Annals of Surgical Oncology 9:881-886 (2002)
© 2002 Society of Surgical Oncology
Comparison of Hepatic Resection and Hepatic Transplantation in the Treatment of Hepatocellular Carcinoma Among Cirrhotic Patients
Mohsen Shabahang, MD, PhD,
Dido Franceschi, MD,
Noriyo Yamashiki, MD,
Raj Reddy, MD,
Peter A. Pappas, MD,
Kuky Aviles, MD,
Sonia Flores, MD,
Andrea Chaparro, MD,
Joseph U. Levi, MD,
Danny Sleeman, MD,
Andreas G. Tzakis, MD,
Tomoaki Kato, MD,
David M. Levi, MD and
Alan S. Livingstone, MD
From the Divisions of Surgical Oncology (Department of Surgery) (MS, DF, PAP, KA, SF, AC, JUL, DS, ASL), Transplantation (Department of Surgery) (AGT, TK, DML), and Gastroenterology (Department of Medicine) (NY, RR), University of Miami School of Medicine, Miami, Florida.
Correspondence: Address correspondence and reprint requests to: Mohsen Shabahang, MD, PhD, Division of General Surgery, Scott & White Clinic, 2401 S. 31st St., Temple, TX 76508; Fax: 254-724-8587; E-mail: mshabahang{at}swmail.sw.org
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ABSTRACT
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Background: The benefits of hepatic transplantation (HT) compared with hepatic resection (HR) in treating hepatocellular carcinoma (HCC) in patients with cirrhosis are controversial. The aim of this study was to compare the results of these therapeutic options.
Methods: The charts of all patients with cirrhosis who underwent HR or HT for HCC between 1997 and 2000 were analyzed.
Results: The cohort included 44 patients who underwent HR compared with 65 with HT. All patients in the HR group had Child’s A disease, in contrast to the HT group, which included 23% Child’s A and 77% Child’s B and C patients. Whereas all HT patients spent at least three nights in the intensive care unit, 41% of the HR group never required critical care. Perioperative mortality was 7% in both groups. Pathologic analysis revealed T1/T2 disease in 43% of the HR group compared with 75% of the HT group. After 36 months of follow-up, there was no significant difference in overall survival (57% vs. 66%) or disease-free survival (36% vs. 66%) between the two groups.
Conclusions: With overall survival and disease-free survival as the main outcomes, the results of HR versus HT are comparable in Child’s A patients with HCC. In this patient subset, HR not only is an effective form of therapy, but is also associated with quicker recovery.
Key Words: Hepatocellular carcinoma • Hepatic resection • Hepatic transplantation • Cirrhotics
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INTRODUCTION
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Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide.1 It accounts for more than 1 million deaths per year. The incidence of this disease is highest in Southeast Asia and sub-Saharan Africa, where the incidence is 52 cases per 100,000 population, compared with 2.5 cases per 100,000 in Europe and North America.2 Most cases of this malignancy are associated with cirrhosis, with 80% of the patients carrying the diagnosis of hepatitis B or hepatitis C.3,4 HCC in patients with cirrhosis is associated with higher-grade tumors, local portal venous invasion, and poorer prognosis than disease in noncirrhotic patients.5–7 This is especially true of large tumors.
The outlook for HCC is dismal if it is left untreated.2,8 The therapeutic options are mainly surgical.1 The two predominant techniques include hepatic resection (HR) and hepatic transplantation (HT). Nonsurgical methods, including transcatheter arterial chemoembolization, ethanol injection, and radiofrequency ablation, are used mainly in patients with Child’s B and C cirrhosis who are not candidates for transplantation.9 Of the two surgical options, HR is clearly the treatment of choice in those who do not have cirrhosis.10 However, in patients with cirrhosis with Child’s B and C disease, HR is not often performed, because of complications such as hemorrhage, infection, and hepatic decompensation.3 HT is a viable option in those patients with Child’s B and C cirrhosis who have small tumors (<3 cm for multiple tumors and <5 cm for a single tumor), fewer than three lesions, and no portal vein involvement.4 Child’s A patients with cirrhosis can be treated either by resection or by transplantation. This is where the choice between HR and HT is controversial. Several studies have compared these two techniques in regard to perioperative mortality, overall survival, and disease-free survival.9,11–17 The outcomes of these studies are contradictory. In view of the shortage of donated organs, more conclusive data in the comparison of HR and HT take on added importance.18
The purpose of this study was to examine the effectiveness of HR compared with HT as treatment options for HCC in a cohort of patients with cirrhosis. The main outcomes analyzed included disease-free and overall survival.
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METHODS
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The medical records of all patients who were treated surgically for HCC at the University of Miami/Jackson Memorial Hospital between January 1997 and December 2000 were retrospectively reviewed. Forty-four patients were treated with HR, and 65 underwent HT. The charts were reviewed for demographics, operative details, and follow-up, including recurrence of disease and death. SPSSTM version 8.0 (SPSS Inc., Chicago, IL) was used for statistical derivation of overall survival, along with generation of Kaplan-Meier curves and log-rank comparison.
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RESULTS
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In the period between 1997 and 2000, 109 cirrhotic patients with HCC were treated at the University of Miami/Jackson Memorial Hospital. Forty-four patients underwent surgical resection (HR) of the tumor, whereas 65 had HT. Table 1 lists the characteristics of the patients in each of the two treatment groups. The demographics were similar in both cohorts. Male patients comprised 59% of the HR and 69% of the HT group. The median age of the HR patients was older (65 years) than the HT patients (58 years). Most patients in both groups were white; 25% were Hispanic, and there was a small black population.
All 109 patients had cirrhosis. The etiology was known in most of the HT patients and consisted of 71% hepatitis C, 17% hepatitis B, and 6% alcohol-related. In the HR group, the etiology was not known in 48%. Among the rest, hepatitis C was the cause in 20%, hepatitis B in 25%, and alcohol in 7%. The entire HR cohort had Child’s A cirrhosis, and 77% of the HT group had Child’s B and C cirrhosis. Only 23% of the latter group were Child’s A patients. American Joint Committee on Cancer criteria were used to determine the T stage, which is mainly based on the size and number of tumors. The HR group had more advanced tumors, with 43% categorized as T1 or T2 and 57% as T3 or T4. In contrast, 75% of the HT patients had T1 or T2 tumors, with only 25% having a T3 lesion. All of the HR patients and 84% of the HT patients were diagnosed on routine follow-up imaging for cirrhosis. Sixteen percent of the transplanted patients were diagnosed after pathologic analysis of the explanted liver.
The operative details were gathered and analyzed. In the HR group, 52% of the lesions were excised by performing at least a lobectomy (Table 2). In five of these cases, a trisegmentectomy was required. Forty-three percent were treated with segmentectomy alone, and 4% were subjected only to cryosurgery. The length of the operation ranged from 90 to 400 minutes, with a median of 210 minutes. For the HT patients, the average length of the operation was 600 minutes. The blood loss in the resections ranged from 50 to 4000 mL, with a median of 500 mL. It is interesting to note that 70% of the HR patients were extubated in the operating room, and only 55% required critical care monitoring. The majority of those who were kept in the intensive care unit were there for only one night. This was in contrast with the transplanted patients, who were all kept in the intensive care unit for at least 3 days. The hospital stay for the HR group ranged from 1 to 47 days. The median length of stay was 6 days. This differed from the transplanted group, who spent at least 10 days in the hospital. Perioperative mortality for the HR and HT groups was 7%.
To determine the significance of lesion size, number of lesions, and presence of vascular invasion on long-term survival, all 109 patients were divided into those with T1 or T2 lesions and those with T3 or T4 disease. Comparison of the overall survival showed a median survival of 48 months compared with 41 months, respectively (Fig. 1). The 3-year survival was 65% compared with 50%. This difference was not statistically significant (P = .37).
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FIG. 1. Kaplan-Meier curve comparing the overall survival of patients with T1/T2 hepatocellular carcinoma with that of those with T3/T4 disease among the entire cohort. The log-rank test did not demonstrate a statistically significant difference between the curves (P = .37).
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The 3-year overall survival for all patients in the HR and HT groups was compared (Fig. 2A). No significant difference was demonstrated. The 3-year survival was 57% in the HR and 66% in the HT cohort. When the comparison was limited to include only patients with Child’s A cirrhosis, the result was no different (Fig. 2B).
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FIG. 2. Kaplan-Meier curves comparing the overall survival among patients who were treated with hepatic resection (HR) and those who underwent hepatic transplantation (HT). (A) Comparison among all 44 HR and 65 HT patients. No significant difference was seen (P = .414). (B) Comparison among the 44 HR patients with Child’s A cirrhosis and the 15 HT patients with Child’s A cirrhosis. No significant difference was seen (P = .43).
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Comparison of the 3-year disease-free survival among the HR and HT patients yielded results that were more divergent. The HT patients had a 66% disease-free survival after 36 months, compared with 36% for the HR group (Fig. 3A). However, the difference seen did not reach statistical significance (P = .1). In comparing only Child’s A patients, results were similar, with a P value of .19. Hence, the 3-year overall and disease-free survival in patients who underwent HR and those who received transplants for HCC were not significantly different.
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FIG. 3. Kaplan-Meier curves comparing the disease-free survival among patients who were treated with hepatic resection (HR) and those who underwent hepatic transplantation (HT). (A) Comparison among all 44 HR and 65 HT patients. The log-rank test yielded a P value of .1. (B) Comparison among the 44 HR patients with Child’s A cirrhosis and the 15 HT patients with Child’s A cirrhosis. The log-rank test yielded a P value of .19.
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DISCUSSION
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This study was designed as a retrospective analysis of patients with cirrhosis and HCC. The two cohorts compared included 44 patients who had undergone HR and 65 who had HT. The main objective of the study was to compare the disease-free and overall survival of the patients in each of the two groups. This is important because both HR and HT are practical options in patients with cirrhosis and HCC. This is most pertinent in those with Child’s A cirrhosis, because patients with more advanced cirrhosis may be candidates only for HT.9 This discussion becomes even more relevant because of the shortage of organs and limitations of resources.
The patient and tumor characteristics in the two groups were similar. In both the HR and HT groups, a slight majority was composed of male patients. This is a trend seen in other studies. Even though the age range is variable, the median age was 58 to 65 years. It is interesting to note that several studies have shown age to be of no particular significance in perioperative mortality or survival in patients who undergo HR.19,20 The etiology of cirrhosis was mainly hepatitis, which is very similar to most other series.6,7 As expected, the entire HR cohort had Child’s A cirrhosis, whereas most of the HT group had more advanced disease. The size of the tumor, vascular invasion, and number of liver lobes involved were all taken into consideration by staging the patients on the basis of American Joint Committee on Cancer criteria. This was done in lieu of simply comparing the size of the tumors because in addition to diameter, vascular invasion is of prognostic significance.14,21,22 Once again, as expected by the criteria of eligibility for transplantation, 75% of the patients in this group had early lesions, compared with 43% of the HR group. On the basis of most other studies, the size of HCC is an important prognostic factor. In a study from Shanghai Medical University comparing 1000 patients with lesions <5 cm and 1366 patients with tumors >5 cm, the smaller lesions were more easily resected, and these patients had a lower operative mortality, demonstrated fewer portal vein emboli, and survived for a longer period of time.23 Also, in studies from Memorial Sloan-Kettering Cancer Center, the 5-year survival of patients with small versus large tumors was 57% compared with 32%.6,7 Surprisingly, in our study, despite a longer overall survival in patients with T1/T2 lesions compared with those with T3/T4 tumors, the difference (3-year survival of 65% vs. 50%) was not statistically significant. This can be explained mainly by small numbers of patients in each of the T groups. Also, some of the patients may have been under- or overstaged.
A comparison of the operative details for the HR and HT groups is of great interest because many of the factors that pertain to resource utilization have to be accounted for in a comparison of these therapeutic options. Segmentectomy and lobectomy were the predominant methods of HR. The goal in cirrhotic patients is to preserve as much liver parenchyma as possible. The margins of resection were all negative. The status of the margin is of importance because those with positive margins clearly have a higher rate of recurrence.24 However, the width of the margin does not seem have any significance. The median operative time for HRs was 210 minutes, and the median blood loss was 500 mL. The operative time for the transplanted patients ranged from 270 to 1200 minutes, with a median of 600 minutes. Decreased blood loss, shorter operative time, and less need for transfusion have all been associated with better outcomes in large series of HRs for HCC.25–27 In discussing the use of resources, it is worth noting that 55% of the HR patients did not require admission to critical care units; 70% left the operating room extubated, and the median hospital stay was 6 days. This is in contrast to a minimum of three nights in the intensive care unit and a median hospital stay of 13 days for the HT patients. The perioperative mortality was similar in both groups at 7%.
As stated previously, the main objective of this study was to compare the overall and disease-free survival of patients undergoing HR and HT. Several other centers have also attempted to compare the results of these two therapeutic options. In a collaborative study between the University of Pittsburgh and the National Cancer Center Hospital in Japan, HR in 294 patients was compared with HT in 270.11 Unlike the results in our study, the perioperative mortality was much higher in the transplantation group, at 17.3%, compared with 5.8% in the resection group. The overall survival of both groups was approximately 60% after 3 years. However, the disease-free survival was significantly higher in the patients who underwent transplantation, with a 3-year survival of 70% compared with 20% for the HR patients. Similar results were seen in a study from Mt. Sinai Medical Center, where 240 patients with HCC were treated with HR and HT.13 The 5-year disease-free survival was 48% in the HT patients and only 7% in the HR group. A French study from Hôpital Paul Brousse showed trends similar to the previously cited analyses.17 The resected and transplanted groups had an overall 3-year survival of 50%, but the disease-free survival for HT patients was 44% compared with 23% for those in the HR group. A German and an Italian study both showed better overall survival with transplantation.15,16 In our study, the overall survival of the patients in the HT and HR groups was indistinguishable after 3 years. This was true both when the entire cohorts were compared and when the Child’s A patients with cirrhosis alone were analyzed. In this respect, this study corroborates the results of many of the other studies. However, in contrasting the disease-free survival, unlike the other studies, our results did not demonstrate a significant difference between HT and HR patients. This applies both to the comparison of all of the patients in the cohorts and to that of Child’s A patients alone. There may have been a trend toward a better disease-free survival in the HT patients, but this did not reach statistical significance. This is an important departure from much of the literature. This becomes most significant when one is treating a Child’s A patient with cirrhosis and HCC who fits the criteria for both resection and transplantation. These results take on added importance when one considers the fact that many patients who are on waiting lists for HT have tumor progression and drop off the list. The survival values in this study and the other cited studies do not take the survival of this group of patients into consideration.
In conclusion, this study retrospectively compared HR and HT in the treatment of HCC in patients with cirrhosis. The main focus was on the best treatment for patients with HCC who have Child’s A cirrhosis. Our study did not show a significant difference in the 3-year overall or disease-free survival of HCC patients after treatment with resection or transplantation. Hence, we conclude that in view of the use of significantly fewer resources and similar survival data, HR is an effective treatment for patients with mild cirrhosis and HCC.
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Footnotes
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This retrospective study compares hepatic transplantation and hepatic resection in patients with cirrhosis and hepatocellular carcinoma. The disease-free and overall survival in Child’s A patients were similar after 3 years of follow-up.
Received for publication March 22, 2002.
Accepted for publication June 17, 2002.
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ABSTRACT
INTRODUCTION
