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Radiofrequency Ablation for Unresectable Tumors of the Liver/ DISCUSSION

August 29, 2008

By Howard, J Harrison Tzeng, Ching-Wei D; Smith, J Kevin; Eckhoff, Devon E; Bynon, J Steve; Wang, Thomas; Arnoletti, J Pablo; Heslin, Martin J

Surgical resection of primary or metastatic tumors of the liver offers patients the best long-term survival. Liver resections may not be appropriate in patients with bilobar metastases, liver dysfunction, or severe comorbidities. Radiofrequency ablation (RFA) is a technique used to destroy unresectable hepatic tumors through thermocoagulation. We retrospectively reviewed a consecutive series of patients undergoing RFA with unresectable hepatic tumors for local recurrence and overall survival. Under an Institutional Review Board-approved protocol, all patients treated with RFA at the University of Alabama at Birmingham from September 1, 1998, to June 15, 2005, were identified. During this time period, 189 lesions in 107 patients were treated with RFA. Patients’ charts were retrospectively reviewed. Data is presented as mean +- SEM. Significance is defined as P

The reasons for unresectability are many: size, anatomic location, vascular and extrahepatic involvement, and multiple lesions with bilobar involvement may technically hinder surgical intervention.3 Severe patient comorbidities and poor hepatic functional reserve may be relative contraindications to hepatic resection, Radiofrequency ablation (RFA) has emerged as a safe and effective method for treating liver malignancies that are otherwise not amenable to resection.4

Application of RFA has been described by open laparotomy, laparoscopically, and as a percutaneous procedure with either CT or ultrasound guidance. This technique uses thermal energy that is conducted to surrounding tissue to kill tumor tissue by thermocoagulation. By destroying only the localized tumor tissue and a margin of normal hepatic parenchyma, RFA effectively increases the number of patients who potentially have surgically treatable disease.3, 4 The results of RFA have not been compared with surgical resection in a randomized trial because it would be difficult to have resectable patients agree to RFA and it would be unethical to have unresectable patients undergo laparotomy. The recurrence rates appear high, but RFA may afford a long-term survival benefit in conjunction with more effective chemotherapy and may be more efficacious than when compared with chemotherapy alone.1, 5-7

TABLE 1. Clinicopathologic Data by Histology

The purpose of this study was to review our institution’s experience with RFA in treating primary and metastatic tumors of the liver with recurrence and survival as the primary end points.

Materials and Methods

Using an Institutional Review Board-approved protocol, all patients treated witii RFA for liver tumors from September 1, 1998, to June 15, 2005, were identified. During this time period, 189 lesions in 107 patients were treated with RFA. Patients were evaluated preoperatively with triple-phased CT to determine potential resectability. Tumor measurements were obtained from preoperative scans. Patients were grouped as RFA with open laparotomy, laparoscopic RFA, or percutaneous RFA. Tumors were compared as primary liver tumors, colorectal carcinoma metastasis, or other metastatic liver tumors. Quality of the procedure was judged by the attending surgeon at the time of the ablation and was judged by whether there was radiographic evidence of residual tumor. The RITA electrosurgical device and intraoperative ultrasound were used for tumor localization and ablation as previously described.8 RFA was performed at a large-volume referral center. Surgeons participating in this study were fellowship-trained in surgical oncology or transplantation.

TABLE 2. Laparoscopic Radiofrequency Ablation of Unresectable Hepatocellular Carcinoma as a Bridge to Liver Transplantation in Childs-Pugh Class C Patients

The charts from this prospectively collected patient database were retrospectively reviewed for collection of demographics. Clinicopathologic data were also collected and include tumor histology, tumor size, tu- mor number, and follow-up data (Table 1). Recurrence was identified by postoperative radiographic imaging (Fig. 1) or pathologic data at time of orthotopic liver transplant (OLT). At time of last follow up, patients were identified as having no evidence of disease, alive with disease, or died of disease. Tumor marker levels, including alpha-fetoprotein and carcinoembryonic antigen, were not available.

Univariate comparison of factors was by chi^sup 2^ test of categorical variables and unpaired t test of continuous variables. Survival data was evaluated using the Kaplan-Meier method. All data were presented as mean +- SEM or median (range) and significance was defined as P

FIG. 1. Representative illustrations of preoperative CT scan illustrating unresectable liver tumor (A) followed by postoperative scan with ablated lesion and surrounded normal liver parenchyma (B).

Results

Patient demographics revealed 67 (62%) males and 40 (38%) females with an age range of 25 to 83 and a mean age of 59 (+- 1) years. Eighty-four (78%) patients were white, 18 (17%) were black, and the remaining five (5%) were Asian. Hepatocellular carcinoma represented 58 (54%) of the tumors treated, metastatic CRC represented 24 (22%), and the remaining 25 (24%) were other metastatic tumors, including pancreatic cancer, cholangiocarcinoma, sarcoma, breast cancer, renal cell carcinoma, gastrointestinal stromal tumor, esophageal and neuroendocrine tumors. Several differences were noted between the two patient populations (Table 1). A significantly increased number of men had HCC. Patients with HCC also had a significant increase in the frequency of hepatitis (hepatitis B or hepatitis C virus) and cirrhosis as documented by the Child’s classification. There were otherwise no significant differences in the two patient populations treated with RFA. Open procedures were performed for 23 (21%) patients, laparoscopic procedures in 21 (20%) patients, and the remaining 63 (59%) patients had percutaneous RFA of their liver tumors. The morbidity rate for the procedure was 11 per cent. Morbidities of this procedure included pneumothorax (n = 1), bleeding (n = 1), urinary retention (n = 1), reoperation for colonic perforation and development of colocutaneous fistula (n = 1), intrahepatic abscess (n = 2), and ileus (n = 4). There was one mortality (0.9%) caused by perioperative development of portal vein thrombosis and subsequent multisystem organ failure. Average blood loss for this procedure was less than 10 mL. Patients receiving percutaneous RFA were often discharged the same day. Hospitalizations ranged from 1 to 12 days with a median stay of 1 day.

Overall local recurrence from RFA was 33.6 per cent. When evaluated by histology, local recurrence was 27.6 per cent for HCC, 29.1 per cent for metastatic CRC, and 52 per cent for all other metastases. Respective mean time to local recurrence was 6.7 months, 7.7 months, and 7.4 months. Local recurrence rates for all tumors varied by method of ablation. Open laparotomy (n = 23) had a 42 per cent local recurrence, laparoscopy (n = 21) had a 19 per cent local recurrence, and percutaneous ablation (n = 63) had a 33 per cent local recurrence rate.

Survival was evaluated as disease-free survival (DFS) and overall survival for the three groups. Median DFS for patients with HCC treated with RFA was 13 months and disease-free 5-year survival was 19.2 per cent. Mean overall survival for the same group was 31.4 months with a 39 per cent 5-year survival rate (Fig. 2). This includes 14 patients who received OLT for their disease. Median DFS for CRC treated witii RFA was 7 months and 1-year DFS was 10.8 per cent. All patients with CRC were either censored or recurred within 24 months of their treatment. Overall median survival for patients with CRC treated with RFA was 13.1 months with a 3-year survival rate of 14.3 per cent. Patients with all other forms of metastatic disease treated with RFA had a median DFS of 13 months and a 5-year DFS rate of 16.7 per cent. Overall median survival was 22.7 months and 5-year survival rate was 25.7 per cent (Fig. 3). Disease-free survival and overall survival for patients with HCC were compared with all patients with metastatic disease. Median DFS and overall survival for patients with HCC treated with RFA was nearly twice that of patients with metastatic disease (P

FIG. 3. Kaplan-Meier survival analysis of ablated patients with metastatic cancer divided into colorectal cancer metastases and other high-risk metastatic disease. Curves represent disease-free survival (A) and overall survival (B) in months from time of ablation.

FIG. 4. Kaplan-Meier survival analysis comparing hepatocellular carcinoma with metastatic disease treated by radiofrequency ablation. Curves represent disease-free survival (A) and overall survival (B) in months from time of ablation.

Laparoscopic RFA for HCC in Childs Class C cirrhotics (n = 6) was an effective bridge to OLT in 50 per cent of these patients (Table 2). Patients who had been transplanted had no evidence of HCC at a median follow-up period of 15 months.

Conclusion

The gold standard for treatment of primary and secondary tumors of the liver continues to be surgical resection. RFA has been shown to potentially increase survival in patients with unresectable tumors otherwise treated only with chemotherapy.7, 9 It has been suggested that this modality may specifically have better outcomes for HCC.3 Our data collected from 107 patients receiving RFA for unresectable liver tumors support these hypotheses, especially if patients are candidates for and receive a liver transplant. In a large patient population, we have shown mean survival in patients with unresectable HCC to be 47.3 months, mean survival of patients with unresectable CRC hepatic metastases to be 17.5 months, and mean survival of all other treated metastases to be 38.7 months. Five- year survival for HCC treated with RFA in our study was 39 per cent, which compares favorably with the 5-year survival rate of 40 per cent to 50 per cent quoted for formal resection.1 The survival rate seen for metastatic disease is a much more modest survival benefit when compared with chemotherapy alone.

RFA offers the ability of converting patients deemed “unresectable” into surgically treatable disease and thus giving an opportunity for cure. As we have shown, along with many others, this has promise in extending survival outcomes in primary and metastatic liver tumors.1, 5, 7,9 Our mean overall survival for patients with HCC of 47.3 months and 5-year overall survival of 39 per cent compares favorably with median survival rates of 9 months and 3- year survival of 13 per cent to 26 per cent quoted for medical and supportive care alone.10-12 We have shown that these benefits can be obtained with a low morbidity and mortality rate. Our morbidity rate of 11 per cent and mortality rate of 0.9 per cent are consistent with other studies.2-4, 9, 13 Additionally, this procedure is well tolerated with little blood loss and often no or short hospitalization.

High recurrence rates continue to be the most significant limiting factor with the oncologic outcomes of RFA. As shown by White et al., local tumor progression-free survival after RFA for colorectal metastases is approximately half of that seen with patients receiving surgical resection.14 Abdalla et al. report a fourfold increase in recurrence after treatment of metastatic CRC with RFA when compared with resection and only slightly superior survival rates with chemotherapy alone.7 Others have quoted recurrence rates as high as 53 per cent after ablation for unresectable HCC.15 Similarly, we had an overall recurrence of 50 per cent and a local recurrence rate of 27.6 per cent for HCC treated with RFA. These high recurrence rates for HCC may be related to the field defect of cirrhosis seen in the majority (88%) of our patients with HCC and making the development of a new primary more likely. Our overall recurrence for CRC was 58.3 per cent and local recurrence rate was 29.1 per cent. All other metastatic lesions treated with RFA had an overall recurrence rate of 56 per cent and a local recurrence rate of 52 per cent. High recurrence rates for our patients with metastatic disease are likely affected by not having a pure population of metastatic disease. This study includes patients who are at high risk for systemic recurrences (pancreas, sarcoma, breast, esophageal, and so on) but had other good prognostic factors to be considered such as young age, long disease-free interval, and often solitary tumors. This makes the population particularly susceptible to selection bias and an overall worse prognosis. Second, many of the patients with CRC were treated before the era of modern chemotherapy regimens, including oxaliplatin and biologic modifiers. The addition of these agents has roughly doubled the median survival in patients with metastatic CRC, which could have improved our outcomes.16 High recurrence rates of metastatic tumors at distant sites from RFA (25%) suggest that treatment of metastatic lesions will be better served with a multidisciplinary approach of chemotherapy and ablation. It remains to be seen if the higher response rates that have been reported in CRC with new chemotherapy and biologic agents translate into prolonged survival in conjunction with RFA.

It has been suggested that HCC may respond more favorably to RFA than other tumors and our survival data support this theory.3 The 39 per cent 5-year survival rate seen in our patients with HCC treated with RFA is augmented by 24 per cent of these patients being successfully transplanted after ablation. Of the 14 patients who were transplanted, 50 per cent had radiographically cured disease at the time of transplant. However, after pathologic examination of the explanted livers, 86 per cent of transplanted patients were found to have either recurrent or incompletely ablated HCC. This suggests that there is a higher probability of residual tumor being present than we are able to recognize radiographically and supports OLT as the best means for pathologic cure of HCC.

Another encouraging aspect of our data is the role of RFA as a bridge to OLT as a curative measure for otherwise unresectable HCC. Although the number of patients we studied that were bridged effectively to OLT is very small, this role for RFA has been validated in other studies.17, 18 Of particular interest, RFA was performed in Childs-Pugh Class C patients showing that this procedure can be performed safely in an otherwise high-risk population. As discussed by Mazzaferro et al., the patients with successful treatment of their HCC all had small tumors (3 cm or less) and were transplanted less than 1 year from their initial ablation.18

In this population of patients, we believe there are a number of reasons for the outcomes and high recurrence rates in our study. First, many patients were treated witii technology that, at that time, had relatively small burn areas. This necessitated multiple overlapping burns, which anecdotally appears to have worse outcomes. Unfortunately, the data about which needle was used on each individual patient were not available. Second, a radiologic complete response to RFA does not always appear to be a pathologic complete response. Some have suggested that there is a higher local recurrence rate as a result of the technique used for RFA. Specifically, it has been suggested that recurrence rates are higher with percutaneous ablation resulting from decreased resolution of liver tumors associated with transabdominal visualization and imprecise needle placement.19 Other studies have suggested no difference in recurrence rates based on ablation technique.15 In our population, there was not an association of increased recurrence rates with technique.

RFA is a safe and effective way for treating primary HCC and metastatic tumors of the liver in patients not eligible for hepatic resection. It is important to be reminded that this is not an independent modality for treating either primary or metastatic liver cancers.18 More effective control of systemic recurrence will dictate survival in the majority of patients with metastatic cancers. Local ablation for HCC in cirrhotic patients may be an effective bridge to transplantation; however, OLT may still be the most effective long-term treatment for localized HCC.

REFERENCES

1. Machi J, Bueno RS, Wong LL. Long-term follow-up outcome of patients undergoing radiofrequency ablation for unresectable hepatocellular carcinoma. World J Surg 2005;29:1364-73.

2. Leen E, Horgan PG. Radiofrequency ablation of colorectal liver metastases. Surg Oncol 2007;16:47-51.

3. Jiao LR, Hansen PD, Havlik R, et al. Clinical short-term results of radiofrequency ablation in primary and secondary liver tumors. Am J Surg 1999;177:303-6.

4. Tepel J, Hinz S, Klomp HJ, et al. Intraoperative radiofrequency ablation (RFA) for irresectable liver malignancies. Eur J Surg Oncol 2004;30:551-5.

5. Siperstein AE, Berber E, Ballem N, Parikh RT. Survival after radiofrequency ablation of colorectal liver metastases: 10-year experience. Ann Surg 2007;246:559-65. 6. Kornprat P, Jarnagin WR, DeMatteo RP, et al. Role of intraoperative thermoablation combined with resection in the treatment of hepatic metastasis from colorectal cancer. Arch Surg 2007;142:1087-92.

7. 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;239:818-25.

8. Arch-Ferrer JE, Smith JK, Bynon S, et al. Radio-frequency ablation in cirrhotic patients with hepatocellular carcinoma. Am Surg 2003;69:1067-71.

9. Amersi FF, McElrath-Garza A, Ahmad A, et al. Long-term survival after radiofrequency ablation of complex unresectable liver tumors. Arch Surg 2006;141:581-7.

10. Arii S, Yamaoka Y, Futagawa S, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: A retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan. Hepatology 2000;32:1224-9.

11. Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of 412 cases of hepatocellular carcinoma at a western center. Ann Surg 1999;229:790-9.

12. Livraghi T, Bolondi L, Buscarini L, et al. No treatment, resection and ethanol injection in hepatocellular carcinoma: A retrospective analysis of survival in 391 patients with cirrhosis. Italian Cooperative HCC Study Group. J Hepatol 1995;22:522-6.

13. Abitabile P, Hartl U, Lange J, Maurer CA. Radiofrequency ablation permits an effective treatment for colorectal liver metastasis. Eur J Surg Oncol 2007;33:67-71.

14. 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;11:256-63.

15. Raut CP, Izzo F, Marra P, et al. Significant long-term survival after radiofrequency ablation of unresectable hepatocellular carcinoma in patients with cirrhosis. Ann Surg Oncol 2005;12: 616-28.

16. Saad ED, Hoff PM. Chemotherapy of metastatic colorectal cancer. Curr Treat Options Gastroenterol 2005;8:239-47.

17. Lu DS, Yu NC, Raman SS, et al. Percutaneous radiofrequency ablation of hepatocellular carcinoma as a bridge to liver transplantation. Hepatology 2005;41:1130-7.

18. Mazzaferro V, Battiston C, Perrone S, et al. Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: A prospective study. Ann Surg 2004;240:900-9.

19. Curley SA. Radiofrequency ablation of malignant liver tumors. Ann Surg Oncol 2003;10:338-47.

J. HARRISON HOWARD, M.D.,* CHING-WEI D. TZENG, M.D.,* J. KEVIN SMITH, M.D.4 DEVON E. ECKHOFF, M.D.,[dagger] J. STEVE BYNON, M.D.,[dagger] THOMAS WANG, M.D.,* J. PABLO ARNOLETTI, M.D.,* MARTIN J. HESLIN, M.D.*

From the Departments of Surgery, Sections of * Surgical Oncology and [dagger] Transplant Surgery, and the [double dagger] Department of Radiology, the University of Alabama at Birmingham, Birmingham, Alabama

Presented at the Annual Scientific Meeting and Postgraduate Course Program, Southeastern Surgical Congress, Birmingham, AL, February 9-12, 2008.

Address correspondence and reprint requests to Martin J. lin, M.D., Section of Surgical Oncology, Department of Surgery, 1922 Seventh Avenue, KB 321, Birmingham, AL 35243. E-mail: marty.heslin@ccc.uab.edu.

DISCUSSION

WILLIAM G. CHEADLE, M.D. (Louisville, KY; Opening Discussion): Dr. Howard’s presentation emphasizes the importance of maintaining a patient database. Over a 7-year period, the authors had 107 patients with 189 lesions of varying types. The most common histology was hepatocellular carcinoma (HCC) followed by metastatic colorectal cancer with the remaining being various metastatic tumors. This distribution is similar to others reported in the literature.

The overall recurrence rate was 67 per cent for HCC and 50 per cent for colorectal cancer. This is a bit high and a cause for concern with this fairly new technique. Can you give us an idea of what your postimaging strategy is in these patients? How are the authors assured that this high percentage of recurrence was not incomplete hepatic ablations? Are these findings a combination of both incompletely treated lesions as well as recurrences? When adapting any new technology, there is a learning curve. Have the authors evaluated these recurrences based on time intervals and noted a trend to decreases in radiofrequency ablation (RFA) site recurrences over time? This RITA electrosurgical device has seen three major transitions or developments in the last decade. Has the recurrence rate correlated with these developments, as in a reduction in your recurrence rate correlated with better technology over this observation period? Do you always use intraoperative intraprocedural ultrasound during the ablation entirely to quantify it? In the subset analysis of patients with HCC who underwent local ablation and transplantation, was a tumor present in explanted livers?

J. HARRISON HOWARD, M.D. (Birmingham, AL; Closing Discussion): Our overall recurrence rate was high, as noted with the majority of HCC recurrences in the liver. Most of these patients have cirrhosis, so there is a field defect of the whole liver and an increased likelihood of developing a new HCC in a different area that was not ablated. Approximately one-third of our recurrences in the liver were at a new location. Of the 50 per cent of recurrences seen with colorectal and other metastatic diseases, approximately one-half (25%) of the recurrences were at the site of ablation. The other half were either in a new site in the liver or a different systemic recurrence. That will likely require RFA and systemic therapy to ultimately make a difference in their survival.

We re-evaluate these patients after RFA with a CT scan every 3 months for the first year.

Regarding a local recurrence or incomplete ablation, in three patients who had been transplanted, we had treatment during a relatively short timeframe from their RFA until time of transplant; the minimum was approximately 2 weeks, and there was a viable tumor at the site of ablation. So, there were incomplete ablations in some of these patients.

As far as recurrence by time interval or changes in technology, we examined recurrence rates per year, and there was not a statistical difference in the recurrence rates. However, in the past 2 to 3 years, we have begun to see a decrease in recurrence rates, which could be for a number of reasons such as a change in technology or methods of ablation. Smaller tumors will respond better to RFA.

We use the help of our radiology staff to assist with intraoperative ultrasound to help localize the tumor we are treating as well as other tumors that might have been missed on CT.

Regarding the explanted livers, 14 of those subsequently received a transplant; 50 per cent of them were radiographically disease- free at the time of their transplant. However, when livers were studied pathologically, the number of recurrences went from 50 per cent up to 86 per cent. Some of those were recurrences at the site of ablation. Some were very close to the site of ablation and likely represent an incomplete ablation. Some were HCC in new locations in the cirrhotic liver.

JOSEPH COFER, M.D. (Chattanooga, TN): There are little or no prospective, randomized data comparing RFA with other therapy. It is important to emphasize the treatment of liver cancer, whether metastatic or hepatocellular carcinoma, is ideally by resection. These were unresectable lesions either by reason of cirrhosis or the location of the tumor.

Do you have tumor markers or carcinoembryonic antigen levels that go to normal? In your institution with your large database, did you consider comparing HCC treated with RFA and their survival with other patients with HCC who refused RFA? Do you know that RFA made a difference?

J. HARRISON HOWARD, M.D. (Birmingham, AL; Closing Discussion): This is a therapy used for otherwise unresectable disease, patients that would be treated medically. How do we know if we have disease- free survival? The majority of our follow up is with CT, and that is what we based our disease-free survival on. We follow tumor markers but could not reliably find tumor markers on all of these patients in our database. In the explanted liver that you can have the pathologist section, what we thought was disease-free survival radiographically does not always correlate pathologically.

As far as patients treated with HCC with RFA versus no RFA, I do not have a database from our institution, but our survival seems to be better than patients treated with medical therapy alone. There are no randomized trials to prove that.

JOHN CHRISTEIN, M.D. (Birmingham, AL): Some RFAs are done in the radiology suite. I feel strongly that a surgeon should be involved in the decision of whether or not these are resectable. Do you have any comparison on those done by radiologists versus those with a surgeon’s involvement?

J. HARRISON HOWARD, M.D. (Birmingham, AL; Closing Discussion): At the University of Alabama at Birmingham, all of these patients had care directed by surgeons. The majority were treated percutaneously in the operating room or radiology suite. If it was in radiology, the surgeon may or may not have been present. There is argument in the literature about whether an open or laparoscopic ablation is better because of better visualization of the tumor with intraoperative ultrasound compared with transabdominal visualization of the tumor in a percutaneous method. Some studies have shown poor results with the percutaneous methods, whereas others have shown no difference in recurrence rates or complications in an open or laparoscopic population versus a percutaneous one. We saw no differences in recurrence rates.

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