4b. Twelve tumors lay adjacent to a large ( 3 mm diameter) vessel. No tumor was adjacent to the common hepatic duct. Twenty patients had undergone an intervention for metastatic disease: 14 had undergone one liver resection, two had undergone two liver resections, two had undergone laser ablation, and two had undergone lung resection and ablation. Comorbidity precluded safe resection in 12 patients. Three patients had a history of another malignancy: breast, prostate, and uveal melanoma. Four were not offered resection because of tumor location on the hepatic venous confluence and/or vena cava, one had multiple metastases with a sustained response to chemotherapy and only one active site of tumor at the time of RF ablation, and one had poor primary tumor biology such that the development of extrahepatic disease was considered very likely and indeed occurred. A complete ablation as shown by contrast medium enhanced CT was achieved in 39 of 40 patients at the first session, including the four patients with tumors next to the venous confluence. One patient had residual disease next to the gallbladder that was successfully ablated at a second session. The mean number of electrode positions was three (range, 1 4) and the mean duration of ablation (ie, generator activation) was 18 minutes (range, 7 33 min). There were no local complications. Two patients with significant preexisting comorbidity developed systemic complications: one exacerbation of known asthma and the other pneumonia. Both were successfully treated but required additional hospital stays of 1 day and 7 days, Table 1 Patterns of Recurrent Disease Disease location Subgroup Total No new tumor 8 8 Extrahepatic disease 21 Alone 5 With new liver metastases and local recurrence 5 With new liver metastases but no local recurrence 7 With local recurrence but no new liver metastases 4 New liver tumor without extrahepatic disease 6 With local recurrence 3 Without local recurrence 3 Recurrence without new hepatic or extrahepatic disease 5 5 Total Cum Survival Time (months) respectively, and therefore would be classified as having major complications based on Society of Interventional Radiology criteria (10). Mean follow-up after ablation was 38 months (range, months). Eight patients remained tumor-free and the remainder developed more tumor in the form of extrahepatic disease (n 21), new liver metastases in previously normal liver (n 18), or local recurrence adjacent to the original ablation (n 17; Table 1). Two of the four patients with tumor adjacent to the venous confluence exhibited local recurrence and two did not. Of the 21 patients who developed extrahepatic disease, 11 developed lung metastases, three developed pelvic recurrence, and three developed nodal metastases (one of whom had lung Figure. Kaplan-Meier survival plot for all patients (N 40). The solid line represents survival from the diagnosis of liver metastases and the broken line survival from time of ablation metastases as well): two peritoneal, one brain, and one adrenal. Seventeen patients had only one ablation session. Further ablation for new or recurrent liver disease was performed in 23 patients, and the mean number of ablation sessions was two (range, 1 5). Thirteen patients died during follow-up: two of cardiac ischemia and 11 of cancer. Median survival duration and 1-, 3-, and 5-year survival rates from the time of ablation were 59 months and 97%, 84%, and 40%, respectively. Median survival time and 1-, 3-, and 5-year survival rates from the time of diagnosis of liver metastases were 63 months and 100%, 88%, and 54%, respectively (Figure). Median survival time and 3- and 5-year survival rates after ablation in patients who had undergone liver resection (n

4 Volume 19 Number 5 Gillams and Lees 715 Table 2 Survival Analysis 16) were 59 months and 84% and 39%, respectively. There was no significant difference in survival based on location of the primary tumor, Dukes stage, timing of liver metastases after primary resection, history of liver resection, year of treatment, proximity to vessels larger than 3 mm, or presence or absence of chemotherapy (Table 2). DISCUSSION Factor Median Survival from Ablation (months) P Value Location of primary tumor (n 36).3 Rectum (n 15) 59 Colon (n 21) 50 Dukes stage (n 35).97 A/B (n 14) 48 C(n 21) 50 Timing of liver metastases after primary resection (n 39) months (n 27) months (n 12) 59 Previous liver resection.55 Yes (n 16) 59 No (n 24) 50 Year of treatment (n 13) (n 27) 50 Chemotherapy.73 Yes (n 32) 50 No (n 8) 59 Adjacent vessels 3 mm in diameter.38 Yes (n 12) 48 No (n 28) 59 The first report to suggest that thermal ablation may impact survival described 69 patients treated in the 1990s with bare-tip laser interstitial thermal coagulation (11). Overall median survival was 27 months, and for those with fewer than four tumors smaller than 5 cm, median survival was 33 months. There are few published reports of survival after RF ablation of colorectal liver metastases (4,6 9, 12,13) (Table 3). Solbiati et al (9) reported a 3-year survival rate of 46% in 117 patients. Patients with more limited disease fared better. Median survival for patients with metastases smaller than 2.5 cm was 42 months, and that for patients with solitary metastases was 33 months. Gillams and Lees (6) reported their entire RF ablation experience until 2003 in 167 patients with a wide spectrum of disease burden. The median survival duration and 5-year survival rate for patients with five or fewer tumors smaller than 5 cm were 38 months and 30%, respectively, from diagnosis, and 31 months and 26%, respectively, from ablation. Jakobs et al (12) reported a 3-year survival rate of 68% in 68 patients treated with CT guidance and expandable electrodes. Sorensen et al (8) reported a median survival duration of 52 months with 3- and 5-year survival rates of 64% and 44%, respectively, from diagnosis, and 3- and 4-year survival rates of 46% and 26%, respectively, from ablation in 102 patients. Early results from open RF ablation were not as good. Abdalla et al (4) reported 3-year survival rates of 37% for all patients and 43% for those with solitary metastases. This group (4) compared RF ablation in 30 patients with liver resection in 180 patients and found liver resection provided superior survival. This result contradicts the findings of another retrospective comparison of surgery and percutaneous RF ablation in solitary tumors of any size (14) that showed comparable survival rates: 52.6% for RF ablation and 55.4% for resection at 3 years. This apparent contradiction can be explained by the different practice protocols. RF ablation performed at open surgery is associated with a higher morbidity rate and is harder to repeat if required. Patients were selected for RF ablation at laparotomy when tumor location on a major vessel rendered them inoperable. However, vessel proximity is a well established cause of tumor recurrence, a problem that may be overcome by repeat ablation (15). The combination of a procedure that is difficult to repeat and vessel proximity may explain the poor 5-year survival rate. Another factor is the use of US to monitor and guide intraoperative treatments, as CT or MR which provide superior monitoring information are not generally available in the operating room. More recent results from open RF ablation show some improvement but are not as good as the latest percutaneous RF ablation results. Aloia et al (13), from the same group as Abdalla (6), reported a 3-year survival rate of 57% for patients with solitary metastases, and Abitabile et al (7) reported a 3-year survival rate of 57% in a cohort of 47 patients with 147 metastases with a mean size of 2.4 cm. In the current study, the population was restricted to those with solitary tumors no larger than 4 cm, and the long-term survival was better than previously reported, with median survival times and 3- and 5-year survival rates of 59 months and 84% and 40%, respectively, from ablation, and 63 months and 88% and 54%, respectively, from diagnosis of liver metastases. The median survival duration and 3-year survival rate figures may prove more representative, as the overall median follow-up is still only 38 months, and the 5-year survival figures may strengthen with further follow-up. Three- and 5-year survival rates in the 16 patients who had undergone liver resection were 84% and 39%, respectively. This compares well with the results of repeat hepatectomy and even approaches the results for de novo resection. In a recent review of repeat resection (16), 3-year survival rates ranged from 24% to 68% and 5-year survival rates ranged from 21% to 49%. A retrospective comparison by Elias et al (17) showed comparable survival. Factors that impact survival after liver resection eg, location of

5 716 Five-year Survival after RF Ablation of Small, Solitary Liver Metastases May 2008 JVIR Table 3 Summary of Published Results of RF Ablation of Hepatic Metastases (4,6 9,12,13) Study No. of Pts. Mean No. of Metastases (Range) Mean (Range) Maximum Diameter (cm) Median Survival (months) Solbiati et al, 2001 (9) (1 4) 2.8 ( ) Abdalla et al, 2004 (4) 57 1 (1 8) Gillams and Lees, 2004 (6) Aloia et al, 2006 (13) (1 7) Not reached 57 Jakobs et al, 2006 (12) (0.5 5) Not reached 68 Abitabile et al, 2007 (7) (0.3 12) Sorensen et al, 2007 (8) (1 17) 2.2 ( ) Current study (0.8 4) Year Survival (%) primary tumor, Dukes stage, timing of liver metastasis after primary resection, history of liver resection, and whether the patient received chemotherapy did not prove significant in this group, probably because the subdivided patient groups were too small. Reported rates of local recurrence vary. The highest reported rate of 55% (18) was in a group of patients with aggressive tumor biology, many of whose tumors had recurred after previous surgery. Solbiati et al (9) reported local recurrence rates by tumor size: 21.6% among those smaller than 2.5 cm and 52.8% in those cm in size. In the study of Livraghi et al (19) of RF ablation as a test of time in operable disease before resection, the local recurrence rate was 40%. Jakobs et al (12) reported a local recurrence rate of 18%. Our recurrence rate lies within the reported spectrum. The aim should be to minimize local recurrence, but the impact of local recurrence is reduced in a population in which the development of new foci of disease, either hepatic or extrahepatic, is high. Twenty-seven of 40 in this patient cohort (68%) developed new sites of disease. Our policy is to aggressively diagnose early recurrence based on three monthly high-quality CT examinations, with particular attention paid to interval change, and then to treat any recurrence early. Despite similar rates of local recurrence, our overall survival results are better than those reported in previous studies. Possible explanations for this difference could be patient selection and our policy of detailed follow-up and early repeat intervention if new or recurrent tumor is detected. Not only was the survival in this select patient population very good, but the associated morbidity from these small treatments, even in patients with significant preexisting medical comorbidity, was also good. The percutaneous approach is preferable to the open approach; it is minimally invasive with a limited hospital stay, low cost, and rapid recovery time. It can be readily repeated if required and also allows for accurate monitoring of the ablation zone with CT or MR scanning. Limitations of this study include the lack of randomization between treatment modalities, the small numbers in the different subgroups, and the fact that it was a retrospective review of patients treated over a 10-year period. In conclusion, RF ablation of solitary liver metastases no larger than 4 cm resulted in excellent long-term survival with minimal morbidity, even in patients who were not candidates for surgical resection. References 1. Douillard JY, Cunningham D, Roth AD, et al. Colorectal cancer. In: Steward BW, Kleihues P, eds. World Cancer Report Lyon, France: IACR Press, 2003; Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 2002; 235: Kornprat P, Jarnagin WR, Gonen M, et al. Outcome after hepatectomy for multiple (four or more) colorectal metastases in the era of effective chemotherapy. Ann Surg Oncol 2007; 14: Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ ablation for colorectal liver metastases. Ann Surg 2004; 239: Lee JJ, Chu E. An update on treatment advances for the first-line therapy of metastatic colorectal cancer. Cancer J 2007; 13: Gillams AR, Lees WR. Radio-frequency ablation of colorectal liver metastases in 167 patients. Eur Radiol 2004; 14: Abitabile P, Hartl U, Lange J, Maurer CA. Radiofrequency ablation permits an effective treatment for colorectal liver metastasis. Eur J Surg Oncol 2007; 33: Sorensen SM, Mortensen FV, Nielsen DT. Radiofrequency ablation of colorectal liver metastases: long-term survival. Acta Radiol 2007; 48: Solbiati L, Livraghi T, Goldberg SN, et al. Percutaneous radio-frequency ablation of hepatic metastases from colorectal cancer: long-term results in 117 patients. Radiology 2001; 221: Goldberg SN, Grassi CJ, Cardella JF, et al. Image-guided tumor ablation: standardization of terminology and reporting criteria. Radiology 2005; 235: Gillams AR, Lees WR. Survival after percutaneous, image-guided, thermal ablation of hepatic metastases from colorectal cancer. Dis Colon Rectum 2000; 43: Jakobs TF, Hoffmann RT, Trumm C, Reiser MF, Helmberger TK. Radiofrequency ablation of colorectal liver metastases: mid-term results in 68 patients. Anticancer Res 2006; 26: Aloia TA, Vauthey JN, Loyer EM, et al. Solitary colorectal liver metastasis: resection determines outcome. Arch Surg 2006; 141: Oshowo A, Gillams A, Harrison E, Lees WR, Taylor I. Comparison of resection and radiofrequency ablation for treatment of solitary colo-

6 Volume 19 Number 5 Gillams and Lees 717 rectal liver metastases. Br J Surg 2003; 90: Ni Y, Mulier S, Miao Y, Michel L, Marchal G. A review of the general aspects of radiofrequency ablation. Abdom Imaging 2005; 30: Yan TD, Sim J, Black D, Niu R, Morris DL. Systematic review on safety and efficacy of repeat hepatectomy for recurrent liver metastases from colorectal carcinoma. Ann Surg Oncol 2007; 14: Elias D, de Baere T, Smayeara T, Ouellet JF, Roche A, Lasser P. Percutaneous radiofrequency thermoablation as an alternative to surgery for treatment of liver tumour recurrence after hepatectomy. Br J Surg 2002; 89: White RR, Avital I, Sofocleous CT, et al. Rates and patterns of recurrence for percutaneous radiofrequency ablation and open wedge resection for solitary colorectal liver metastasis. J Gastrointest Surg 2007; 11: Livraghi T, Solbiati L, Meloni F, Ierace T, Goldberg SN, Gazelle GS. Percutaneous radiofrequency ablation of liver metastases in potential candidates for resection: the test-of-time approach. Cancer 2003; 97: