There is an ongoing debate about expanding the resection criteria for hepatocellular carcinoma (HCC) beyond the Barcelona Clinic Liver Cancer (BCLC) guidelines. We sought to determine the factors that held the most prognostic weight in the pre- and postoperative setting for each BCLC stage by applying a machine learning method. Patients who underwent resection for BCLC-0, A and B HCC between 2000 and 2017 were identified from an international multi-institutional database. A Classification and Regression Tree (CART) model was used to generate homogeneous groups of patients relative to overall survival (OS) based on pre- and postoperative factors. Among 976 patients, 63 (6.5%) had BCLC-0, 745 (76.3%) had BCLC-A, and 168 (17.2%) had BCLC-B HCC. Five-year OS among BCLC-0/A and BCLC-B patients was 64.2% versus 50.2%, respectively (p = 0.011). The preoperative CART model selected α-fetoprotein (AFP) and Charlson comorbidity score (CCS) as the first and second most important preoperative factors of OS among BCLC-0/A patients, whereas radiologic tumor burden score (TBS) was the best predictor of OS among BCLC-B patients. The postoperative CART model revealed lymphovascular invasion as the best postoperative predictor of OS among BCLC-0/A patients, whereas TBS remained the best predictor of long-term outcomes among BCLC-B patients in the postoperative setting. On multivariable analysis, pathologic TBS independently predicted worse OS among BCLC-0/A (hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.02–1.07) and BCLC-B patients (HR 1.13, 95% CI 1.06–1.19) undergoing resection. Prognostic stratification of patients undergoing resection for HCC within and beyond the BCLC resection criteria should include assessment of AFP and comorbidities for BCLC-0/A patients, as well as tumor burden for BCLC-B patients.

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Utilizing Machine Learning for Pre- and Postoperative Assessment of Patients Undergoing Resection for BCLC-0, A and B Hepatocellular Carcinoma: Implications for Resection Beyond the BCLC Guidelines.

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 = 6). Five-year OS after resection of multinodular HCC beyond Milan criteria was 52.8%. A preoperative TBS-based model (5-year OS: low-risk, 73.7% vs intermediate-risk, 45.1% vs high-risk, 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 = 0.012; post: 61.4% vs 42.5% vs not reached, P = 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 = 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 5-year 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.

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

While tumor burden (TB) has been associated with outcomes among patients with hepatocellular carcinoma, the role of overall TB in intrahepatic cholangiocarcinoma (ICC) remains poorly defined. Patients undergoing curative-intent resection of ICC between 2000 and 2017 were identified from a multi-institutional database. The impact of TB on overall (OS) and disease-free survival (DFS) was evaluated in the multi-institutional database and validated externally. Among 1101 patients who underwent curative-intent resection of ICC, 624 (56.7%) had low TB, 346 (31.4%) medium TB, and 131 (11.9%) high TB. OS incrementally worsened with higher TB (5-year OS; low TB: 48.3% vs medium TB: 29.8% vs high TB: 17.3%, p < 0.001). Similarly, patients with low TB had better DFS compared with medium and high TB patients (5-year DFS: 38.3% vs 18.7% vs 6.9%, p < 0.001). On multivariable analysis, TB was independently associated with OS (medium TB: HR = 1.40, 95% CI 1.14–1.71; high TB: HR = 1.89, 95% CI 1.46–2.45) and DFS (medium TB, HR = 1.61, 95% CI 1.33–1.96; high TB: HR = 2.03, 95% CI 1.56–2.64). Survival analysis revealed an excellent prognostic discrimination using the TB among the external validation cohort (3-year OS; low TB: 44.8%, medium TB: 29.3%; high TB: 23.3%, p = 0.03; 3-year DFS: low TB: 32.7%, medium TB: 10.7%; high TB: 0%, p < 0.001). While neoadjuvant chemotherapy was not associated with survival across the TB groups, receipt of adjuvant chemotherapy was associated with increased survival among patients with high TB (5-year OS: 24.4% vs 13.4%, p = 0.02). Overall TB dictated prognosis among patients with resectable ICC. TB may be used as a tool to help guide post-resection treatment strategies.

Tumor Burden Dictates Prognosis Among Patients Undergoing Resection of Intrahepatic Cholangiocarcinoma: A Tool to Guide Post-Resection Adjuvant Chemotherapy?

Liver transplantation (LT) remains a mainstay of treatment for hepatocellular carcinoma (HCC). Tumor factors such as size and number of tumors define eligibility for LT using the Milan criteria. The tumor burden score (TBS) incorporates both tumor number and size into a single continuous variable and has been used to differentiate prognosis among patients undergoing resection for HCC. The objective of the present study was to evaluate the ability of the TBS to predict overall and recurrence-free survival in patients undergoing LT for HCC. The Scientific Registry of Transplant Recipients (SRTR) was used to analyze all liver transplants for HCC, with initial tumor size data from 2004 to 2018. There were 12,486 patients in the study period. In the unadjusted analyses, patients with a high TBS had worse overall (p < 0.0001) and recurrence-free (p < 0.0001) survival. In the adjusted analyses, a high TBS was associated with a greater hazard ratio (HR) of death (HR = 1.21; 95%CI, [1.13-1.30]; p < 0.001) and recurrence (HR = 1.49; 95%CI [1.3-1.7]; p < 0.001). When we superimposed the TBS on the Milan criteria, we saw that a higher TBS was associated with a higher hazard of recurrence at values that were either all within (HR = 1.20; 95%CI, [1.04-1.37]; p = 0.011) or variably within (HR = 1.53; 95%CI, [1.16-2.01]; p = 0.002) the Milan criteria. In conclusion, the TBS is a promising tool in predicting outcomes in patients with HCC after LT.

Using Hepatocellular Carcinoma Tumor Burden Score to Stratify Prognosis after Liver Transplantation.

BACKGROUND AND AIM Size and number are major determinants of tumor burden in hepatocellular carcinoma (HCC). Patients with HCC undergoing transarterial chemoembolization (TACE) have variable outcomes due to heterogeneity of tumor burden. Recently, tumor burden score (TBS) was proposed to evaluate the extent of tumor involvement. However, the prognostic accuracy of TBS has not been well evaluated in HCC. This study aimed to assess its prognostic role in HCC patients undergoing TACE. METHODS A total of 935 treatment-naive HCC patients receiving TACE were retrospectively analyzed. Multivariate Cox proportional hazards model was used to determine independent prognostic predictors. RESULTS Tumor burden score tended to increase with increasing size and number of tumors in study patients. The Cox model showed that serum creatinine ≥ 1.2 mg/dL (hazard ratio [HR]: 1.296, 95% confidence interval [CI]: 1.077-1.559, P = 0.006), serum α-fetoprotein ≥ 400 ng/dL (HR: 2.245, 95% CI: 1.905-2.645, P < 0.001), vascular invasion (HR: 1.870, 95% CI: 1.520-2.301, P < 0.001), medium TBS (HR: 1.489, 95% CI: 1.206-1.839, P < 0.001) and high TBS (HR: 2.563, 95% CI: 1.823-3.602, P < 0.001), albumin-bilirubin (ALBI) grade 2-3 (HR: 1.521, 95% CI: 1.291-1.792, P < 0.001), and performance status 1 (HR: 1.362, 95% CI: 1.127-1.647, P < 0.001) and status 2 (HR: 1.553, 95% CI: 1.237-1.948, P < 0.001) were associated with increased mortality. Patients with high TBS had poor overall survival in Barcelona Clinic Liver Cancer stage B/C and different ALBI grades. CONCLUSIONS Tumor burden score is a feasible new prognostic surrogate marker of tumor burden in HCC and can well discriminate survival in patients undergoing TACE across different baseline characteristics.

Tumor burden score as a new prognostic marker for patients with hepatocellular carcinoma undergoing transarterial chemoembolization.

BACKGROUND Although the Barcelona Clinic Liver Cancer (BCLC) staging system has been largely adopted in clinical practice, recent studies have emphasized the need for further refinement and subclassification of this system. METHODS Patients who underwent hepatectomy with curative intent for BCLC-0, -A or -B hepatocellular carcinoma (HCC) between 2000 and 2017 were identified using a multi-institutional database. The tumour burden score (TBS) was calculated, and overall survival (OS) was examined in relation to TBS and BCLC stage. RESULTS Among 1053 patients, 63 (6·0 per cent) had BCLC-0, 826 (78·4 per cent) BCLC-A and 164 (15·6 per cent) had BCLC-B HCC. OS worsened incrementally with higher TBS (5-year OS 77·9, 61 and 39 per cent for low, medium and high TBS respectively; P < 0·001). No differences in OS were noted among patients with similar TBS, irrespective of BCLC stage (61·6 versus 58·9 per cent for BCLC-A/medium TBS versus BCLC-B/medium TBS, P = 0·930; 45 versus 13 per cent for BCLC-A/high TBS versus BCLC-B/high TBS, P = 0·175). Patients with BCLC-B HCC and a medium TBS had better OS than those with BCLC-A disease and a high TBS (58·9 versus 45 per cent; P = 0·005). On multivariable analysis, TBS remained associated with OS among patients with BCLC-A (medium TBS: hazard ratio (HR) 2·07, 95 per cent c.i. 1·42 to 3·02, P < 0·001; high TBS: HR 4·05, 2·40 to 6·82, P < 0·001) and BCLC-B (high TBS: HR 3·85, 2·03 to 7·30; P < 0·001) HCC. TBS could also stratify prognosis among patients in an external validation cohort (5-year OS 79, 51·2 and 28 per cent for low, medium and high TBS respectively; P = 0·010). CONCLUSION The prognosis of patients with HCC varied according to the BCLC stage but was largely dependent on the TBS.

J M Hyer

Papers

Hepatocellular carcinoma tumour burden score to stratify prognosis after resection.