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Annals of Surgical Oncology, 10(9):1059–1069
Combined Resection and Radiofrequency Ablation for Advanced Hepatic Malignancies: Results in 172 Patients Timothy M. Pawlik, MD, MPH, Francesco Izzo, MD, Deborah S. Cohen, MS, Jeffery S. Morris, PhD, and Steven A. Curley, MD Background: Resection combined with radiofrequency ablation (RFA) is a novel approach in
patients who are otherwise unresectable. The objective of this study was to investigate the safety andefficacy of hepatic resection combined with RFA.
Methods: Patients with multifocal hepatic malignancies were treated with surgical resection
combined with RFA. All patients were followed prospectively to assess complications, treatmentresponse, and recurrence.
Results: Seven hundred thirty seven tumors in 172 patients were treated (124 with colorectal
metastases; 48 with noncolorectal metastases). RFA was used to treat 350 tumors. Combinedmodality treatment was well tolerated with low operative times and minimal blood loss. Thepostoperative complication rate was 19.8% with a mortality rate of 2.3%. At a median follow-up of21.3 months, tumors had recurred in 98 patients (56.9%). Failure at the RFA site was uncommon(2.3%). A combined total number of tumors treated with resection and RFA Ͼ10 was associatedwith a faster time to recurrence (P ϭ .02). The median actuarial survival time was 45.5 months.
Patients with noncolorectal metastases and those with less operative blood loss had an improvedsurvival (P ϭ .03 and P ϭ .04, respectively), whereas radiofrequency ablating a lesion Ͼ3 cmadversely impacted survival (HR ϭ 1.85, P ϭ .04).
Conclusions: Resection combined with RFA provides a surgical option to a group of patients
with liver metastases who traditionally are unresectable, and may increase long-term survival.
Key Words: Hepatocellular cancer—Liver metastases—Resection—Radiofrequency ablation.
Patients with primary and secondary malignancies of their liver and a significant subset of these patients has the liver are extremely common. Worldwide, hepatocel- isolated hepatic disease (20%).2 Although less frequent, lular carcinoma (HCC) is one of the most widespread other solid malignancies, such as neuroendocrine, breast, solid cancers, with an estimated incidence of at least one and sarcoma, can also metastasize solely to the liver.
million new patients per year.1 In the United States, Surgical resection of primary and metastatic liver tumors colorectal cancer represents the third most common type is considered to be the optimal treatment modality with a of cancer for both men and women, with an annual curative effect, offering a 5-year survival rate between incidence of 130,000 new cases. A majority of these 20% and 35%.3–5 Despite this, surgical extirpation is patients develop secondary metastatic disease within seldom undertaken. The majority of patients with pri-mary or metastatic malignancies confined to the liver are Received March 7, 2003; accepted July 11, 2003.
not candidates for curative resection because of tumor From the Departments of Surgery (TMP, SAC) and Biostatistics location, multifocality, proximity of tumor to vessels, or (DSC, JSM), The University of Texas, M.D. Anderson Cancer Center, inadequate functional hepatic reserve. In fact, only 5% to Houston, Texas; and the Department of Surgery (FI), The G. PascaleNational Cancer Institute, Naples, Italy.
15% of newly diagnosed primary or secondary liver Address correspondence and reprint requests to: Steven A. Curley, malignancies are amenable to surgical resection.6,7 In an MD, The University of Texas MD Anderson Cancer, Department ofSurgical Oncology, Box 444, 1515 Holcombe Blvd, Houston, TX attempt to provide treatment for the overwhelming ma- 77030; Fax: 713-745-5235; E-mail: [email protected]
jority of patients who are not candidates for isolated Published by Lippincott Williams & Wilkins 2003 The Society of Surgical hepatic resection, novel treatment approaches to control and potentially cure primary and secondary liver disease reserve inadequate to tolerate major hepatic resection. In all cases, the intent of the surgical procedure could not Radiofrequency ablation (RFA) has become a widely have been curative had it not been associated with RFA.
used ablative technique for primary and secondary liver Patients were considered for RFA even if they had tumor tumors. RFA involves the localized application of ther- abutting a major portal or hepatic vein branch or the mal energy to destroy tumor cells. Alternating electric inferior vena cava, but they were excluded if tumor current in the range of radiofrequency (RF) waves (460 involved the main right or left bile duct (or both) because kHz) is applied from an RF generator through a needle of the probability of destruction of the major bile ducts electrode placed directly into the tumor.8 This agitates ions in tissue surrounding the electrodes, causing local- All patients were evaluated with a baseline history and ized frictional heating and thermal coagulative necrosis.
physical examination; serum laboratory tests consisting Others have shown that RFA of liver malignancies is of a complete blood count, platelets, coagulation profile, safe, efficacious, and has acceptable local recurrence and hepatitis B and C virus serology (HCC patients only), short-term survival rates.9–14 Virtually all studies to date, renal panel, electrolytes, albumin, alanine aminotransfer- however, have investigated RFA as an isolated, alterna- ase, aspartate aminotransferase, gamma-glutamyl trans- tive therapy for unresectable hepatic disease. To our ferase, alkaline phosphatase, total bilirubin, and serum knowledge, hepatic resection combined with simulta- alpha-fetoprotein (AFP) or serum carcinoembryonic an- neous RFA of unresectable secondary lesions in a large tigen (CEA) as deemed appropriate; computed tomogra- series of patients has not been reported.
phy (CT) or magnetic resonance imaging (MRI) scan of Combining hepatic resection with RFA allows the the abdomen and pelvis; and a chest radiograph. Patients surgeon to remove the bulk of disease or larger tumors were excluded for combined modality treatment if their while ablating any residual smaller lesions. By combin- platelet count was Ͻ40,000/␮L or if the prothrombin ing techniques, more patients may become candidates for time was prolonged more than 1.5 times above normal.
hepatic resection, as any remaining “unresectable” tu- However, if platelet or fresh-frozen plasma transfusions mors can be ablated while still preserving an adequate corrected the abnormal laboratory values to meet these volume of perfused functional liver. Although conceptu- criteria, the patient received treatment. Those patients ally appealing, there is presently little empirical data to with a white blood count below 2,000 or a bilirubin Ͼ2.0 support the use of this combination of therapy. In this study, we review a large cohort of patients who under- All patients were treated surgically with both resection went combined multimodality treatment consisting of and RFA during one operation. Upon entering the abdo- hepatic resection with RFA of additional lesions for the men, an initial exploration was performed to preclude the treatment of primary or secondary hepatic malignancies.
presence of extrahepatic disease. An intraoperative he- The objective of this study was to investigate and eluci- patic ultrasound was then performed to identify, count, date the feasibility, safety, and potential efficacy of he- and characterize the nature and vascular proximity of the hepatic lesions. Routinely, the hepatic resection was per-formed first. The location of the hepatic lesion and its MATERIALS AND METHODS
relation to surrounding vascular and biliary structuresdictated whether or not a formal anatomic resection was Between January 1996 and April 2002, a series of 172 performed. In general, hepatic resection was performed patients underwent combined hepatic resection with in- using a stapling technique as previously described.15 traoperative RFA. All patients with histologically con- After removal of the index lesion(s), the remaining un- firmed primary or metastatic hepatic malignancies with resectable lesions were treated with RFA after a stan- no clinical, radiographic, or intraoperative evidence of dardized treatment algorithm.16,17 Intraoperative ultra- extrahepatic disease were eligible for combined treat- sonography was used to place the RF needle into the ment. To be eligible, patients had to have multifocal lesions to be treated by RFA. RFA was administered hepatic disease that was deemed unresectable by classic using the RF 2000 or 3000 generator system (Boston standards due to either the location of the disease or the Scientific Corp, Natick, MA), a LeVeen monopolar nee- volume of liver involved. Patients were deemed surgi- dle electrode (4.0-cm maximum array diameter), and cally unresectable for cure based on the number or bilo- four indifferent dispersive grounding pads applied to the bar location of tumors, tumor proximity to major vascu- patient’s skin. The RF 2000 system consists of a gener- lar structures precluding a margin-negative resection, ator that supplies up to 100 W of power, whereas the RF and/or the presence of cirrhosis with a functional hepatic 3000 provides up to 200 W of power. The LeVeen needle Ann Surg Oncol, Vol. 10, No. 9, 2003 MULTIMODAL TREATMENT OF HEPATIC MALIGNANCIES electrode is a 15-gauge, 12- to 15-long insulated cannula these patients are shown in Table 1. Combined hepatic that contains 10 to 12 individual hook-shaped electrode resection and RFA was used to treat metastatic colorectal arms that are deployed in situ. For tumors Ͻ2.5 cm in cancer in the overwhelming majority of cases: 124 pa- diameter, the multiple array was deployed into the center tients (72.1%). Metastatic leiomyosarcoma was the sec- of the tumor. For larger lesions, the array was first ond most commonly treated lesion (n ϭ 13, 7.6%), deployed at the most posterior interface (ultrasono- whereas only 5 patients (2.9%) had multifocal HCC.
graphically) between tumor and normal liver parenchy- Other more uncommon lesions included metastatic car- ma; it was subsequently withdrawn and redeployed at cinoid, pancreatic cancer, neuroendocrine tumors, breast 1.5-cm intervals in the tumor. Each tumor or area within metastases, cholangiocarcinoma, and one patient with a large tumor was treated with a two-phase application of ocular melanoma. This latter group of patients, however, RF power before retracting the multiple array and repo- only accounted for 17.6% of the total patients treated and sitioning or removing the needle electrode. The electrode represents a highly selected cohort of patients. The com- was optimally positioned to achieve complete destruc- mon factor in these patients with noncolorectal liver tion of tumor and at least a 1-cm zone of normal liver metastases was liver-only disease confirmed on multiple imaging studies that was responding or stable on suitable After hepatic resection and tumor ablation, the same battery of serum blood tests as had been drawn preoper- Resection combined with RFA was used to treat 737 atively were again obtained postoperatively on days 1, 7, tumors. A total of 387 tumors were treated with hepatic and 30. At 1 month and every 3 months up to 2 years resection, whereas 350 tumors underwent RFA. The me- after treatment, and then every 6 months thereafter, a CT dian number of tumors per patient was 3 (range, 2–21); or MRI scan of the abdomen, a chest radiograph, and the median number of tumors surgically excised per serum laboratory tests were obtained.
patient was 2 (range, 1–9), and the median number of For purposes of this study, the following were col- tumors ablated was 1 (range, 1–12). Surgery involved lected for all patients: patient age and sex; tumor histol- resection of a single tumor in 81 patients (47.1%), two ogy, number, location, and size; type of surgical resec- tumors in 30 patients (17.4%), three tumors in 31 pa- tion; operative details; disease status; follow-up date; tients (18.1%), and more than three in 30 patients death date; and complication data. Disease status was (17.4%) (Table 2). In performing the hepatic resection, classified as no evidence of disease (NED), alive with the type of procedure employed varied widely (Table 3).
disease (AWD), dead of disease (DOD), or dead of other The majority of patients (n ϭ 101, 58.7%) had a resec- causes at last known follow-up. Recurrences were de- tion that involved the removal of at least 2 hepatic tected by CT/MRI imaging or via biopsy diagnosis and segments and a full one-half of the patients underwent at were defined as tumors occurring either at local sites of least a formal hepatic lobectomy in addition to the RFA prior ablation, distant sites within the liver, or distant treatment. Specifically, 31 patients (18%) underwent a Distribution of survival time and time to progression were analyzed in relation to the different variables col- Characteristics of the 172 patients treated with lected. Univariate tests (log-rank) were used to test for differences in these distributions by any single factor.
Those factors that appeared to have significant impact on survival or time to progression were entered into a Cox proportional hazards model to test for significant effects while adjusting for multiple factors simultaneously.
During the study period, a total of 172 patients were treated using the combined modality of hepatic resection with RFA. There were 102 men (59.9%) and 70 women (40.1%), with a median age of 56.2 years (range, 12– 80 years). In all cases, RFA treatment and hepatic resection were performed at The University of Texas M.D. Ander-son Cancer Center. The primary cancer diagnoses in RFA, radiofrequency ablation; NOS, not otherwise specified.
Ann Surg Oncol, Vol. 10, No. 9, 2003 Patient tumor burden characteristics the operation. The median operative time for the com-bined procedure was 3.0 hours (range, 1– 8.13 hours) with a median blood loss of 200 cc (range, 50 –2000 cc).
Only one intraoperative RFA-associated complication occurred: a partial thickness thermal injury to the adja- cent stomach, which was recognized and repaired at the time of injury; there were no long-term consequences of The postoperative complication rate was 19.8% (34 complications occurring in 25 patients), including 4 post- operative deaths for an overall mortality rate of 2.3% (Table 4). A number of complications were minor and not necessarily related to the type of procedure per- formed. These included prolonged postoperative ileus (2.3%), urinary tract infections (.6%), and pleural effu- sion (.6%). Intermediate morbidity complications in- cluded cardiac events such as tachycardia or dysrhyth- mias (1.7%), biloma (2.3%), perihepatic abscess (1.7%),and pneumonia (2.9%). There was no correlation be- right lobectomy, 11 patients an extended right lobectomy tween the extent of the liver resection or number of (6.4%), 28 patients a left lobectomy (16.3%), 14 patients tumors treated with RFA and the development of post- an extended left lobectomy (8.1%), and 2 patients (1.1%) operative complications. Major complications such as a right trisegmentectomy. Only 21 patients (12.2%) had adult respiratory distress syndrome (.6%), multisystem organ failure/hepatic failure (1.7%), postoperative bleed After removal of the index lesion(s), the remaining (.6%), and pulmonary embolus (.6%) were more uncom- unresectable lesions were treated with RFA following a mon and predominantly occurred in the 4 patients who standardized treatment algorithm. RFA was used to treat died postoperatively (Table 5). A review of the 4 post- 350 lesions: a single tumor in 97 patients (56.4%), two operative deaths revealed that 2 deaths were related to tumors in 34 patients (20.0%), and three or more tumors liver failure. Patient 1 had cirrhosis and did not tolerate in 41 patients (23.6%) (Table 2). The diameter of each a limited resection involving the removal of hepatic tumor was measured in three dimensions by ultrasonog- segments V and VI. In contrast, patient 4 had normal raphy before RFA. The median size of the lesions treated preoperative liver function, but did not have enough with RFA was 1.8 cm ϫ 1.6 cm ϫ 1.5 cm (range, .3 cm hepatic reserve to tolerate an extended right lobectomy ϫ .3 cm ϫ .3 cm to 12.0 cm ϫ 12.0 cm ϫ 5.5 cm). In with RFA and postoperatively developed multisystem general, adding RFA to the hepatic resection was welltolerated and added minimal complexity or morbidity to Postoperative complications and deaths: complications (34 complications in 25 patients) Multisystem organ failure/hepatic failure Ann Surg Oncol, Vol. 10, No. 9, 2003 MULTIMODAL TREATMENT OF HEPATIC MALIGNANCIES Postoperative complications and deaths: postoperative deaths (n ϭ 4, 2.3%) HCC, hepatocellular carcinoma; CRC, colorectal carcinoma metastasis; RFA, radiofrequency ablation; OR, operating room; EBL, estimated blood loss; ARDS, adult respiratory distress syndrome; MSOF, multiple system organ failure.
organ failure. Patient 3 had a postoperative bleed result- pared to those patients with fewer tumors (7.6 –10.3 months) (Fig. 1). Although the total numbers of tumors At a median follow-up of 21.3 months, tumor had treated seemed to impact time to recurrence, the number and size of tumors treated with RFA did not effect The site of first recurrence was isolated to the RFA site median time to recurrence (P ϭ .44 and P ϭ .42, re- in 8 patients (8.2%), a non-RFA hepatic recurrence in 38 spectively) (Fig. 2). Similarly, other factors such as age, patients (38.8%), a non-RFA hepatic recurrence plus type of cancer, simultaneous vs. metachronous metasta- distant disease in 31 patients (31.6%), and isolated dis- ses, and type of resection all did not impact time to tant disease in 21 patients (21.4%). Interestingly, the recurrence on univariate analysis (all P Ͼ .05). In all median time to failure was about 7.5 months in all cases cases, the median time to recurrence was Ͻ12 months, (Table 6). Not unexpectedly, the most common site of suggesting that the majority of patients who do recur will distant disease was pulmonary metastases. A detailed do so within a short period of time after surgery.
review of the 8 patients with RFA site recurrences re- On multivariate analysis, the total number of tumors vealed that 4 patients had lesions ablated that were Ն 3 was again the only significant variable that affected time cm (Table 7). One patient had a 12-cm lesion treated to recurrence. Those patients who had more than 10 with RFA but recurred Ͻ2 months postoperatively. It is tumors treated with combined hepatic resection and RFA important to note that although 8 patients out of 172 were significantly more likely to have a shorter time to recurred at the RFA site for an overall patient failure rate recurrence than those with less disease (HR ϭ 1.63, CI ϭ of 8.2%, there were only 8 treatment site failures out of With regard to survival, at last follow-up 60 patients Univariate analysis was performed to detect which (34.8%) had died of disease, whereas 112 patients factors possibly had an effect on the time to recurrence.
(65.2%) were still alive. The overall median actuarial As shown in Table 8, the only factor that affected time to survival time was 45.5 months. Univariate analysis re- recurrence was the total number of tumors treated (i.e., vealed that the type of cancer as well as the amount of the total number of tumors surgically resected plus those blood loss were significant factors affecting overall sur- treated with RFA). When tested in a four-category sys- vival. Those patients with noncolorectal metastases had a tem, there was a statistically significant difference in the significantly better median survival (59 months) as com- time to recurrence in those patients who had more than pared to those patients with colorectal metastases (37.3 10 tumors treated (P ϭ .02). These patients had a shorter months) (P ϭ .03) (Fig. 3). The amount of surgical blood median disease-free survival time (2.3 months) as com- loss also significantly affected overall survival. Patientswith Ͼ 1000 cc blood loss had a median survival of 30.5 Details of tumor recurrence after hepatic months as compared to 42.6 months and 56.6 months for resection and RFA: overall recurrence rates patients with Ͻ250 cc and 250 to 1000 cc blood loss, respectively (P ϭ .04). The effect of blood loss on survival was not seen in the immediate postoperative period but rather became more evident in long-term follow-up (Fig. 4). Although not statistically significant, those patients who had RFA of a lesion Ͼ3 cm showed a trend toward worse survival (P ϭ .14). Other factors such as age, number of RFA tumors, type of surgery, and total number of tumors treated did not significantly affect survival on univariate analysis (all P Ͼ .05).
Ann Surg Oncol, Vol. 10, No. 9, 2003 Details of tumor recurrence after hepatic resection and RFA: recurrence at the RFA site As colorectal cancer is the major type of hepatic On multivariate survival analysis, the size of the RFA metastasis confronting surgeons in the United States, we lesion was the only factor that significantly impacted felt it important to analyze this group separately. As survival. Patients who underwent RFA of a lesion Ͼ3 cm noted above, those patients with colorectal metastases had a higher likelihood of death than those who under- had a median actuarial survival of 37.3 months. Addi- went RFA of a lesion Յ3 cm (HR ϭ 1.85, CI ϭ 1.02– tional analysis revealed that patients with synchronous 3.37, P ϭ .04). Similar to univariate analysis, there was colorectal metastasis had a better overall survival as a trend suggesting that patients with synchronous hepatic compared to patients with metachronous metastases metastases did better than those patients with metachro- nous lesions (HR ϭ .64, CI ϭ .36 –1.14, P ϭ .13).
Univariate analysis of factors affecting time DISCUSSION
Primary and secondary malignancies of the liver are extremely common. The liver is second only to lymphnodes as the most frequent site of metastasis from other solid cancers.2 In fact, liver failure from extensive me- tastases often constitutes the main cause of death in patients with both colorectal cancer as well as a number of other common carcinomas. Surgical resection for pri- mary and secondary hepatic malignancies is considered Total burden of disease-treated (i.e., the total number of tumors surgically resected plus those treated with radiofrequency ab- lation ) impacts recurrence. Those patients with a total tumor burden of Ͼ10 lesions treated do have a shorter median disease-free survival time as compared to those with fewer tumors (P ϭ .02).
Ann Surg Oncol, Vol. 10, No. 9, 2003 MULTIMODAL TREATMENT OF HEPATIC MALIGNANCIES Patients with noncolorectal metastases had a significantly better median survival (59 months) as compared with those patientswith colorectal metastases (37.3 months) (P ϭ .03).
for hepatic malignancies is critical if higher long-termsurvival rates are to be achieved. Unfortunately, mostpatients (80% to 90%) are not candidates for surgicalresection either due to extent or distribution of disease.20Traditionally, for a tumor to be considered appropriatefor resection, there must not be any extrahepatic diseaseor severe hepatic dysfunction, the tumor or tumors mustnot be so extensive that too little functioning liver re-mains after the resection, at least a 1-cm tumor-freeresection margin should be attained, and there should notbe any involvement of the confluence of the portalvein.20,21 Recent advances have led to the development Although the total number of tumors treated seemed to impact time to recurrence, the number (A) and the size (B) of tumors
treated with radiofrequency ablation (RFA) did not affect median time
to recurrence (P ϭ .44 and P ϭ .42, respectively).
the only treatment modality with potential for a curativeeffect. In selected patients with metastatic disease con-fined to the liver, reported five-year survival rates forpatients undergoing resection of secondary metastaticliver tumors range from 20% to 35%.3–5 In contrast,without any treatment, the median survival after thedetection of liver metastases is approximately 9 months,depending on the extent of the disease at the time ofdiagnosis.18 The outcomes for patients treated with sys-temic chemotherapy strongly depend on the regimenused and type and organ of origin of the cancer, butgenerally a 1-year survival rate of approximately 60% isreported, with a 2-year survival rate below 30%.19 Five- Patients with Ͼ1000 cc blood loss had a median survival less year survival and cure are both exceedingly rare for than that of patients who had Ͻ250 cc and 250 to 1000 cc blood loss(P ϭ .04). Effect of blood loss on survival was not seen in the patients with hepatic metastases treated with chemother- immediate postoperative period but rather became evident in long-term apy alone. Given this, the availability of surgical therapy Ann Surg Oncol, Vol. 10, No. 9, 2003 of several alternative treatment methods designed to pro- a population of patients who have a larger tumor burden vide therapy for the majority of patients diagnosed with associated with biologically more aggressive disease and liver cancer who are not candidates for surgical an inherently poorer prognosis. Performing a potentially morbid procedure (such as a resection with RFA) would Interstitial local ablative techniques involving either be unwarranted if it could not lead to meaningful long- freezing (cryoablation),22,23 chemical desiccation (alco- term survival in a subset of patients. In reviewing the hol ablation),24,25 or RFA9,26,27 have all been described.
literature, there have been occasional reports of RFA Among these, rapid freezing of tissue with exposure to being used as an adjunct to resection, but these studies liquid nitrogen cryoprobes at 196°C has a high risk of have included only small numbers of patients.40,41 The liver fracture, hemorrhage, and tumor-lysis syndromes, current study represents the largest series of patients whereas alcohol injection results in nonhomogeneous dis- reported to date who have been treated simultaneously tribution within tumors and results in incomplete areas of necrosis.28 Neither of these local therapies produces ex- This study was performed to address the question of tended long-term survival in most patients.29–33 In contrast, feasibility and safety concerning the use of combined isolated RFA of unresectable liver malignancies has been hepatic resection and RFA applications. As other studies shown to be safe and efficacious; however, local recurrence have reported, intraoperative complications from RFA rates ranging from 5% to 30% have been reported.9–14 are uncommon.9,17,40,41 In the current series, there was In general, most data concerning RFA treatment of only one intraoperative complication: a partial thickness hepatic tumors has come from studies involving patients thermal injury to the stomach that resulted in no long- with unresectable disease who have had RFA as primary term consequences. The complication rate for hepatic therapy. In these studies, RFA has proven to be an resection and RFA was 19.8%, which is comparable to extremely safe procedure with a complication rate lower the 11% to 35% morbidity rates reported for hepatic than 10%.9,10 Previous studies using both imaging stud- resection alone.42,43 Most of the complications were mi- ies and pathological evaluation of ablated lesions have nor or intermediate, including urinary tract infections, shown complete tumor eradication.34–37 Recent studies bilomas, or abscesses that were amenable to percutane- with isolated RFA show a median survival of 34 months ous drainage. Serious complications were less common, and a 3-year survival rate of 36% from the time of but when they did occur they were strongly associated thermal ablation.38,39 Recurrence rates at the RFA site with mortality. Overall the perioperative mortality rate have been reported to be Ͻ10% after surgical RFA, with was 2.3%, which again compares favorably to reported most treatment failures occurring in larger tumors (Ͼ3– 4 rates of 0% to 3% for hepatic resection alone.42,43 It cm in diameter).9,10,13,40 One explanation for local RFA appears, therefore, that hepatic resection combined with site failure in 4 of the 8 patients in the present study is the RFA is safe and well tolerated. A review of the periopera- large size of the ablated lesion with a corresponding tive deaths, however, mandates a cautionary note. Two inadequate tumor kill. Local RFA failure, however, deaths were associated with liver failure, subsequent mul- could not be completely attributed to the size of the tisystem organ failure and death. These patients serve to lesion ablated as the other 4 patients had tumors Յ3 cm.
emphasize that although combined therapy appears to be We do not advocate use of RFA as a replacement for safe in the majority of cases, resection combined with resection, which remains the gold standard for the treat- thermal destruction of too great a volume of liver may lead ment of malignant liver tumors. Rather, RFA has been to liver failure and death. Patients with cirrhosis and pre- advocated as a treatment solely for those tumors that are operative hepatic compromise, as well as those patients unresectable by virtue of their number, location, or size with normal liver function but in whom an extended resec- relative to liver volume. At the University of Texas M.D.
tion combined with RFA is being considered must be care- Anderson Cancer Center, in an attempt to increase the fully evaluated to determine if an adequate volume of number of patients who are eligible for aggressive sur- perfused normal liver will remain after resection and RFA.
gical removal or destruction of tumors, we now perform In general, adding RFA to the hepatic resection was RFA in combination with hepatic resection. Despite the well tolerated and added minimal complexity to the theoretical appeal of combination therapy, there is some operation. In the majority of cases, the operation in- concern in the surgical community that the addition of an volved a formal hepatic lobectomy plus RFA. Despite ablative therapy to a major hepatic resection would be this, the median operative time was only 3 hours and the unsafe and add significant complexity to an already median blood loss was only 200 cc. These numbers are demanding operation. Additionally, there is concern that comparable to historical operative data of isolated hepatic patients with traditionally unresectable disease represent resection performed at our institution. On univariate anal- Ann Surg Oncol, Vol. 10, No. 9, 2003 MULTIMODAL TREATMENT OF HEPATIC MALIGNANCIES ysis, the amount of blood loss did seem to affect overall study, multivariate analysis revealed that a total number survival with patients experiencing Ͼ 1000 cc blood loss of tumors Ͼ10 was significantly associated with a short having a significantly decreased median survival. One pos- time to recurrence (Ͻ3.0 months). Patients with Ͼ10 sible reason for this is that blood loss may have acted as a tumors clearly represent a cohort of patients with a surrogate marker for not only the complexity of the surgical significant tumor burden who may be more likely to resection, but also the extent of hepatic disease.
harbor micrometastatic disease. Based on our data, we The patients in the present study had a wide spectrum would recommend caution in offering combined modal- of tumors, with the majority having colorectal metasta- ity therapy to this subset of patients, as a meaningful ses. The study did include patients with other secondary malignancies of the liver such as leiomyosarcoma, breast At last follow-up, 65.2% of patients were alive, yield- cancer, pancreatic cancer, and neuroendocrine tumors.
ing a median actuarial survival time of 45.5 months.
This latter group represented a minority of the patients Three factors seemed to affect overall survival. As noted treated with resection and RFA. Previously studies have above, patients with noncolorectal metastasis and those shown that RFA for noncolorectal hepatic metastases can with Ͻ1000 cc blood loss had a significantly greater be effective if the patient population is chosen careful- probability of long-term survival. RFA of a tumor Ͼ3 cm ly.9,40,44 In the present study, on univariate analysis, in diameter was a significant factor on multivariate anal- those patients with noncolorectal metastases had a sta- ysis with these patients having a higher likelihood of tistically significant better median survival as compared death from cancer recurrence than those who underwent to those patients with colorectal metastases. This may be ablation of a lesion Յ3 cm (HR ϭ 1.85, CI ϭ 1.02–3.37, related to selection bias. The therapeutic threshold for P ϭ .04). Previous studies have also shown a correlation operating on noncolorectal hepatic metastasis is consid- between lesion size, recurrence risk, and survival. We do erably higher than that for colorectal disease. Most pa- not recommend abandoning combined hepatic resection tients with noncolorectal liver metastases have been and RFA of lesions Ͼ 3 cm, but this data does show that heavily pretreated with systemic or regional chemother- there is an increased risk of failure in this subset of apy and have been followed for a period of time in order patients. This may be because RFA of lesions Ͼ3 cm in to document stable isolated hepatic disease. In contrast, diameter requires more experience and creation of mul- colorectal patients are more likely to undergo resection tiple overlapping zones of thermal necrosis is usually sooner, without a period of time to monitor the stability required. For this reason, hepatic resection combined of their disease. Thus, colorectal patients may be more with RFA should be performed by those who have ex- likely to harbor unsuspected regional or distant micro- pertise in both techniques. Due to the inherent learning metastatic disease that becomes clinically evident curve associated with RFA, one should initially attempt months or years after an operation. Our data supports the ablation of smaller lesions before undertaking more com- safety of an appropriately aggressive treatment plan for plex larger lesions. Furthermore, clinical trials of adju- patients with both colorectal and noncolorectal hepatic vant systemic and/or regional therapies following resec- metastasis. In patients with stable isolated noncolorectal tion and RFA of hepatic malignancies must be performed hepatic metastases, hepatic resection in combination with to assess for reduction in rates of cancer recurrence.
RFA can lead to significant long-term survival periods.
One of the most surprising outcomes of the study was Recurrence of cancer after liver resection and RFA the finding that patients with synchronous colorectal occurred in 56.9% of patients. RFA site recurrence oc- metastases seemed to enjoy a better survival than pa- curred in 8 patients (8.2%), but local recurrence occurred tients with metachronous lesions. Although this was in only 8 of 350 tumors ablated (2.3%). Thus, RFA site found to be significant in univariate analysis, in the recurrence was uncommon with regional or distant re- multivariate model, it did not withstand competing risk currence being much more frequent. RFA and resection adjustment but a trend did persist (P ϭ .13). This finding are treatments designed to achieve local control of ma- is at odds with traditional reports showing that patients lignant hepatic tumors. Resection or local destruction of with synchronous lesions tend to have a relatively poor tumor can produce long-term disease-free and overall survival probability. Although we do not have a clear survival in a subset of patients but cannot overcome the explanation for this finding in the current study, it may tumor biology in patients who already have micrometa- be related to patient selection and pretreatment bias. The static disease at the time of their surgical therapy. Thus, majority of our patients who developed metachronous even though we had a RFA site failure rate of only 2.3%, colorectal liver metastases did so after receiving adjuvant recurrent disease developed in over one-half of the pa- fluoropyrimidine-based systemic therapy after resection tients after combined resection and RFA. In the current of their primary colorectal cancer. Thus, they had already Ann Surg Oncol, Vol. 10, No. 9, 2003 failed one chemotherapy regimen and had fewer subse- NIH conference on hepatocellular carcinoma. Ann Intern Med quent treatment options. In contrast, patients with syn- 2. Weiss L, Grundmann E, Torhorst J, et al. Hematogenous metastatic chronous liver metastases underwent resection of their patterns in colonic carcinoma: an analysis of 1541 necropsies.
primary cancer followed by three drug-combined sys- temic chemotherapy (IFL: irinotecan, 5-fluorouracil, leu- 3. Fong Y, Cohen AM, Fortner JG, et al. Liver resection for colo- rectal metastases. J Clin Oncol 1997;15:938 – 46.
covorin) both before and after liver resection and RFA.
4. Blumgart LH, Fong Y. Surgical options in the treatment of hepatic This aggressive multimodality approach may have a metastases from colorectal cancer. Curr Probl Surg 1995;32:333– greater impact on patient survival probabilities; however, 5. Tuttle TM. Hepatectomy for noncolorectal liver metastases. In: further accrual and follow-up of these patients is needed.
Curley SA, ed. Liver Cancer. New York: Springer-Verlag Publish- Our group of 172 patients treated with combined he- patic resection and RFA of malignant liver tumors is the 6. Liver Cancer Study Group of Japan. Primary liver cancer in Japan: clinicopathologic features and results of surgical treatment. Ann largest series reported to date. Other reports contain either patients treated with RFA alone or have small 7. Nagorney DM, van Heerden JA, Ilstrup DM, Adson MA. Primary number of patients who underwent combined modality hepatic malignancy: surgical management and determinants ofsurvival. Surgery 1989;106:740 – 8.
treatment. In this study, we showed that concurrent treat- 8. Rhim H, Dodd GD III. Radiofrequency thermal ablation of liver ment with surgical resection and RFA is feasible and tumors. J Clin Ultrasound 1999;27:221–9.
safe. Local recurrence rates at RFA sites treated using 9. Curley SA, Izzo F, Delrio P, et al. Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies: results intraoperative ultrasound-guided therapy with multiple in 123 patients. Ann Surg 1999;230:1– 8.
overlapping zones of thermal treatment is uncommon.
10. Wood TF, Rose DM, Chung M, Allegra DP, Foshag LJ, Bilchik Regional or distant recurrence of disease is the more AJ. Radiofrequency ablation of 231 unresectable hepatic tumors:indications, limitations, and complications. Ann Surg Oncol 2000; frequent pattern of failure. We demonstrated that tumor burden influences the time to recurrence, but age, gender, 11. de Baere T, Elias D, Dromain C, et al. Radiofrequency ablation of histological type, RFA lesion size, and the type of resec- 100 hepatic metastases with a mean follow up of more than 1 year.
Am J Roentgenol 2000;175:1619 –25.
tion performed do not. At a median follow-up of 21.3 12. Solbiati L, Ierace T, Tonolino M, Orti V, Cova L. Radiofrequency months, 65.2% of patients were still alive for a median thermal ablation of hepatic metastases. Eur J Ultrasound 2001;13: actuarial survival of 44.5 months. It is difficult to com- 13. Bilchik AJ, Wood TF, Allegra DP. Radiofrequency ablation of pare objectively resection plus RFA results with other unresectable hepatic malignancies: lessons learned. Oncologist modalities such as RFA alone or resection alone because of the differences in the patient populations treated. Neverthe- 14. Vogl T, Mack M, Straub R. Thermal ablation of liver metastases.
Current status and prospects. Radiologe 2001;41:49 –55.
less, our data is provocative as it suggests that even patients 15. Curley SA, Cusack JC, Tanabe KK, Stoelzing O, Ellis LM. Ad- with multifocal, liver-only, but otherwise unresectable liver vances in the treatment of liver tumors. Curr Probl Surg 2002;39: cancer may derive a significant survival benefit from com- 16. Pearson AS, Izzo F, Fleming RY, et al. Intraoperative radiofre- bined hepatic resection and RFA. The selection of such quency ablation or cryoablation for hepatic malignancies. Am J patients is critical and results of this nonrandomized, retro- spective study must be corroborated by further clinical 17. Curley SA, Izzo F, Ellis LM, Vauthey J, Vallone P. Radiofre- quency ablation of hepatocellular cancer in 110 patients with trials. Further studies will also be needed to evaluate the cirrhosis. Ann Surg 2000;232:381–91.
impact of combining liver resection and RFA on patient 18. Stangl R, Altendorf-Hofmann A, Charnley RM. Factors influenc- quality of life. Moreover, although local tumor control may ing the natural history of colorectal liver metastases. Lancet 1994;343:1405–10.
be achieved with hepatic resection and RFA, the high 19. Ruers T, Bleichrodt RP. Treatment of liver metastases, an update propensity for these malignant liver tumors to recur region- on the possibilities and results. Eur J Cancer 2002;38:1023–33.
ally and systemically in a significant number of patients 20. Steele G, Ravikumar T. Resection of hepatic metastases from colorectal cancer. Biologic perspective. Ann Surg 1989;210:127– emphasizes the need for effective multimodality approaches to aid in the control of distant disease.
21. Adson MA, van Heerden JA, Adson MH, Wagner JS, Ilstrup DM.
Resection of hepatic metastases from colorectal cancer. Arch Surg1984;119:647–51.
ACKNOWLEDGMENTS
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