Overall Tumor Burden Dictates Outcomes for Patients Undergoing Resection of Multinodular Hepatocellular Carcinoma Beyond the Milan Criteria

Abstract

Objective: The objective of the current study was to define surgical outcomes after resection of multinodular hepatocellular carcinoma (HCC) beyond the Milan criteria, and develop a prediction tool to identify which patients likely benefit the most from resection. Background: Liver resection for multinodular HCC, especially beyond the Milan criteria, remains controversial. Rigorous selection of the best candidates for resection is essential to achieve optimal outcomes after liver resection of advanced tumors. Methods: Patients who underwent resection for HCC between 2000 and 2017 were identified from an international multi-institutional database. Patients were categorized according to Milan criteria status. Pre-and postoperative overall survival (OS) prediction models that included HCC tumor burden score (TBS) among patients with multinodular HCC beyond Milan criteria were developed and validated. Results: Among 1037 patients who underwent resection for HCC, 164 (15.8%) had multinodular HCC beyond the Milan criteria. Among patients with multinodular HCC, 25 (15.2%) patients experienced a serious complication and 90-day mortality was 3.7% (n ¼ 6). Five-year OS after resection of multinodular HCC beyond Milan criteria was 52.8%. A preoperative TBSbased model (5-year OS: low-risk, 73.7% vs intermediate-risk, 45.1% vs highrisk, 13.1%), and postoperative TBS-based model (5-year OS: low-risk, 80.1% vs intermediate-risk, 37.2% vs high-risk, not reached) categorized patients into distinct prognostic groups relative to long-term prognosis (both P < 0.001). Pre-and postoperative models could accurately stratify OS in an external validation cohort (5-year OS; low vs medium vs high risk; pre: 66.3% vs 25.2% vs not reached, P ¼ 0.012; post: 61.4% vs 42.5% vs not reached, P ¼ 0.045) Predictive accuracy of the pre-and postoperative models was good in the training (c-index; pre: 0.68; post: 0.71), internal validation (n ¼ 2000 resamples) (c-index, pre: 0.70; post: 0.72) and external validation (c-index, pre: 0.67; post 0.68) datasets. TBS alone could stratify patients relative to 5year OS after resection of multinodular HCC beyond Milan criteria (c-index: 0.65; 5-year OS; low TBS: 70.2% vs medium TBS: 54.7% vs high TBS: 16.7%; P < 0.001). The vast majority of patients with low and intermediate TBS were deemed low or medium risk based on both the preoperative (98.4%) and postoperative risk scores (95.3%). Conclusion: Prognosis of patients with multinodular HCC was largely dependent on overall tumor burden. Liver resection should be considered among patients with multinodular HCC beyond the Milan criteria who have a low-or intermediate-TBS.

Synergistic Impact of Alpha-Fetoprotein and Tumor Burden on Long-Term Outcomes Following Curative-Intent Resection of Hepatocellular Carcinoma

“…Tumor burden has been considered a major predictor of outcomes and an important element in the treatment decision-making process of patients with resectable HCC [11,15]. Our group recently demonstrated the prognostic utility of TBS, a relatively new marker of tumor burden, which dictated prognosis among patients with resectable HCC [11].…”

Hepatocellular carcinoma beyond Barcelona clinic liver cancer resection criteria: resecting the aggressive tumor

“…Kudo et al [40] (2015) "Kinki criteria": BCLC-B1: Child Pugh 5-6, within up-to-7 criteria -Tsilimigras et al [42] (2020) BCLC-B and pTBS ≤ 11 5-year OS: 60.1%…”

“…Recently, machine learning methods have been utilized to identify subgroups of patients with BCLC-B HCC who may benefit the most from resection [42] . Among all patient-and tumor-related factors, the classification and regression tree (CART) model demonstrated that radiologic and pathologic TBS were the most important predictors of outcomes among BCLC-B patients in the pre-and post-operative setting, respectively [42] .…”

“…Recently, machine learning methods have been utilized to identify subgroups of patients with BCLC-B HCC who may benefit the most from resection [42] . Among all patient-and tumor-related factors, the classification and regression tree (CART) model demonstrated that radiologic and pathologic TBS were the most important predictors of outcomes among BCLC-B patients in the pre-and post-operative setting, respectively [42] . Of note, patients with BCLC-B HCC and pathologic TBS ≤ 11 (n = 111) had a 5-year survival of 60.1%, whereas patients with BCLC-B HCC and TBS > 11 (n = 39) had a 5-year survival of 13.9%, further validating the utility of TBS in identifying the best candidates for resection beyond the BCLC criteria [42] .…”

“…Among all patient-and tumor-related factors, the classification and regression tree (CART) model demonstrated that radiologic and pathologic TBS were the most important predictors of outcomes among BCLC-B patients in the pre-and post-operative setting, respectively [42] . Of note, patients with BCLC-B HCC and pathologic TBS ≤ 11 (n = 111) had a 5-year survival of 60.1%, whereas patients with BCLC-B HCC and TBS > 11 (n = 39) had a 5-year survival of 13.9%, further validating the utility of TBS in identifying the best candidates for resection beyond the BCLC criteria [42] . In turn, TBS-based risk scores have been proposed to enhance prognostication among patients undergoing resection for multinodular HCC beyond Milan criteria [43] .…”