Defining the chance of cure after resection for hepatocellular carcinoma within and beyond the Barcelona Clinic Liver Cancer guidelines: A multi-institutional analysis of 1,010 patients

Abstract

Background

Surgery is considered the only potentially curative treatment option for patients with hepatocellular carcinoma. However, the chance that patients will eventually be “cured” after liver resection for hepatocellular carcinoma remains ill defined.

Methods

Patients who underwent curative-intent hepatectomy for hepatocellular carcinoma between 1998 and 2017 were identified using an international multi-institutional database. A nonmixture cure model was used with disease-free survival as a primary measure to estimate cure fractions after matching patients with the general population by age, race, and sex.

Results

Among 1,010 patients, the median and 5-year disease-free survival were 2.8 years and 36.6%, respectively. The probability of being cured after hepatocellular carcinoma resection was 42.2% and the median time to cure was 3.35 years. The multivariable cure model revealed preoperative alpha-fetoprotein level, tumor size, tumor number, and margin status as independent predictors of cure. The cure fraction for patients with an alpha-fetoprotein level ≤ 10 ng/mL, largest tumor size ≤5 cm, ≤3 nodules, and R0 resection was 61.6%. In contrast, patients who had all 4 unfavorable prognostic factors (ie, alpha-fetoprotein >11 ng/mL, nodules ≥4, size >5cm, R1 resection) had a cure fraction of 15.8%. Although the probability of cure was 47.6% among Barcelona Clinic Liver Cancer-A patients, patients undergoing resection for Barcelona Clinic Liver Cancer-B hepatocellular carcinoma had a 37.6% cure fraction. Only alpha-fetoprotein levels predicted the probability of cure among Barcelona Clinic Liver Cancer-B patients.

Conclusion

Roughly 4 in 10 patients could be considered “cured” after liver resection for hepatocellular carcinoma. Although cure was achieved more often after resection for Barcelona Clinic Liver Cancer-A hepatocellular carcinoma, surgery still provided a reasonable probability of cure among select patients with Barcelona Clinic Liver Cancer-B hepatocellular carcinoma.

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and accounts for more than 70% of primary liver malignancies.1, 2 Possible etiologies related to the development of HCC include cirrhosis, hepatitis B and C infection, alcohol abuse, and nonalcoholic fatty liver disease.³ In the United States, HCC is the fastest rising cause of cancer-related deaths, with model-based simulations forecasting a continued increase in the incidence of HCC until at least 2030.3, 4 Surgery—in the form of liver resection or transplantation—is still considered the only potentially curative treatment option for patients with HCC. However, the percentage of patients who will eventually be “cured” after liver resection for HCC remains ill defined.

In epidemiologic studies, “cure” is often defined as the time when the mortality risk of patients treated for a particular disease reaches a level expected in the general population.5, 6 Although first introduced in the statistical literature, cure models have been particularly popular recently among clinicians because these models can help answer real-world questions about the probability of “cure” after treatment for cancer.⁷ Indeed, previous investigators have reported on the probability of cure among patients with various types of tumors, including colorectal, pancreas, breast, and prostate cancer.⁸ Our group has also assessed the probability of cure among patients undergoing resection for intrahepatic cholangiocarcinoma, extrahepatic biliary tract cancer, and neuroendocrine liver metastases.9, 10, 11 Nevertheless, the possibility of cure after resection of HCC remains largely unknown.

The use of cure models may be particularly relevant to patients with HCC, especially given that surgical resection for patients beyond the Barcelona Clinic Liver Cancer (BCLC) guidelines has been a matter of great debate. According to the BCLC guidelines, liver resection should be offered only to patients with very early (ie, BCLC-0) and early stage (ie, BCLC-A) HCC.¹² Recently, however, a number of studies have advocated for resection beyond the BCLC criteria (ie, BCLC-B/C patients), with favorable results among select HCC patients.13, 14, 15 However, although liver resection has been associated with acceptable long-term survival, whether it can provide a long-term “cure” for patients with early (BCLC-A) and especially intermediate stage (BCLC-B) HCC remains largely unknown. As such, the objective of the current study was to define the probability of cure after curative-intent resection for HCC. In addition, using a large multi-institutional database, we sought to identify factors associated with the probability of cure within (ie, BCLC-A) and beyond (ie, BCLC-B) the BCLC resection criteria.