Advances in the surgical management of hepatocellular carcinoma (HCC) have expanded the indications for curative hepatectomy, including more extensive liver resections. The purpose of this study was to examine long-term survival trends for patients treated with major hepatectomy for HCC.
Patients and Methods
Clinicopathologic data for 1,115 patients with HCC who underwent hepatectomy between 1981 and 2008 at five hepatobiliary centers in France, China, and the USA were assessed. In addition to other performance metrics, outcomes were evaluated using resection of ≥4 liver segments as a novel definition of major hepatectomy.
Major hepatectomy was performed in 539 patients. In the major hepatectomy group, median tumor size was 10 cm (range: 1–27 cm) and 22 % of the patients had bilateral lesions. The TNM Stage distribution included 29 % Stage I, 31 % Stage II, 38 % Stage III, and 2 % Stage IV. The postoperative histologic examination indicated that chronic liver disease was present in 35 % of the patients and tumor microvascular invasion was identified in 60 % of the patients. The 90-day postoperative mortality rate was 4 %. After a median follow-up time of 63 months, the 5-year overall survival rate was 40 %. Patients treated with right hepatectomy (n = 332) and those requiring extended hepatectomy (n = 207) had similar 90-day postoperative mortality rates (4 % and 4 %, respectively, p = 0.976) and 5-year overall survival rates (42 % and 36 %, respectively, p = 0.523). Postoperative mortality and overall survival rates after major hepatectomy were similar among the participating countries (p > 0.1) and improved over time with 5-year survival rates of 30 %, 40 %, and 51 % for the years 1981–1989, 1990–1999, and the most recent era of 2000–2008, respectively (p = 0.004). In multivariate analysis, factors that were significantly associated with worse survivals included AFP level >1,000 ng/mL, tumor size >5 cm, presence of major vascular invasion, presence of extrahepatic metastases, positive surgical margins, and earlier time period in which the major hepatectomy was performed.
This multinational, long-term HCC survival analysis indicates that expansion of surgical indications to include major hepatectomy is justified by the significant improvement in outcomes over the past three decades observed in both the East and the West.
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The authors thank Stephanie Deming and Ruth J. Haynes for their assistance with manuscript preparation.
This study was supported, in part, by the National Institutes of Health through MD Anderson's Cancer Center Support Grant, CA016672.
Conflict of interest
Dr. Sharon Weber (Madison, WI): The authors are to be congratulated for this outstanding multi-institutional study. The improvements in overall survival and 90-day mortality over time are very encouraging, particularly since this is such a difficult patient population due to the large tumor size and underlying liver dysfunction.
Any HPB surgeon who reads this excellent manuscript will likely want to gain a better understanding of the specific changes that occurred over time to account for these fantastic results, particularly in regard to perioperative management and patient selection, in order to better assess how these factors impacted mortality and long-term outcome.
Specific perioperative parameters that should be included in your analyses include EBL, blood transfusions, use of low CVP anesthesia, and use of the Pringle for liver transection, as these factors have been found to have a significant impact on perioperative mortality and, for some of these factors, also on survival.
In addition, can you help us understand how better assessment of liver reserve may have impacted perioperative mortality? How often was PVE or CT volumetry utilized, and were patients excluded from consideration for resection if they were unable to grow their remnant liver following PVE?
Many other series analyzing long-term results following complex resections for cancer have found a detrimental effect of complications on overall survival. I understand why you did not include that data here, but it would be very useful to assess this in order for us to understand the significance of complications relative to the other negative prognostic indicators you have nicely outlined in the paper. This is particularly relevant, since, to some degree, it is more controllable than tumor-specific factors like AFP level, tumor size, and vascular invasion.
Finally, did the improvement in mortality apply to patients with and without cirrhosis? Attempting to better understand the independent predictors of 90-day mortality are so important for this disease; thus, it would be very useful to include a multivariable analysis of predictors of mortality in the final MS.
Again, congratulations on an excellent paper.
Dr. Andreas Andreou: On behalf of the authors, I would like to thank Dr. Weber for her positive comments and interesting questions.
In regard to the inquiry about specific factors that have changed over time and may directly account for improved survival, it is difficult to separate the multiple components. Undoubtedly, there have been contributions in the areas of preoperative imaging, patient selection, surgical techniques, and anesthetic monitoring that have increased the safety of liver resection and contributed to forward progress. However, the design of this large multicenter study, which extended over a long period of time, did not allow for analysis of specific perioperative parameters such as EBL, blood transfusions, and use of low CVP anesthesia.
As our study focused on major hepatectomy, one of the most meaningful advances that occurred over time was likely in the area of evaluating the future liver remnant (FLR). With modern cross-sectional imaging, configuration, contour, and volume of the FLR can now be reliably assessed. More recently, the ability to additionally measure the functional capacity of the FLR, through either the indocyanine green clearance test or via hypertrophic response to portal vein embolization, has significantly impacted patient selection and postoperative liver failure rates. Although each center approached FLR evaluation with a unique strategy, the universal development of FLR assessment is certainly a key factor contributing to their shared successes.
In reference to your excellent question regarding the impact of complications on survival, we have reassessed the 90-day outcomes in this study. Although we do not have sufficient detail regarding specific complications to individually report them, the 90-day survival may act as a useful surrogate to differentiate meaningful complications from recoverable complications. The 90-day postoperative mortality rate for all patients undergoing major hepatectomy was 4 %, and it did not differ between patients who underwent right and those who underwent extended hepatectomy (p = 0.976; Table 1). However, an analysis according to both extent of resection and underlying liver disease showed that whereas fibrosis or cirrhosis did not negatively affect the 90-day mortality of patients undergoing right hepatectomy (p = 0.940), the presence of fibrosis or cirrhosis was associated with worse 90-day mortality rate among patients treated with extended hepatectomy (p = 0.002; Table 4).
Our additional analysis of early outcomes identified major vascular resection and earlier time period for resection as the two independent factors associated with 90-day survival. Interestingly, underlying liver disease in the form of fibrosis or cirrhosis was not a significant factor. Taken together, these data suggest that underlying liver disease has its largest impact when resection requires extended hepatectomy and/or major vascular resection.
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Andreou, A., Vauthey, J., Cherqui, D. et al. Improved Long-Term Survival after Major Resection for Hepatocellular Carcinoma: A Multicenter Analysis Based on a New Definition of Major Hepatectomy. J Gastrointest Surg 17, 66–77 (2013). https://doi.org/10.1007/s11605-012-2005-4
- Hepatocellular carcinoma
- Major hepatectomy
- Multicenter study
- Long-term survival