2 [95% CI, 4.8-7.8] local; 25.3 [95% CI, 22.5-28.3] limited nonlocal; and 9.7 [95% CI, 8.0-11.7] advanced nonlocal). The 3- and 5-year cumulative incidences of first recurrence were 70.8% (95% CI, 66.8-74.7) and 81.7% (95% CI, 77.7-85.3) (Fig. 1A,B). Median time to first recurrence was 18 (IQR, 7-42) months. Multivariate analysis identified age (P = 0.030), tumor size (P = 0.047), and number of nodules (P < 0.001) as significant predictors

of first recurrence (Table 2). All three variables were independent predictors of local recurrence (Supporting Appendix 1), but only age and number of nodules Selleckchem Ibrutinib correlated with nonlocal recurrences (Supporting Appendix 2). Table 3 shows the type of first recurrence as a function of time of detection and initial HCC nodule/s size. Figure 2 summarizes the events observed during follow-up and their management (details in Supporting Appendix 3). Three-fourths of the patients whose HCC recurred experienced multiple episodes of local and/or limited nonlocal recurrence, and about one-third of these ultimately developed advanced nonlocal recurrences. The median times to second, third, and fourth recurrences (measured from CRs of the previous recurrence) were 6.5 (IQR, 2.0-16.0), 4.4 (IQR, 1.0-10.0), and 2.0 (IQR, 1.0-6.0) Small molecule library months, respectively. Altogether, there were 877 episodes of recurrence: 134 (15.7%) local, 513 (58.1%) limited nonlocal

and 230 (26.2%) advanced nonlocal. Of the 134 local recurrences, 7 (4.4%) were observed in 159 HCC nodules ≤2.0 cm, 49 (12.9%) in 378 nodules > 2.0 ≤3.0 cm, and 78 (25.0%) in 312 nodules >3.0 ≤3.5 cm. Details are shown in Supporting Appendix 3. Briefly, RFA was used to treat 110 (82.0%) of the 134 local and 467 (91.0%) of the 513 limited nonlocal recurrences. CRs were obtained in 102 (92.7%) and 455 (97.4%)

cases, respectively. Of the 102 local recurrences that exhibited CRs, only seven (6.8%) had a TF. Local recurrence was detected in 54 (11.8%) of the 455 limited nonlocal recurrences with CRs. In all, 315 patients died (incidence rate: 15.4 per 100 person-years). Overall, 127 (40.3%) deaths were unrelated to the tumor (Supporting Appendix 4); there were 188 (59.7%) Nintedanib (BIBF 1120) HCC-related death (incidence rate: 9.2 per 100 person-years). Estimated cumulative overall survival rates at 3 and 5 years were 67.0% (95% CI, 62.7-70.9) and 40.1% (95% CI, 35.0-45.1) (Fig. 3A-C) and median overall survival was 43 (IQR, 12-124) months. Multivariate analysis identified Child-Pugh class B (P = 0.013), first recurrence ≤24 months after RFA (P < 0.001), local recurrence (P < 0.001), and advanced nonlocal recurrence (P < 0.001) as independent predictors of death (Table 4). Estimated 3- and 5-year cumulative tumor-specific survival rates were 78.6% (95% CI 74.5-82.1) and 56.6% (95% CI 50.6-62.1), and median tumor-specific survival was 71 (IQR: 41-124) months (Fig. 3D). Multivariate analysis identified local (P < 0.001) and advanced nonlocal recurrences (P < 0.