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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.03.042 on February 9, 2004

Annals of Surgical Oncology 11:298-303 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Surgery for Hepatocellular Carcinoma: Does It Improve Survival?

Jerome H. Liu, MD, MSHS, Pauline W. Chen, MD, Steven M. Asch, MD, MPH, Ronald W. Busuttil, MD, PhD and Clifford Y. Ko, MD, MSHS

From the Department of Surgery (JHL, PWC, RWB, CYK), David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Surgery (JHL, CYK) and Division of General Internal Medicine (JHL, SMA), Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, California; and Department of Medicine (SMA), David Geffen School of Medicine at UCLA, Los Angeles, California.

Correspondence: Address correspondence and reprint requests to: Jerome H. Liu, MD, MSHS, 11301 West Olympic Boulevard, #648, Los Angeles, CA 90064; Fax: 310-979-7050; E-mail: jerome8{at}ucla.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The incidence and mortality of hepatocellular carcinoma (HCC) are increasing in the United States. Whether surgery is associated with improved survival at the population level is relatively unknown. To address this question, we used a population-based cancer registry to compare survival outcomes between patients receiving and not receiving surgery with similar tumor sizes and health status.

Methods: By using the Surveillance, Epidemiology, and End Results database, we identified HCC patients who had surgically resectable disease as defined by published expert guidelines. After excluding patients with contraindications to surgery, we performed both survival analysis and Cox regression to identify predictors of improved survival.

Results: Of the 4008 patients diagnosed with HCC between 1988 and 1998, 417 were candidates for surgical resection. The mean age was 63.6 years; mean tumor size was 3.3 cm. The 5-year overall survival with surgery was 33% with a mean of 47.1 months; without surgery, the 5-year overall survival was 7% with a mean of 17.9 months (P < .001). In the multivariate Cox regression, surgery was significantly associated with improved survival (P < .001). Specifically, patients who received surgery had a 55% decreased rate of death compared with patients who did not have surgery, even after controlling for tumor size, age, sex, and race.

Conclusions: This study shows that surgical therapy is associated with improved survival in patients with unifocal, nonmetastatic HCC tumors <5 cm. If this is confirmed in future studies, efforts should be made to ensure that appropriate patients with resectable HCC receive high-quality care, as well as the opportunity for potentially curative surgery.

Key Words: Hepatocellular carcinoma • HCC • Surgery • Survival • Outcomes • Liver cancer


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Multiple researchers have cited the increasing incidence and mortality of hepatocellular carcinoma (HCC) in the United States.1 Between 1976 and 1991 in the general population, the incidence increased >70%, and mortality and hospitalization increased >50%.2,3 In fact, HCC has become a significant health problem in the United States. With an estimated annual mortality of 15,000, HCC is now the fourth leading cause of death among gastrointestinal cancers in the United States.4 Individuals infected with hepatitis B or hepatitis C virus, particularly those who subsequently develop cirrhosis, are at an increased risk of developing these tumors. As the number of these high-risk individuals increases, the potential effect of HCC in the United States may become enormous.

Although there are no randomized controlled trials that establish a superior mode of treatment, the current recommendation for patients with resectable tumors is complete surgical removal. This recommendation is based on prevailing expert opinion and surgical case series literature.1,5,6 The reported 5-year overall survival for surgery ranges from 35% to 60%, whereas the 3-year overall survival for best supportive care ranges from 13% to 26%.7–13

However, most reports that evaluate surgical treatment are single-institution series. These studies often incorporate patients with significant differences in tumor size or physical health, and these differences introduce potential confounding factors into the evaluation of the effect of surgical treatment on survival. To eliminate these factors, we have used a nationally representative population-based cancer registry to compare survival outcomes between patients receiving and not receiving surgery with similar tumor sizes and health status.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Data Source
De-identified patient-level data were obtained from the population-based Surveillance, Epidemiology, and End Results (SEER) database maintained by the National Cancer Institute (August 2000 submission; version 4.1.3). Originally, the database included nine geographically varied regions: Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco, Seattle, and Utah. In 1992, Los Angeles and San Jose were added, thus increasing its sample to 14% of the nation’s population. The population captured by the SEER database is representative of the US population.14 To ensure the accuracy of the data, chart abstracters undergo extensive training, as described in National Cancer Institute/SEER publications.15 Malignancies are encoded by the ninth revision of the International Classification of Diseases for Oncology.

Inclusion/Exclusion Criteria
All patients diagnosed with histologically confirmed HCC (International Classification of Diseases for Oncology code 8170) from 1988 to 1998 were analyzed. Demographic and clinical data were abstracted from the SEER database. Demographic information included age, race, sex, and geography. Age was treated as a continuous variable during statistical analysis. Race and ethnicity were coded as white, black, Asian, and Hispanic. Geographical location was assigned to Northeast, South, Midwest, or West on the basis of the location of the cancer registry. The following clinical variables were obtained: tumor size, surgical treatment (if any), stage, and extent of disease.

Tumor size, stage, and extent of disease variables were used to identify patients with resectable disease. Patients were considered resectable for surgery on the basis of published criteria: (1) <=5-cm solitary lesion confined to a single lobe of the liver and (2) no medical contraindications (e.g., cirrhosis).1,5,6 The presence of medical contraindications to surgery was determined on the basis of specific statements or criteria abstracted from the medical record (A. Fritz, verbal communication, SEER/National Institutes of Health, March 2003).

Statistical Analysis
Patients who fulfilled the inclusion criteria were stratified on the basis of whether or not they received surgery (cancer-directed surgery performed vs. not performed). Although it is unknown why certain patients with resectable tumors did not receive surgery, they were similar to the patients who had surgery in terms of the inclusion criteria. Because the treatment of interest was surgical resection, patients who received local therapy (e.g., cryoablation) or underwent transplantation were excluded from analysis.

Survival was measured in months until death or until the last recorded follow-up. Survival analysis was performed with the Kaplan-Meier method for estimation of the survival function. The log-rank test was used to compare the survival functions of patients who had surgery and those who did not have surgery. A multivariate Cox proportional hazard regression model was used to evaluate the effects of the independent variables on survival. The Efron method for ties was used. Further, we specifically tested and confirmed that our model did not violate the proportional hazards assumption. All statistical analyses were performed with SAS version 8.01 (SAS Institute, Cary, NC) and Stata (Stata Corp., College Station, TX). Tests were deemed to be significant at the .05 level.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Demographics
A total of 4008 HCC patients were evaluated. Four-hundred eighty-three (12.1%) surgical candidates were identified with unifocal, nonmetastatic tumors <=5 cm. Sixty-six patients were excluded: 53 patients received either ablative therapy or transplantation, and treatment data were not available for 13 patients. Of the 417 remaining surgical candidates, 229 (55%) received cancer-directed surgery, whereas 188 (45%) did not. Overall, 69% of the patients were male, and the mean age was 63.6 years. The patients had the following ethnicities: white (59.9%), black (8.9%), Asian (29.3%), and Hispanic (11.7%). The mean tumor size was 3.3 cm, with an SD of 1.3 cm (Table 1).


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  		TABLE 1. Patient demographics
 
Although all patients had tumor sizes <=5.0 cm, patients who underwent surgery were younger (60.9 vs. 66.8 years; P < .01) and had smaller tumors (3.0 vs. 3.7 cm; P < .01) compared with patients who did not have surgery. No differences were seen in rates of surgery between men and women or among different geographical regions. Only 30% of blacks received surgery, compared with 67% of whites, 57% of Asians, and 62% of Hispanics (P < .01 for blacks compared with all other racial and ethnic groups). Whites were slightly older than Asians, Hispanics, and blacks (P < .05 for all). No significant differences in age were detected among Asians, Hispanics, and blacks or between men and women. Tumor size did not vary by race, ethnicity, or sex.

Survival
Patients who underwent surgery had improved overall survival compared with patients who did not receive surgery (P < .001). The Kaplan-Meier survival functions are shown in Fig. 1. Patients who underwent surgical resection for their HCC had a 1-year survival of 72.7% and a 5-year survival of 32.5%, compared with 40.9% and 7.3%, respectively, for patients who did not have surgery. The mean overall survival for patients who had surgery was 47.1 ± 3.3 months compared with 17.9 ± 2.1 months for patients who did not have surgery (Table 2).



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  		FIG. 1. Kaplan-Meier survival estimates by treatment.

 

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  		TABLE 2. Survival by treatment group
 
The mean, 1-year, and 5-year overall survival outcomes for patients who had surgery were also examined by race (Table 3). All three measured survivals (i.e., mean, 1-year, and 5-year) were highest for Asians. However, the Kaplan-Meier survival function for Asians was better only when compared with that of blacks (P < .01) and Hispanics (P = .01); no survival differences were found between Asians and whites (P = .13). Finally, the Kaplan-Meier survival was worse for blacks compared with whites (P = .04), and no differences were seen in survival between whites and Hispanics (P = .18) or between blacks and Hispanics (P = .41). The Kaplan-Meier overall survival functions are shown in Fig. 2.


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  		TABLE 3. Survival after surgery, by race
 


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  		FIG. 2. Kaplan-Meier survival for patients receiving surgery, by race.

 
Multivariate Cox Regression
By using a multivariate Cox regression model, the effect of each variable on overall survival was identified. After controlling for sex and the different regions in the United States, the variables that had a significant association with survival were surgical treatment, age, and tumor size. The hazard of dying for patients who received surgery for the treatment of their HCC was 55% less than for patients who did not have surgery, even after controlling for tumor size, age, sex, race, and geographical region. As the size of the tumor increased, the hazard of dying also increased. An increase in tumor size by 1 cm resulted in a 26% increase in the hazard of dying. Likewise, an increase in age by 10 years resulted in a 15% increase in the hazard of dying.

To further illustrate the effect of surgery at various tumor sizes, the hazard of dying for a white man of average age (63.6 years) was calculated for those who received surgery and those who did not receive surgery. Figure 3 shows that patients who received surgery had a lower hazard of dying than patients who did not receive surgery for all tumor sizes between 1 and 5 cm. In fact, the effect of surgery on the hazard of dying seemed to increase as the tumor size increased.



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  		FIG. 3. Hazard of dying for a white man of average age (63.6 years).

 
Race/ethnicity had a modest multivariate association with survival as well. Blacks had a 53% increased hazard of dying compared with whites (P = .052). Hispanics seemed to have poorer survival than whites as well, although this did not reach statistical significance (P = .34). Asians, however, seemed to have better survival than whites. However, this difference also did not reach statistical significance (P = .48). The results of the Cox regression are listed in Table 4.


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  		TABLE 4. Results of multivariate Cox regression, by variable
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Using retrospective analysis of cancer registry data, we have examined the potential benefits of surgical therapy for HCC patients with operable tumors. Our study population included all patients with resectable HCC tumors (i.e. unifocal, nonmetastatic tumors <5 cm confined to a single lobe). Also, patients coded to have medical contraindications to surgery and patients who received ablative local therapy, underwent transplantation, or had unknown surgical treatment were excluded. The remaining patients were divided between those who received surgery (study group) and those who did not (control group).

Three main findings are apparent. First, it is striking that 45% of patients with resectable tumors did not receive surgery. Such a finding illustrates a fairly high degree of underuse of potentially beneficial surgery. Although there are no randomized controlled trials, surgery is commonly recommended by experts as the treatment of choice, especially in the absence of transplantation.1,5,6 Unfortunately, on the basis of the data source, it is impossible to ascertain why these patients did not undergo surgery. However, because patients with medical contraindications to surgery were excluded from the analysis, it is assumed that the patients who did not undergo surgery may have received either alternative treatment or, worse, no treatment.

Second, surgical resection is associated with improved survival, even after controlling for age, tumor size, race, sex, and geographical region. The hazard of dying of patients who received surgery for the treatment of their HCC was 55% lower than that of patients who did not have surgery. In many other studies, this relationship is less clear because the nonoperative group had either significantly larger tumors or significantly worse health status. Although small differences were seen between our surgical and nonsurgical groups in terms of tumor size and age, the differences were minimal and were controlled for in the multivariate Cox regression. Specifically, the effect of surgery on the hazard of dying was apparent for tumors up to 5 cm in size (Fig. 3). This study presents evidence that suggests a role for surgery in patients with nonmetastatic and isolated small HCC.

Third, we identified race disparities for survival. Black patients had poorer survival than whites and Asians after surgery. Significant differences were seen in 1-year, 5-year, and mean overall survivals between blacks and whites and Asians. However, the interpretation of this finding requires caution. In this analysis, race most likely represents a proxy for other variables—such as insurance, income, or other socioeconomic factors—that were not available in our data source.16 If such variables were available in SEER, the race variable may have been less significant than in this case. Although the lack of such data may make interpretation of the race variable difficult, this finding highlights an area that requires careful evaluation and more comprehensive data collection in the future. This area is especially important in regard to other reported findings of racial disparities in health care.17,18 Investigating these disparities may ultimately lend insight toward improving the quality of care for all patients.

Despite the significant findings of this study, there are several limitations. First, given the data that SEER collects, the factors associated with the decision to forgo surgery are unknown. Potentially, some patients were inappropriately denied or not offered surgery, or patients may have opted for other treatments such as chemotherapy or radiation. However, if patients were offered alternative treatment, the effect of surgery compared with no treatment might in fact be underestimated in this study. Further studies investigating the reasons for the underuse of surgery are necessary.

Second, SEER does not provide comorbidity data. Although patients with contraindications to surgery were excluded, specific coexistent diseases were not explicitly identified (e.g., coronary artery disease, chronic obstructive pulmonary disease, or renal failure). We assumed that if comorbidity precluded operative treatment, then the patient would be coded as having a contraindication to surgery, but we were unable to validate this assumption. Unmeasured comorbidity differences between the surgical and nonsurgical groups could explain some of the differences in observed survival. Therefore, the lack of comorbidity data limits the ability of this study to unequivocally support the use of surgery for resectable HCC. This limitation demonstrates the need for improved data collection regarding the level and severity of coexistent disease. Such data are being collected in other surgical outcomes databases in a prospective fashion.19,20

Despite these potential limitations, this study, by using a highly regarded population-based cancer registry, highlights the potential survival benefit of surgery for patients with resectable HCC.14,21 Whereas previous studies have compared patients with differing tumor sizes or medical status, this study compared only patients with small tumors and without medical contraindications. However, several questions are raised for future evaluation. First, why are some patients not receiving surgery? Specifically, is there potential underuse of a therapy (surgery) that improves survival? Second, why do black patients have worse postoperative survival than white and Asian patients? Is this a true race effect, or is it a phenomenon of certain omitted socioeconomic and demographic variables? Finally, is there a role for alternative therapies in the treatment of HCC? If so, what is it?

HCC is rapidly becoming a major health problem in the United States. Although survival after diagnosis is generally poor, effective therapy is available. If this is confirmed in future studies, efforts should be made to ensure that every patient with resectable HCC receives high-quality care, as well as the opportunity for potentially curative surgery.


   FOOTNOTES
 
Presented at the 56th Annual Cancer Symposium of the Society of Surgical Oncology, Los Angeles, California, March 5–9, 2003.

Whether surgery for hepatocellular carcinoma is associated with improved survival at the population level is relatively unknown. By using Surveillance, Epidemiology, and End Results data, survival was compared between patients undergoing and not undergoing surgery. In the multivariate Cox regression, surgical resection was a significant correlate of survival (P < .001).

Received for publication March 30, 2003. Accepted for publication October 16, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Di Bisceglie AM, Carithers RL Jr, Gores GJ. Hepatocellular carcinoma. Hepatology 1998; 28: 1161–5.[CrossRef][Medline]
  2. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999; 340: 745–50.[Abstract/Free Full Text]
  3. El-Serag HB, Mason AC, Key C. Trends in survival of patients with hepatocellular carcinoma between 1977 and 1996 in the United States. Hepatology 2001; 33: 62–5.[CrossRef][Medline]
  4. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer J Clin 1999; 49: 8–31.[Abstract/Free Full Text]
  5. Giovannini M, Elias D, Monges G, Raoul JL, Rougier P. Hepatocellular carcinoma. Br J Cancer 2001; 84: 74–7.
  6. Farinati F, Gianni S, Marin G, Fagiuoli S, Rinaldi M, Naccarato R. Does the choice of treatment influence survival of patients with small hepatocellular carcinoma in compensated cirrhosis? Eur J Gastroenterol Hepatol 2001; 13: 1217–24.[CrossRef][Medline]
  7. Arii S, Yamaoka Y, Futagawa S, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan. Hepatology 2000; 32: 1224–9.[CrossRef][Medline]
  8. Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg 1999; 229: 790–9;discussion 799–800.
  9. Lai EC, Fan ST, Lo CM, Chu KM, Liu CL, Wong J. Hepatic resection for hepatocellular carcinoma. An audit of 343 patients. Ann Surg 1995; 221: 291–8.[Medline]
  10. Livraghi T, Bolondi L, Buscarini L, et al. No treatment, resection and ethanol injection in hepatocellular carcinoma: a retrospective analysis of survival in 391 patients with cirrhosis. Italian Cooperative HCC Study Group. J Hepatol 1995; 22: 522–6.[CrossRef][Medline]
  11. Poon RT, Fan ST, Lo CM, et al. Improving survival results after resection of hepatocellular carcinoma: a prospective study of 377 patients over 10 years. Ann Surg 2001; 234: 63–70.[CrossRef][Medline]
  12. Vauthey JN, Klimstra D, Franceschi D, et al. Factors affecting long-term outcome after hepatic resection for hepatocellular carcinoma. Am J Surg 1995; 169: 28–34;discussion 34–5.
  13. Ebara M, Ohto M, Shinagawa T, et al. Natural history of minute hepatocellular carcinoma smaller than three centimeters complicating cirrhosis. A study in 22 patients. Gastroenterology 1986; 90: 289–98.[Medline]
  14. Surveillance, Epidemiology, and End Results. Surveillance, Epidemiology, and End Results (SEER) Program Public-Use Data (1973–1998). National Cancer Institute, DCCPS, Cancer Surveillance Research Program, Cancer Statistics Branch, released April 2001, based on the August 2000 submission. Available at: http://seer.cancer.gov./ Web site accessed March 2002, verbal communication March 26, 2002.
  15. Surveillance, Epidemiology, and End Results. SEER Program Code Manual. Bethesda, MD: National Institutes of Health, 1998.
  16. LaVeist TA. Beyond dummy variables and sample selection: what health services researchers ought to know about race as a variable. Health Serv Res 1994; 29: 1–16.[Medline]
  17. Howard J, Hankey BF, Greenberg RS, et al. A collaborative study of differences in the survival rates of black patients and white patients with cancer. Cancer 1992; 69: 2349–60.[CrossRef][Medline]
  18. Otten MW Jr, Teutsch SM, Williamson DF, Marks JS. The effect of known risk factors on the excess mortality of black adults in the United States. JAMA 1990; 263: 845–50.[Abstract]
  19. Fink AS, Campbell DA Jr, Mentzer RM Jr, et al. The National Surgical Quality Improvement Program in non-veterans administration hospitals: initial demonstration of feasibility. Ann Surg 2002; 236: 344–53;discussion 353–4.
  20. Khuri SF, Daley J, Henderson W, et al. The Department of Veterans Affairs’ NSQIP: the first national, validated, outcome-based, risk-adjusted, and peer-controlled program for the measurement and enhancement of the quality of surgical care. National VA Surgical Quality Improvement Program. Ann Surg 1998; 228: 491–507.[CrossRef][Medline]
  21. Malin J, Kahn KL, Adams J, Kwan L, Laouri M. Validity of cancer registry data for measuring the quality of breast cancer care. J Natl Cancer Institute 2002; 94: 835–44.[Abstract/Free Full Text]



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