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Radiofrequency ablation for unresectable hepatic tumors
The American Journal of Surgery 182 (2001) 552–557
Scientific paper
Radiofrequency ablation for unresectable hepatic tumors Sandra L. Wong, M.D.a,b, Michael J. Edwards, M.D.a,b, Celia Chao, M.D.a,b, Diana Simpson, R.N.a,b, Kelly M. McMasters, M.D., Ph. D.a,b,* b
a Division of Surgical Oncology, Department of Surgery, University of Louisville, Louisville, KY, USA J. Graham Brown Cancer Center, University of Louisville, 529 S. Jackson St., No. 318, Louisville, KY 40202, USA
Manuscript received July 31, 2001; revised manuscript September 12, 2001 Presented at the 53rd Annual Meeting of the Southwestern Surgical Congress, Cancun, Mexico, April 29 –May 2, 2001.
Abstract Background: Radiofrequency ablation (RFA) is a relatively new treatment for unresectable hepatic tumors. The purpose of this analysis was to examine the frequency of complications and local recurrence associated with RFA. Methods: Patients who underwent RFA of hepatic tumors with curative intent were included in this study. At laparotomy, RFA was performed using intraoperative ultrasound guidance. Computed tomography scans were obtained in the immediate postoperative period and every 3 to 6 months thereafter. Results: Forty patients underwent RFA for 122 hepatic tumors. Thirty-one patients had metastatic lesions from colorectal cancer; 9 had other liver tumors. Complications occurred in 8 patients. With 9.5 months median follow-up, 6 patients had local recurrence of their ablated tumors. Conclusions: Our initial experience shows that RFA can effectively eradicate unresectable hepatic tumors. The rate and severity of complications appear acceptable. However, further study is necessary to assess long-term recurrence rates and effect on overall survival. © 2002 Excerpta Medica, Inc. All rights reserved. Keywords: Radiofrequency ablation; Hepatic neoplasms; Colorectal cancer; Hepatocellular cancer; Liver metastases; coagulation necrosis
Hepatic resection is associated with improved survival and should be standard treatment for most patients with resectable hepatic malignancies. The 5-year survival rate after liver resection for metastatic colorectal cancer is between 25% and 40% with a median survival of 23 to 25 months. However, 85% to 90% of patients with hepatic metastases are deemed unresectable, and the prognosis for these patients is dismal with only anecdotal 5-year survivors [1]. Most lesions are not amenable to surgical resection because of tumor size, location, or multifocality. Furthermore, many patients with primary tumors of the liver such as hepatocellular carcinoma (HCC) face the additional challenge of comorbid health problems and poor liver reserve due to cirrhosis. Only 5% to 15% of newly diagnosed HCC patients are candidates for a potentially curative resection [2]. Alternate modalities of treatment must be considered. Radiofrequency ablation (RFA) is a relatively new proce-
* Corresponding author. Tel.: ⫹1-502-629-3380; fax: 502-629-3393. E-mail address: [email protected]
dure for treatment of hepatic tumors not amenable to resection. RFA employs a high-frequency alternating current to cause thermal coagulation and protein denaturation. The procedure is carried out using a needle electrode connected to a radiofrequency generator. As ions attempt to follow the change in direction of the alternating current, there is frictional heating within the tissue. The result is a coagulative necrosis of the targeted tissue. Previous studies have employed both imaging studies and pathologic evaluation of ablated lesions to show complete tumor eradication [3,4]. The purpose of this analysis was to evaluate our initial experience with RFA of hepatic tumors, and specifically to examine the associated complications and local recurrence rate.
Methods Review of medical records was performed under Institutional Review Board approval for all patients who underwent RFA of hepatic tumors between May 1998 and August
0002-9610/01/$ – see front matter © 2002 Excerpta Medica, Inc. All rights reserved. PII: S 0 0 0 2 - 9 6 1 0 ( 0 1 ) 0 0 8 1 3 - 3
S.L. Wong et al. / The American Journal of Surgery 182 (2001) 552–557
2000 at the University of Louisville Hospital or Norton Hospital, Louisville, Kentucky. Follow-up was evaluated up to April 1, 2001. Patients with metastatic lesions to the liver from colorectal or other primary sites who were not candidates for liver resection as the primary treatment were eligible for RFA. Two patients had unresectable primary hepatocellular carcinoma and underwent RFA as their primary treatment modality. Unresectability was determined by the operating surgeon and based upon preoperative imaging studies showing the number, size, and location of tumors, as well as comorbid conditions. Patients who had previously received systemic or intrahepatic chemotherapy were eligible for the procedure. Patients treated with curative intent (complete resection or ablation of all liver tumors) were included in this analysis. Patients with tumor involvement of the hepatic duct bifurcation, extensive tumor not treatable with curative intent, or evidence of extrahepatic disease (found either preoperatively or intraoperatively) were excluded. RFA was performed using the RadioTherapeutics ablation system (RadioTherapeutics Corp., Mountain View, California). All but 1 patient underwent laparotomy for their RFA procedure; 1 patient underwent percutaneous RFA under ultrasound guidance. Probe sizes were selected in accordance with the size of the lesion, with the goal of ablating at least a 1.0 cm margin of normal liver parenchyma around the tumor. Placement of the radiofrequency electrode was guided by real-time intraoperative ultrasonography. In accordance with the recommendations of the device manufacturer, two cycles of radiofrequency were performed for each deployment of the electrode. The electrode was repositioned as necessary to produce overlapping spherical thermal lesions to completely ablate the tumor. In some cases, RFA was performed concomitantly with other procedures such as resection of the primary tumor or placement of a hepatic artery infusion pump. Tumors in all locations in the liver were ablated, except for tumors involving the hepatic duct bifurcation. Specifically, we did not consider tumor proximity to hepatic veins, inferior vena cava, or the main right or left portal vein to be contraindications to RFA. Computed tomography (CT) scans were obtained in the immediate postoperative period (within 1 to 2 weeks) and approximately every 3 to 6 months thereafter in the majority of cases. CT scans from the immediate postoperative period were examined for evidence of complete tumor ablation. Recurrences were defined as new tumors evident on follow-up studies. Comparison to prior CT scans was performed to distinguish recurrence from the typical nonenhancing radiofrequency ablation sites.
Results Forty patients underwent RFA of 122 hepatic tumors (mean 3.1 tumors per patient, range 1 to 10) during 45
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Table 1 Clinicopathologic characteristics of patients undergoing radiofrequency ablation for unresectable metastases Patient characteristics
n ⫽ 40
Age (median) Gender Female Male Primary tumor Colorectal metastasis Hepatocellular carcinoma Neuroendocrine metastasis Other (breast, esophageal, sarcoma, carcinoid) Concomitant liver resection performed Concomitant other operative procedures performed
63 years 14 (35%) 26 (65%) 31 (77.5%) 2 (5%) 3 (7.5%) 4 (10%) 19 (47.5%) 20 (50%)
separate procedures. The clinicopathologic characteristics of the patient population are shown in Table 1. All procedures were performed via laparotomy except 1, which was performed percutaneously with ultrasound guidance. Nineteen patients underwent concomitant hepatic resection for other hepatic tumors, with segmentectomies or lobectomies in 10 patients and wedge resection of at least 1 lesion in 9 patients. RFA was the sole treatment modality for hepatic tumors in 21 patients. Other major operative procedures were performed concurrently in 20 patients, including placement of a hepatic artery infusion pump (n ⫽ 8) or resection of colorectal, pancreatic, gastric, or other primary tumors (n ⫽ 12). Complete ablation of tumors was achieved in all but 2 patients, 1 of whom had undergone percutaneous RFA. That patient later underwent a second RFA procedure via laparotomy and had a successful ablation. The second patient with incomplete ablation had initially undergone resection of a pancreatic neuroendocrine tumor with concomitant RFA of a presumed liver metastasis. On final pathology, the patient was found to have a benign pancreatic neoplasm, with a primary intrahepatic cholangiocarcinoma. She subsequently underwent extended hepatic resection. With a median follow-up time of 9.5 months, 9 patients have died of progressive disease, 11 are alive with recurrent disease, and 20 are free of disease (Table 2). Local recurrence of ablated tumors was detected in 6 patients (15%). Table 2 Patterns of recurrence in patients undergoing radiofrequency ablation for liver tumors Patient status
Number
No evidence of disease Alive with disease* Local recurrence at ablated site Liver recurrence at new site Extrahepatic recurrence Dead of progressive disease
20 11 4 5 6 9
* Two patients had both locally recurrent and new hepatic lesions. Two patients had new hepatic lesions and distant extrahepatic disease.
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S.L. Wong et al. / The American Journal of Surgery 182 (2001) 552–557
Table 3 Complications from radiofrequency ablation Complication
Number
Wound infection requiring antibiotics Pneumonia Right-sided pleural effusion* Intra-abdominal abscess† Biloma Sepsis/respiratory, renal failure‡
2 1 2 1 1 1
* The two cases of right-sided pleural effusion occurred following en bloc resection of liver and involved diaphragm. † The intra-abdominal abscess was noted in a patient with a colostomy who had a hepatic artery infusion pump placed after RFA. ‡ This patient, with a history of cardiac and cerebrovascular disease, underwent hepatic resection followed by RFA of 4 hepatic lesions and had a postoperative course complicated by a fall and hip fracture just prior to planned discharge from the hospital. She developed respiratory and renal failure and died after a prolonged hospital course.
There was a trend toward increased local recurrence in larger tumors compared with smaller tumors (mean tumor size 3.8 ⫾ 1.5 cm versus 2.5 ⫾ 1.5 cm, respectively). Two thirds of those with local recurrences (4 patients) also had new hepatic lesions. Two patients who had both locally recurrent and new lesions have died. Currently, 5 patients are alive with liver-only disease; 4 patients are alive with extrahepatic disease only; 2 are alive with liver plus distant metastatic disease. A second RFA procedure was performed in 5 patients—3 of the patients had both local recurrences and new lesions, 1 had new hepatic metastases, and 1 patient was reablated in the face of incomplete initial percutaneous RFA. The 3 patients who underwent repeat RFA for local recurrence and new liver metastases are among those who eventually died. Complications occurred in 8 patients (20%): 2 wound infections, 1 pneumonia, 2 pleural effusions, 1 intra-abdominal abscess, 1 biloma, and 1 with prolonged ventilatory dependence and renal failure (Table 3). There were no cases of postoperative hemorrhage and no major vascular injuries, bile duct injuries, intrahepatic abscesses, or damage to adjacent organs. There were no deaths as a direct result of the RFA procedure. None of the complications occurred after repeat RFA procedures.
Comments Although resection of primary or metastatic hepatic lesions can be curative in some cases, most patients have unresectable tumors. Unfortunately, systemic chemotherapy is rarely effective, with few complete responses and rare long-term progression-free survival. RFA is a relatively new treatment modality for unresectable hepatic lesions that has the potential to provide long-term survival by accomplishing complete tumor eradication.
Our experience with a heterogeneous group of patients shows that RFA can be used effectively to treat unresectable hepatic tumors. Although the rate of complications was 20%, most complications were minor and easily treated. There were no major bleeding complications, and no deaths related to the RFA procedure. Given the high frequency of concomitant liver resection and other major operative procedures, we consider the rate and severity of complications to be acceptable. The local recurrence rate in the present study was 15%. Previous studies have reported highly variable local recurrence rates associated with RFA, ranging from 0% to 100% [5–14]. Curley et al [6] reported a local recurrence rate of 1.8% in one of the largest series published to date. In our experience, local recurrences were evident at a median follow-up time of 7 months and were associated with ablation of larger tumors. It is possible that the rate of local recurrence may be reduced by specific interventions. For example, we are now more likely to deploy the electrode in several overlapping ablation sites to encompass tumors greater than 3 cm in diameter. For larger tumors requiring more than one deployment, we have learned to ablate on the medial and deep margins of the tumor initially to disrupt blood flow to the tumor. This often limits the time needed to perform ablations and may result in a more complete eradication. Selective use of the Pringle maneuver in patients with larger tumors or tumors in the vicinity of large vessels may provide larger zones of ablation. Additionally, newer probes have been developed to produce larger spheres of coagulation necrosis. Cryoablation, which involves freezing of liver tumors with liquid nitrogen, has also been used for treatment of unresectable liver tumors. However, RFA is less expensive, less time consuming, and less cumbersome to use than cryoablation. A prospective, nonrandomized study found fewer complications with RFA compared with cryoablation (3% versus 41%, respectively). The local recurrence rate was 14% for cryoablation compared with 2% for RFA [8]. Furthermore, cryoablation was compared with RFA in a study of over 300 patients during a 7-year period; again, findings suggest that RFA is safer than cryoablation [9]. Cryoablation can be associated with major complications, including myoglobinuria, hemorrhage secondary to hepatic “cracking,” arteriovenous or biliary fistulae, abscess formation, and hepatic failure [15]. RFA appears to be associated with fewer of these major complications. At our center, we have used cryoablation for liver tumors in the past, but now use RFA exclusively because of the issues outlined above. In select patients, RFA can be used in conjunction with hepatic resection for patients with multiple tumors. Furthermore, RFA can effectively treat deep hepatic metastases while preserving hepatic parenchyma. This is particularly important in patients with cirrhosis and minimal hepatic reserve. RFA can also be used to treat patients with recurrent tumors after prior liver resection. One of our patients had undergone a trisegmentectomy for hepatic metastases
S.L. Wong et al. / The American Journal of Surgery 182 (2001) 552–557
from a colorectal primary and subsequently developed recurrent disease; RFA was used successfully to ablate recurrent tumor. Based on our limited experience, repeat RFA seems to be well tolerated, but some of these patients developed progressive disease rather promptly. However, recurrence in the liver is frequently accompanied by extrahepatic disease, and careful preoperative staging is essential to select patients who could potentially benefit from repeat RFA. Because repeat liver resection has been shown to result in long-term survival equivalent to patients undergoing initial resection of metastases [16], we believe that it is appropriate to offer repeat RFA for selected patients with isolated hepatic recurrence. In the present study, 9 patients died of progressive disease, with new hepatic metastases or distant metastatic disease. This is not surprising because these are patients with unresectable hepatic tumors at high risk of progressive disease, and they often have recurrences outside of the ablated sites. Certainly, not all patients treated by RFA with “curative intent” will enjoy long-term survival, and further study is necessary to identify patient populations most likely to benefit from this procedure. However, because the durable complete response rate for patients treated with systemic chemotherapy is vanishingly small, we believe that inducing a “surgical complete response” may have a beneficial impact on long-term survival. RFA may be effective as a component of multimodality treatment for hepatic tumors not amenable to surgical resection alone. By analogy to the results obtained after liver resection, use of RFA with adjuvant hepatic artery infusion chemotherapy may decrease recurrence rates and improve survival [17,18]. Accordingly, we have recently embarked on a multicenter phase II study of RFA plus hepatic artery chemotherapy for patients with unresectable colorectal liver metastasis. We report results from a heterogeneous group of patients, and the small size of our study limits our ability to differentiate the application of RFA technology among different tumor types. The 2 patients treated for HCC currently have no evidence of disease with 7- and 8-month followups. Those patients treated for metastatic disease from an esophageal or sarcoma primary tumor died of progressive disease. Clearly, the biology of individual tumors is an important consideration in patient selection. There are, however, rare patients with noncolorectal metastases that may benefit from ablation of liver metastases. In particular, patients with neuroendocrine tumors metastatic to the liver may benefit from ablation because they frequently do not have extrahepatic disease, and often die of progressive liver disease. There is growing interest in applying RFA technology via minimally invasive approaches. Some have reported on the used of percutaneous and laparoscopic RFA procedures. In suitable patients, the percutaneous approach can be performed without general anesthesia. The laparoscopic ap-
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proach can be used to evaluate for extrahepatic disease and spares the patient a laparotomy. There are limitations with the more minimally invasive approaches however, and patients must be carefully selected. We do not have experience with laparoscopic procedures for RFA, and long-term follow-up is necessary to determine whether this approach is equivalent to an open procedure. Furthermore, we have limited experience with percutaneous RFA. One of our cases of incomplete ablation occurred with a percutaneous approach. Difficult localization of the lesion under transcutaneous ultrasound guidance was thought to be the cause of failure. Few data are available regarding long-term follow-up of patients undergoing percutaneous RFA. Major complications, such as bilioperitoneum, intrahepatic abscesses [12], acute thrombosis of the portal vein [19], and a death related to necrosis of the diaphragm have been reported following percutaneous RFA [10]. We have been hesitant to perform percutaneous RFA except in cases of relatively small tumors that are well within the hepatic parenchyma, away from adjacent organs. The potential for inadvertent ablation of the diaphragm, colon, stomach or other organs is an important consideration. In our experience, there are relatively few patients with truly unresectable tumors that fit these criteria; hence, we have chosen to perform RFA as an open operative procedure in the vast majority of cases. We therefore believe that the decision to perform percutaneous ablation should be a multidisciplinary effort that includes appropriate surgical consultation. In summary, our initial experience shows that RFA can be used effectively to treat unresectable hepatic tumors. The complication rate and local recurrence rate appear acceptable given the high-risk patient population and extent of other concomitant surgical procedures. Early results are promising; however, further study is necessary to assess long-term recurrence rates and the effect on overall survival.
References [1] Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230:309 –18. [2] Nagorney DM, vanHeerden JA, Ilstrup DM, Adson MA. Primary hepatic malignancy: surgical management and determinants of survival. Surgery 1989;106:740 – 8. [3] Goldberg SN, Gazelle GS, Compton CC, et al. Treatment of intrahepatic malignancy with radiofrequency ablation: radiologic-pathologic correlation. Cancer 2000;88:2452– 63. [4] Scudamore CH, Lee SI, Patterson EJ, et al. Radiofrequency ablation followed by resection of malignant liver tumors. Am J Surg 1999; 177:411–17. [5] Mahvi DM, Lee FT. Radiofrequency ablation of hepatic malignancies: is heat better than cold? Ann Surg 1999;230:9 –11. [6] Bartlett DL. Treatment of patients with hepatic metastases. Cancer J 2000;6S:169 –76. [7] Curley SA, Izzo F, Delrio P, et al. Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: results in 123 patients. Ann Surg 1999;230:1– 8.
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[8] Pearson AS, Izzo F, Fleming RY, et al. Intraoperative radiofrequency ablation or cryoablation for hepatic malignancies. Am J Surg 1999; 231:752– 61. [9] Bilchik AJ, Wood TF, Allegra D, et al. Cryosurgical ablation and radiofrequency ablation for unresectable hepatic malignant neoplasms: a proposed algorithm. Arch Surg 2000;135:657– 64. [10] Wood TF, Rose DM, Chung M, et al. Radiofrequency ablation of 231 unresectable hepatic tumors: indications, limitations, and complications. Ann Surg Oncol 2000;7:593– 600. [11] Rose DM, Allegra DP, Bostick PJ, et al. Radiofrequency ablation: a novel primary and adjunctive albative technique for hepatic malignancies. Am Surg 1999;65:1009 –14. [12] DeBaere T, Elias D, Dromain C, et al. Radiofrequency ablation of 100 hepatic metastases with a mean follow-up of more than 1 year. AJR Am J Roentgenol 2000;175:1619 –25. [13] Jiao LR, Hansen PD, Havlik R, et al. Clincial short-term results of radiofrequency ablation in primary and secondary liver tumors. Am J Surg 1999;177:303– 6. [14] Curley SA, Izzo F, Ellis LM, et al. Radiofrequency ablation of hepatocellular cancer in 110 patients with cirrhosis. Ann Surg 2000; 232:381–91. [15] McMasters KM, Edwards MJ. Liver cryosurgery: a potentially curative treatment option for patients with unresectable disease. Kentucky Med 1996;94:222–9. [16] Nordlinger B, Vaillant J-C, Guiget M, et al. Survival benefit of repeat liver resections for recurrent colorectal metastases: 143 cases. J Clin Oncol 1994;12:1491– 6. [17] Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999;341:2039 – 48. [18] Kainuma O, Asano T, Adyama H, et al. Combined therapy with radiofrequency thermal ablation and intra-arterial infusion chemotherapy for hepatic metastases from colorectal cancer. Hepato-Gastroenterology 1999;46:1071–7. [19] Francica F, Marone G, Solbiati L, et al. Hemobilia, intrahepatic hematoma and acute thrombosis with cavernomatous transformation of the portal vein after percutaneous thermoablation of a liver metastasis. Eur Radiol 2000;10:926 –9.
Acknowledgments Supported by the Center for Advanced Surgical Technologies (CAST) of Norton Hospital, Louisville, Kentucky.
Discussion Dr. Jameson Forster (Kansas City, KS): I congratulate the authors on a paper that serves to dispel some of the hype associated with radiofrequency ablation. It is not, unfortunately, a panacea for the liver surgeon in the treatment of liver cancer, but rather another weapon to use in the fight against cancer. One question that they did not address was which of the several systems available should one use? I was happy to see that they chose the one that I want to get, not the one I have. I had our hospital purchase the Rita machine early on and have more recurrences than I would like. I just visited Dr. Curley in Houston and believe that the RadioTherapeutics device, which they used in this paper, to be superior.
Question number 1, did you sample periportal nymph nodes? It was not mentioned in your paper, and I continue to do so despite finding positive metastases very infrequently. Number 2, do you use PET in the preoperative assessment of operative candidacy and do you see it as useful in follow up? The radiologists have such a trouble distinguishing recurrence from ablation artifact. Number 3, who should be doing ablations, ie, should physicians with no hepatic surgical expertise be doing ablations since it seems so relatively easy? Dr. Sandra L. Wong (Louisville, KY): We use the RadioTherapeutics system. I don’t have any basis for comparison because that is the system that our hospital has. Dr. Forster asked whether we sample periportal lymph nodes. If the lymph nodes look suspicious, they are sampled. The patients who had positive lymph nodes upon sampling were excluded from the study because the analysis only included patients for whom there was curative intent and no extra hepatic extension of disease. It’s a good question about CT scans. Often there are a lot of questions in terms of whether there is a local recurrence or not. I think the important thing is to get the same group of radiologists to review all the films and, if necessary, if someone comes to you from an outside referral center, to get a CT scan at your center before the procedure so that you will have something reasonable for comparison. I think it’s an excellent question who should be doing these procedures. We only did one percutaneous case, but there have been reports of a lot of radiologists starting to do these procedures. Dr. Forster mentioned Dr. Curly at M.D. Anderson. They did a large series with 123 patients in conjunction with some surgeons in Europe and one third of the patients in that study who had undergone a percutaneous radiofrequency ablation procedure had to be put to sleep secondary to pain. So you can imagine the dilemma, if you’re doing this procedure in the radiology suite, and you have this happen. The other thing that I’ll mention is that we don’t really have any experience with laparoscopic radiofrequency ablation. I think there’s some promising data out there, but we don’t have any experience with it and that also brings up questions about how this procedure should be done. Unidentified Speaker: Looking at the results you have and reading the results in the literature, should this or can this be a bridge to more definitive therapy, where you shrink three or four lesions and then a fourth lesion that doesn’t respond well can be resected, or is it never used in that role? Dr. Sandra L. Wong: I guess that depends on your philosophy, because some people believe that if you can resect a lesion, you should go ahead and do so. It is interesting because you can save a lot of liver tissue, especially in patients with poor reserve. So if you ablate it and you get a recurrence that’s small, you can resect that.
S.L. Wong et al. / The American Journal of Surgery 182 (2001) 552–557
Unidentified Speaker: So you shrink some of them and resect residual disease or do you combine resection and radiofrequency at the same site? Dr. Sandra L. Wong: Right. Forty-eight percent of our cases had concomitant liver resections, so the lesions which could be resected were resected and the ones that couldn’t were ablated. There are people out there who do the ablations even though it’s resectable, and that’s a point of controversy.
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Unidentified Speaker: What size lesion will you do? Are you using a Pringle maneuver for this technique? Dr. Sandra L. Wong: The use of a Pringle maneuver has been shown to improve the results, and that’s another reason why a percutaneous RFA may not be the way to go, because you can’t do that when you’re doing it percutane-ously. I think most results show that if your tumor is larger than 3 or 4 cm, that a Pringle maneuver will enhance your results.
Scientific paper
Radiofrequency ablation for unresectable hepatic tumors Sandra L. Wong, M.D.a,b, Michael J. Edwards, M.D.a,b, Celia Chao, M.D.a,b, Diana Simpson, R.N.a,b, Kelly M. McMasters, M.D., Ph. D.a,b,* b
a Division of Surgical Oncology, Department of Surgery, University of Louisville, Louisville, KY, USA J. Graham Brown Cancer Center, University of Louisville, 529 S. Jackson St., No. 318, Louisville, KY 40202, USA
Manuscript received July 31, 2001; revised manuscript September 12, 2001 Presented at the 53rd Annual Meeting of the Southwestern Surgical Congress, Cancun, Mexico, April 29 –May 2, 2001.
Abstract Background: Radiofrequency ablation (RFA) is a relatively new treatment for unresectable hepatic tumors. The purpose of this analysis was to examine the frequency of complications and local recurrence associated with RFA. Methods: Patients who underwent RFA of hepatic tumors with curative intent were included in this study. At laparotomy, RFA was performed using intraoperative ultrasound guidance. Computed tomography scans were obtained in the immediate postoperative period and every 3 to 6 months thereafter. Results: Forty patients underwent RFA for 122 hepatic tumors. Thirty-one patients had metastatic lesions from colorectal cancer; 9 had other liver tumors. Complications occurred in 8 patients. With 9.5 months median follow-up, 6 patients had local recurrence of their ablated tumors. Conclusions: Our initial experience shows that RFA can effectively eradicate unresectable hepatic tumors. The rate and severity of complications appear acceptable. However, further study is necessary to assess long-term recurrence rates and effect on overall survival. © 2002 Excerpta Medica, Inc. All rights reserved. Keywords: Radiofrequency ablation; Hepatic neoplasms; Colorectal cancer; Hepatocellular cancer; Liver metastases; coagulation necrosis
Hepatic resection is associated with improved survival and should be standard treatment for most patients with resectable hepatic malignancies. The 5-year survival rate after liver resection for metastatic colorectal cancer is between 25% and 40% with a median survival of 23 to 25 months. However, 85% to 90% of patients with hepatic metastases are deemed unresectable, and the prognosis for these patients is dismal with only anecdotal 5-year survivors [1]. Most lesions are not amenable to surgical resection because of tumor size, location, or multifocality. Furthermore, many patients with primary tumors of the liver such as hepatocellular carcinoma (HCC) face the additional challenge of comorbid health problems and poor liver reserve due to cirrhosis. Only 5% to 15% of newly diagnosed HCC patients are candidates for a potentially curative resection [2]. Alternate modalities of treatment must be considered. Radiofrequency ablation (RFA) is a relatively new proce-
* Corresponding author. Tel.: ⫹1-502-629-3380; fax: 502-629-3393. E-mail address: [email protected]
dure for treatment of hepatic tumors not amenable to resection. RFA employs a high-frequency alternating current to cause thermal coagulation and protein denaturation. The procedure is carried out using a needle electrode connected to a radiofrequency generator. As ions attempt to follow the change in direction of the alternating current, there is frictional heating within the tissue. The result is a coagulative necrosis of the targeted tissue. Previous studies have employed both imaging studies and pathologic evaluation of ablated lesions to show complete tumor eradication [3,4]. The purpose of this analysis was to evaluate our initial experience with RFA of hepatic tumors, and specifically to examine the associated complications and local recurrence rate.
Methods Review of medical records was performed under Institutional Review Board approval for all patients who underwent RFA of hepatic tumors between May 1998 and August
0002-9610/01/$ – see front matter © 2002 Excerpta Medica, Inc. All rights reserved. PII: S 0 0 0 2 - 9 6 1 0 ( 0 1 ) 0 0 8 1 3 - 3
S.L. Wong et al. / The American Journal of Surgery 182 (2001) 552–557
2000 at the University of Louisville Hospital or Norton Hospital, Louisville, Kentucky. Follow-up was evaluated up to April 1, 2001. Patients with metastatic lesions to the liver from colorectal or other primary sites who were not candidates for liver resection as the primary treatment were eligible for RFA. Two patients had unresectable primary hepatocellular carcinoma and underwent RFA as their primary treatment modality. Unresectability was determined by the operating surgeon and based upon preoperative imaging studies showing the number, size, and location of tumors, as well as comorbid conditions. Patients who had previously received systemic or intrahepatic chemotherapy were eligible for the procedure. Patients treated with curative intent (complete resection or ablation of all liver tumors) were included in this analysis. Patients with tumor involvement of the hepatic duct bifurcation, extensive tumor not treatable with curative intent, or evidence of extrahepatic disease (found either preoperatively or intraoperatively) were excluded. RFA was performed using the RadioTherapeutics ablation system (RadioTherapeutics Corp., Mountain View, California). All but 1 patient underwent laparotomy for their RFA procedure; 1 patient underwent percutaneous RFA under ultrasound guidance. Probe sizes were selected in accordance with the size of the lesion, with the goal of ablating at least a 1.0 cm margin of normal liver parenchyma around the tumor. Placement of the radiofrequency electrode was guided by real-time intraoperative ultrasonography. In accordance with the recommendations of the device manufacturer, two cycles of radiofrequency were performed for each deployment of the electrode. The electrode was repositioned as necessary to produce overlapping spherical thermal lesions to completely ablate the tumor. In some cases, RFA was performed concomitantly with other procedures such as resection of the primary tumor or placement of a hepatic artery infusion pump. Tumors in all locations in the liver were ablated, except for tumors involving the hepatic duct bifurcation. Specifically, we did not consider tumor proximity to hepatic veins, inferior vena cava, or the main right or left portal vein to be contraindications to RFA. Computed tomography (CT) scans were obtained in the immediate postoperative period (within 1 to 2 weeks) and approximately every 3 to 6 months thereafter in the majority of cases. CT scans from the immediate postoperative period were examined for evidence of complete tumor ablation. Recurrences were defined as new tumors evident on follow-up studies. Comparison to prior CT scans was performed to distinguish recurrence from the typical nonenhancing radiofrequency ablation sites.
Results Forty patients underwent RFA of 122 hepatic tumors (mean 3.1 tumors per patient, range 1 to 10) during 45
553
Table 1 Clinicopathologic characteristics of patients undergoing radiofrequency ablation for unresectable metastases Patient characteristics
n ⫽ 40
Age (median) Gender Female Male Primary tumor Colorectal metastasis Hepatocellular carcinoma Neuroendocrine metastasis Other (breast, esophageal, sarcoma, carcinoid) Concomitant liver resection performed Concomitant other operative procedures performed
63 years 14 (35%) 26 (65%) 31 (77.5%) 2 (5%) 3 (7.5%) 4 (10%) 19 (47.5%) 20 (50%)
separate procedures. The clinicopathologic characteristics of the patient population are shown in Table 1. All procedures were performed via laparotomy except 1, which was performed percutaneously with ultrasound guidance. Nineteen patients underwent concomitant hepatic resection for other hepatic tumors, with segmentectomies or lobectomies in 10 patients and wedge resection of at least 1 lesion in 9 patients. RFA was the sole treatment modality for hepatic tumors in 21 patients. Other major operative procedures were performed concurrently in 20 patients, including placement of a hepatic artery infusion pump (n ⫽ 8) or resection of colorectal, pancreatic, gastric, or other primary tumors (n ⫽ 12). Complete ablation of tumors was achieved in all but 2 patients, 1 of whom had undergone percutaneous RFA. That patient later underwent a second RFA procedure via laparotomy and had a successful ablation. The second patient with incomplete ablation had initially undergone resection of a pancreatic neuroendocrine tumor with concomitant RFA of a presumed liver metastasis. On final pathology, the patient was found to have a benign pancreatic neoplasm, with a primary intrahepatic cholangiocarcinoma. She subsequently underwent extended hepatic resection. With a median follow-up time of 9.5 months, 9 patients have died of progressive disease, 11 are alive with recurrent disease, and 20 are free of disease (Table 2). Local recurrence of ablated tumors was detected in 6 patients (15%). Table 2 Patterns of recurrence in patients undergoing radiofrequency ablation for liver tumors Patient status
Number
No evidence of disease Alive with disease* Local recurrence at ablated site Liver recurrence at new site Extrahepatic recurrence Dead of progressive disease
20 11 4 5 6 9
* Two patients had both locally recurrent and new hepatic lesions. Two patients had new hepatic lesions and distant extrahepatic disease.
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Table 3 Complications from radiofrequency ablation Complication
Number
Wound infection requiring antibiotics Pneumonia Right-sided pleural effusion* Intra-abdominal abscess† Biloma Sepsis/respiratory, renal failure‡
2 1 2 1 1 1
* The two cases of right-sided pleural effusion occurred following en bloc resection of liver and involved diaphragm. † The intra-abdominal abscess was noted in a patient with a colostomy who had a hepatic artery infusion pump placed after RFA. ‡ This patient, with a history of cardiac and cerebrovascular disease, underwent hepatic resection followed by RFA of 4 hepatic lesions and had a postoperative course complicated by a fall and hip fracture just prior to planned discharge from the hospital. She developed respiratory and renal failure and died after a prolonged hospital course.
There was a trend toward increased local recurrence in larger tumors compared with smaller tumors (mean tumor size 3.8 ⫾ 1.5 cm versus 2.5 ⫾ 1.5 cm, respectively). Two thirds of those with local recurrences (4 patients) also had new hepatic lesions. Two patients who had both locally recurrent and new lesions have died. Currently, 5 patients are alive with liver-only disease; 4 patients are alive with extrahepatic disease only; 2 are alive with liver plus distant metastatic disease. A second RFA procedure was performed in 5 patients—3 of the patients had both local recurrences and new lesions, 1 had new hepatic metastases, and 1 patient was reablated in the face of incomplete initial percutaneous RFA. The 3 patients who underwent repeat RFA for local recurrence and new liver metastases are among those who eventually died. Complications occurred in 8 patients (20%): 2 wound infections, 1 pneumonia, 2 pleural effusions, 1 intra-abdominal abscess, 1 biloma, and 1 with prolonged ventilatory dependence and renal failure (Table 3). There were no cases of postoperative hemorrhage and no major vascular injuries, bile duct injuries, intrahepatic abscesses, or damage to adjacent organs. There were no deaths as a direct result of the RFA procedure. None of the complications occurred after repeat RFA procedures.
Comments Although resection of primary or metastatic hepatic lesions can be curative in some cases, most patients have unresectable tumors. Unfortunately, systemic chemotherapy is rarely effective, with few complete responses and rare long-term progression-free survival. RFA is a relatively new treatment modality for unresectable hepatic lesions that has the potential to provide long-term survival by accomplishing complete tumor eradication.
Our experience with a heterogeneous group of patients shows that RFA can be used effectively to treat unresectable hepatic tumors. Although the rate of complications was 20%, most complications were minor and easily treated. There were no major bleeding complications, and no deaths related to the RFA procedure. Given the high frequency of concomitant liver resection and other major operative procedures, we consider the rate and severity of complications to be acceptable. The local recurrence rate in the present study was 15%. Previous studies have reported highly variable local recurrence rates associated with RFA, ranging from 0% to 100% [5–14]. Curley et al [6] reported a local recurrence rate of 1.8% in one of the largest series published to date. In our experience, local recurrences were evident at a median follow-up time of 7 months and were associated with ablation of larger tumors. It is possible that the rate of local recurrence may be reduced by specific interventions. For example, we are now more likely to deploy the electrode in several overlapping ablation sites to encompass tumors greater than 3 cm in diameter. For larger tumors requiring more than one deployment, we have learned to ablate on the medial and deep margins of the tumor initially to disrupt blood flow to the tumor. This often limits the time needed to perform ablations and may result in a more complete eradication. Selective use of the Pringle maneuver in patients with larger tumors or tumors in the vicinity of large vessels may provide larger zones of ablation. Additionally, newer probes have been developed to produce larger spheres of coagulation necrosis. Cryoablation, which involves freezing of liver tumors with liquid nitrogen, has also been used for treatment of unresectable liver tumors. However, RFA is less expensive, less time consuming, and less cumbersome to use than cryoablation. A prospective, nonrandomized study found fewer complications with RFA compared with cryoablation (3% versus 41%, respectively). The local recurrence rate was 14% for cryoablation compared with 2% for RFA [8]. Furthermore, cryoablation was compared with RFA in a study of over 300 patients during a 7-year period; again, findings suggest that RFA is safer than cryoablation [9]. Cryoablation can be associated with major complications, including myoglobinuria, hemorrhage secondary to hepatic “cracking,” arteriovenous or biliary fistulae, abscess formation, and hepatic failure [15]. RFA appears to be associated with fewer of these major complications. At our center, we have used cryoablation for liver tumors in the past, but now use RFA exclusively because of the issues outlined above. In select patients, RFA can be used in conjunction with hepatic resection for patients with multiple tumors. Furthermore, RFA can effectively treat deep hepatic metastases while preserving hepatic parenchyma. This is particularly important in patients with cirrhosis and minimal hepatic reserve. RFA can also be used to treat patients with recurrent tumors after prior liver resection. One of our patients had undergone a trisegmentectomy for hepatic metastases
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from a colorectal primary and subsequently developed recurrent disease; RFA was used successfully to ablate recurrent tumor. Based on our limited experience, repeat RFA seems to be well tolerated, but some of these patients developed progressive disease rather promptly. However, recurrence in the liver is frequently accompanied by extrahepatic disease, and careful preoperative staging is essential to select patients who could potentially benefit from repeat RFA. Because repeat liver resection has been shown to result in long-term survival equivalent to patients undergoing initial resection of metastases [16], we believe that it is appropriate to offer repeat RFA for selected patients with isolated hepatic recurrence. In the present study, 9 patients died of progressive disease, with new hepatic metastases or distant metastatic disease. This is not surprising because these are patients with unresectable hepatic tumors at high risk of progressive disease, and they often have recurrences outside of the ablated sites. Certainly, not all patients treated by RFA with “curative intent” will enjoy long-term survival, and further study is necessary to identify patient populations most likely to benefit from this procedure. However, because the durable complete response rate for patients treated with systemic chemotherapy is vanishingly small, we believe that inducing a “surgical complete response” may have a beneficial impact on long-term survival. RFA may be effective as a component of multimodality treatment for hepatic tumors not amenable to surgical resection alone. By analogy to the results obtained after liver resection, use of RFA with adjuvant hepatic artery infusion chemotherapy may decrease recurrence rates and improve survival [17,18]. Accordingly, we have recently embarked on a multicenter phase II study of RFA plus hepatic artery chemotherapy for patients with unresectable colorectal liver metastasis. We report results from a heterogeneous group of patients, and the small size of our study limits our ability to differentiate the application of RFA technology among different tumor types. The 2 patients treated for HCC currently have no evidence of disease with 7- and 8-month followups. Those patients treated for metastatic disease from an esophageal or sarcoma primary tumor died of progressive disease. Clearly, the biology of individual tumors is an important consideration in patient selection. There are, however, rare patients with noncolorectal metastases that may benefit from ablation of liver metastases. In particular, patients with neuroendocrine tumors metastatic to the liver may benefit from ablation because they frequently do not have extrahepatic disease, and often die of progressive liver disease. There is growing interest in applying RFA technology via minimally invasive approaches. Some have reported on the used of percutaneous and laparoscopic RFA procedures. In suitable patients, the percutaneous approach can be performed without general anesthesia. The laparoscopic ap-
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proach can be used to evaluate for extrahepatic disease and spares the patient a laparotomy. There are limitations with the more minimally invasive approaches however, and patients must be carefully selected. We do not have experience with laparoscopic procedures for RFA, and long-term follow-up is necessary to determine whether this approach is equivalent to an open procedure. Furthermore, we have limited experience with percutaneous RFA. One of our cases of incomplete ablation occurred with a percutaneous approach. Difficult localization of the lesion under transcutaneous ultrasound guidance was thought to be the cause of failure. Few data are available regarding long-term follow-up of patients undergoing percutaneous RFA. Major complications, such as bilioperitoneum, intrahepatic abscesses [12], acute thrombosis of the portal vein [19], and a death related to necrosis of the diaphragm have been reported following percutaneous RFA [10]. We have been hesitant to perform percutaneous RFA except in cases of relatively small tumors that are well within the hepatic parenchyma, away from adjacent organs. The potential for inadvertent ablation of the diaphragm, colon, stomach or other organs is an important consideration. In our experience, there are relatively few patients with truly unresectable tumors that fit these criteria; hence, we have chosen to perform RFA as an open operative procedure in the vast majority of cases. We therefore believe that the decision to perform percutaneous ablation should be a multidisciplinary effort that includes appropriate surgical consultation. In summary, our initial experience shows that RFA can be used effectively to treat unresectable hepatic tumors. The complication rate and local recurrence rate appear acceptable given the high-risk patient population and extent of other concomitant surgical procedures. Early results are promising; however, further study is necessary to assess long-term recurrence rates and the effect on overall survival.
References [1] Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230:309 –18. [2] Nagorney DM, vanHeerden JA, Ilstrup DM, Adson MA. Primary hepatic malignancy: surgical management and determinants of survival. Surgery 1989;106:740 – 8. [3] Goldberg SN, Gazelle GS, Compton CC, et al. Treatment of intrahepatic malignancy with radiofrequency ablation: radiologic-pathologic correlation. Cancer 2000;88:2452– 63. [4] Scudamore CH, Lee SI, Patterson EJ, et al. Radiofrequency ablation followed by resection of malignant liver tumors. Am J Surg 1999; 177:411–17. [5] Mahvi DM, Lee FT. Radiofrequency ablation of hepatic malignancies: is heat better than cold? Ann Surg 1999;230:9 –11. [6] Bartlett DL. Treatment of patients with hepatic metastases. Cancer J 2000;6S:169 –76. [7] Curley SA, Izzo F, Delrio P, et al. Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: results in 123 patients. Ann Surg 1999;230:1– 8.
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[8] Pearson AS, Izzo F, Fleming RY, et al. Intraoperative radiofrequency ablation or cryoablation for hepatic malignancies. Am J Surg 1999; 231:752– 61. [9] Bilchik AJ, Wood TF, Allegra D, et al. Cryosurgical ablation and radiofrequency ablation for unresectable hepatic malignant neoplasms: a proposed algorithm. Arch Surg 2000;135:657– 64. [10] Wood TF, Rose DM, Chung M, et al. Radiofrequency ablation of 231 unresectable hepatic tumors: indications, limitations, and complications. Ann Surg Oncol 2000;7:593– 600. [11] Rose DM, Allegra DP, Bostick PJ, et al. Radiofrequency ablation: a novel primary and adjunctive albative technique for hepatic malignancies. Am Surg 1999;65:1009 –14. [12] DeBaere T, Elias D, Dromain C, et al. Radiofrequency ablation of 100 hepatic metastases with a mean follow-up of more than 1 year. AJR Am J Roentgenol 2000;175:1619 –25. [13] Jiao LR, Hansen PD, Havlik R, et al. Clincial short-term results of radiofrequency ablation in primary and secondary liver tumors. Am J Surg 1999;177:303– 6. [14] Curley SA, Izzo F, Ellis LM, et al. Radiofrequency ablation of hepatocellular cancer in 110 patients with cirrhosis. Ann Surg 2000; 232:381–91. [15] McMasters KM, Edwards MJ. Liver cryosurgery: a potentially curative treatment option for patients with unresectable disease. Kentucky Med 1996;94:222–9. [16] Nordlinger B, Vaillant J-C, Guiget M, et al. Survival benefit of repeat liver resections for recurrent colorectal metastases: 143 cases. J Clin Oncol 1994;12:1491– 6. [17] Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999;341:2039 – 48. [18] Kainuma O, Asano T, Adyama H, et al. Combined therapy with radiofrequency thermal ablation and intra-arterial infusion chemotherapy for hepatic metastases from colorectal cancer. Hepato-Gastroenterology 1999;46:1071–7. [19] Francica F, Marone G, Solbiati L, et al. Hemobilia, intrahepatic hematoma and acute thrombosis with cavernomatous transformation of the portal vein after percutaneous thermoablation of a liver metastasis. Eur Radiol 2000;10:926 –9.
Acknowledgments Supported by the Center for Advanced Surgical Technologies (CAST) of Norton Hospital, Louisville, Kentucky.
Discussion Dr. Jameson Forster (Kansas City, KS): I congratulate the authors on a paper that serves to dispel some of the hype associated with radiofrequency ablation. It is not, unfortunately, a panacea for the liver surgeon in the treatment of liver cancer, but rather another weapon to use in the fight against cancer. One question that they did not address was which of the several systems available should one use? I was happy to see that they chose the one that I want to get, not the one I have. I had our hospital purchase the Rita machine early on and have more recurrences than I would like. I just visited Dr. Curley in Houston and believe that the RadioTherapeutics device, which they used in this paper, to be superior.
Question number 1, did you sample periportal nymph nodes? It was not mentioned in your paper, and I continue to do so despite finding positive metastases very infrequently. Number 2, do you use PET in the preoperative assessment of operative candidacy and do you see it as useful in follow up? The radiologists have such a trouble distinguishing recurrence from ablation artifact. Number 3, who should be doing ablations, ie, should physicians with no hepatic surgical expertise be doing ablations since it seems so relatively easy? Dr. Sandra L. Wong (Louisville, KY): We use the RadioTherapeutics system. I don’t have any basis for comparison because that is the system that our hospital has. Dr. Forster asked whether we sample periportal lymph nodes. If the lymph nodes look suspicious, they are sampled. The patients who had positive lymph nodes upon sampling were excluded from the study because the analysis only included patients for whom there was curative intent and no extra hepatic extension of disease. It’s a good question about CT scans. Often there are a lot of questions in terms of whether there is a local recurrence or not. I think the important thing is to get the same group of radiologists to review all the films and, if necessary, if someone comes to you from an outside referral center, to get a CT scan at your center before the procedure so that you will have something reasonable for comparison. I think it’s an excellent question who should be doing these procedures. We only did one percutaneous case, but there have been reports of a lot of radiologists starting to do these procedures. Dr. Forster mentioned Dr. Curly at M.D. Anderson. They did a large series with 123 patients in conjunction with some surgeons in Europe and one third of the patients in that study who had undergone a percutaneous radiofrequency ablation procedure had to be put to sleep secondary to pain. So you can imagine the dilemma, if you’re doing this procedure in the radiology suite, and you have this happen. The other thing that I’ll mention is that we don’t really have any experience with laparoscopic radiofrequency ablation. I think there’s some promising data out there, but we don’t have any experience with it and that also brings up questions about how this procedure should be done. Unidentified Speaker: Looking at the results you have and reading the results in the literature, should this or can this be a bridge to more definitive therapy, where you shrink three or four lesions and then a fourth lesion that doesn’t respond well can be resected, or is it never used in that role? Dr. Sandra L. Wong: I guess that depends on your philosophy, because some people believe that if you can resect a lesion, you should go ahead and do so. It is interesting because you can save a lot of liver tissue, especially in patients with poor reserve. So if you ablate it and you get a recurrence that’s small, you can resect that.
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Unidentified Speaker: So you shrink some of them and resect residual disease or do you combine resection and radiofrequency at the same site? Dr. Sandra L. Wong: Right. Forty-eight percent of our cases had concomitant liver resections, so the lesions which could be resected were resected and the ones that couldn’t were ablated. There are people out there who do the ablations even though it’s resectable, and that’s a point of controversy.
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Unidentified Speaker: What size lesion will you do? Are you using a Pringle maneuver for this technique? Dr. Sandra L. Wong: The use of a Pringle maneuver has been shown to improve the results, and that’s another reason why a percutaneous RFA may not be the way to go, because you can’t do that when you’re doing it percutane-ously. I think most results show that if your tumor is larger than 3 or 4 cm, that a Pringle maneuver will enhance your results.