Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related mortality worldwide (1). While upfront surgical resection has been established as an effective curative treatment for early-stage disease, up to 53.6% of patients present with moderate-to-advanced stage disease (2). Traditional recommendations as per the latest Barcelona Clinic Liver Cancer (BCLC) 2022 update have advised for palliative transarterial chemoembolization (TACE) or systemic treatment (3), leaving this patient group with only modest response rates of 5% to 40% (4). However, with oncological advancements in recent years, conversion therapy has emerged as an effective strategy to change the therapeutic trajectory of patients with BCLC stage B and BCLC stage C HCC, showing significantly improved long-term outcomes compared to systemic therapy alone (5).
Numerous studies have investigated the range of locoregional and systemic options available for unresectable HCC (2,6), laying the groundwork for the development of conversion therapy regimens. The landmark IMbrave150 (7) and CheckMate 040 (8) trials demonstrated the superiority of combination immunotherapy, and the HIMALAYA (9) trial the superiority of combination targeted therapy. Cross-modality therapy also demonstrated survival benefits, including targeted therapy with radiotherapy (10,11), TACE with radiotherapy (12) and systemic therapy (13). The START-FIT trial (4) was the first to report a sequential trimodality regimen and demonstrated promising results of 55% conversion and 42% complete response; the use of synergistic effect to target different aspects of tumour biology optimised results in tumour downstaging (14,15). Building upon the basis of these findings, this study evaluates the efficacy of conversion therapy for BCLC stage B and stage C tumours.
Retrospective review of data from a tertiary referral centre in Hong Kong was performed for patients with BCLC-B and BCLC-C from January 2010 to December 2022 at Queen Mary Hospital. HCC was diagnosed by pathology or imaging based on American Association for the Study of Liver Disease (AASLD) and European Association for the Study of the Liver (EASL) criteria. Patients were discussed by a multi-disciplinary tumour board; those ineligible for upfront resection were candidates for conversion therapy with reassessment for resection, or were candidates for TACE. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. and informed consent was obtained from all patients.
The inclusion criteria were (I) BCLC-B and BCLC-C HCC patients treated by upfront resection, or conversion [by TACE, systemic chemotherapy, targeted therapy, stereotactic body radiation therapy (SBRT), or trimodal START-FIT therapy (4)] followed by resection, or TACE; (II) aged 18 to 94 years old; (III) Child-Pugh A or B liver function; (IV) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and had (V) adequate organ function (white blood cell count >2.5×109 L, platelet count ≥20×109 L, bilirubin <50 µmol/L, albumin >28 g/L, prothrombin time <4 seconds over control, creatinine ≤180 µmol/L). The exclusion criteria were (I) severe cardiac, pulmonary, or renal disease; (II) concomitant primary malignancy; (III) extra-hepatic disease; (IV) prior treatment with radiofrequency ablation (RFA), microwave ablation (MWA), or high-intensity focused ultrasound (HIFU) before conversion; and (V) loss to follow-up or incomplete data.
Resection included open and laparoscopic hepatic resection. Conventional TACE consisted of lipiodol with cisplatin (1 mg/mL) in 1:1 ratio. Trimodal conversion therapy has been described in detail in our previous START-FIT study (4). Tumour responses were evaluated using computed tomography or positron-emission tomography every 1–2 treatment cycles.
The primary endpoints were overall survival (OS) and disease-free survival (DFS). Propensity score matching (PSM) was adopted to minimise the impact of confounding factors using the nearest neighbour method in 2:1:1 ratio, including age, sex, tumour size, and tumour number. Data analyses were performed using SPSS version 28.0.
A flowchart for this study is illustrated in Figure 1. From January 2010 to December 2022, 4,031 patients were identified with BCLC-B and BCLC-C HCC no extra-hepatic disease or severe co-morbidities. After exclusion according to criteria, 2,254 patients were analysed; 533 underwent upfront resection, 126 conversion therapy followed by resection, and 383 TACE. Sub-analysis was further performed for the BCLC-B and BCLC-C groups.
Figure 1.
Flow chart of BCLC-B and BCLC-C patients in the study. BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; HIFU, high-intensity focused ultrasound; MWA, microwave ablation; PSM, propensity score matching; RFA, radiofrequency ablation; TACE, transarterial chemoembolization.
Baseline demographics are shown in Tables 1,2. The upfront resection group was slightly younger (62 vs. 65 years in BCLC-B), had more hepatitis B (79.8% vs. 72.4% BCLC-B and 75.9% vs. 73.2% BCLC-C), and ECOG 0 patients (94.1% vs. 96.6% in BCLC-C). Both upfront resection and conversion groups had no more than one tumour (median value), but maximum tumour diameter tended to be smaller in the upfront resection group (6.0 vs. 6.5 cm, P=0.01, for both BCLC-B and BCLC-C). After PSM, baseline demographics and tumour characteristics were comparable between the upfront resection and conversion groups. There were no significant differences in serum alpha-fetoprotein (AFP) or Model for End-Stage Liver Disease (MELD) score.
Table 1. BCLC-B patient baseline demographics, surgical and postoperative characteristics, and pathological examination results.
| Variables | Before matching | After matching | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Upfront resection (n=109) | Conversion (n=29) | TACE (n=46) | P value | Upfront resection (n=58) | Conversion (n=29) | TACE (n=29) | P value | ||
| Age (years) | 62.0 [32–81] | 65.0 [45–84] | 63.0 [31–85] | 0.25 | 63.0 [32–81] | 65.0 [45–84] | 63.0 [31–85] | 0.46 | |
| Sex | 0.08 | 0.85 | |||||||
| Male | 92 | 27 | 34 | 52 | 27 | 26 | |||
| Female | 17 | 2 | 12 | 6 | 2 | 3 | |||
| Aetiology | 0.31 | 0.99 | |||||||
| Hepatitis B | 87 (79.8) | 21 (72.4) | 33 (71.7) | 42 (72.4) | 21 (72.4) | 21 (72.4) | |||
| Hepatitis C | 4 (3.7) | 1 (3.4) | 5 (10.9) | 3 (5.2) | 1 (3.4) | 3 (10.3) | |||
| Hepatitis B and C | 1 (0.9) | 0 (0.0) | 0 (0.0) | 1 (1.7) | 0 (0.0) | 0 (0.0) | |||
| Alcoholic liver | 13 (11.9) | 5 (17.2) | 5 (10.9) | 9 (15.5) | 5 (17.2) | 4 (13.8) | |||
| NASH | 4 (3.7) | 2 (6.9) | 3 (6.5) | 3 (5.2) | 2 (6.9) | 1 (3.4) | |||
| Comorbid disease | 65 (59.6) | 23 (79.3) | 35 (76.1) | 0.04 | 33 (56.9) | 23 (79.3) | 24 (82.8) | 0.02 | |
| Heart | 61 (56.0) | 22 (75.9) | 28 (60.9) | 0.14 | 32 (55.2) | 22 (75.9) | 20 (69.0) | 0.13 | |
| Lung | 5 (4.6) | 0 (0.0) | 3 (6.5) | 0.75 | 2 (3.4) | 0 (0.0) | 1 (3.4) | 0.42 | |
| Renal | 2 (1.8) | 0 (0.0) | 1 (2.2) | 0.59 | 0 (0.0) | 0 (0.0) | 1 (3.4) | 0.25 | |
| DM | 29 (26.6) | 11 (37.9) | 16 (34.8) | 0.25 | 15 (25.9) | 11 (37.9) | 11 (37.9) | 0.38 | |
| ECOG | – | – | |||||||
| 0 | 109 (100.0) | 29 (100.0) | 46 (100.0) | 58 (100.0) | 29 (100.0) | 29 (100.0) | |||
| Child-Pugh class | 0.25 | 0.25 | |||||||
| A | 109 (100.0) | 29 (100.0) | 45 (97.8) | 58 (100.0) | 29 (100.0) | 28 (96.6) | |||
| B | 0 (0.0) | 0 (0.0) | 1 (2.2) | 0 (0.0) | 0 (0.0) | 1 (3.4) | |||
| Ascites | 0.06 | 0.06 | |||||||
| Absent | 109 (100.0) | 29 (100.0) | 44 (95.7) | 58 (100.0) | 29 (100.0) | 27 (93.1) | |||
| Present | 0 (0.0) | 0 (0.0) | 2 (4.3) | 0 (0.0) | 0 (0.0) | 2 (6.9) | |||
| Haemoglobin (g/dL) | 14.0 [8.6–17.6] | 13.5 [9.2–15.5] | 13.6 [9.1–16.2] | 0.06 | 14.0 [8.6–17.6] | 13.5 [9.2–15.5] | 13.4 [9.1–16.2] | 0.11 | |
| Platelet (×109/L) | 182.0 [85–661] | 177.0 [78–458] | 139.0 [54–522] | 0.002 | 196.5 [108–661] | 177.0 [78–458] | 158.0 [54–522] | 0.14 | |
| INR | 1.1 [0.9–1.3] | 1.1 [1.0–1.3] | 1.1 [0.8–1.5] | 0.34 | 1.1 [0.9–1.3] | 1.1 [1.0–1.3] | 1.1 [0.9–1.5] | 0.85 | |
| Bilirubin (μmol/L) | 10.0 [4–54] | 11.0 [5–24] | 11.0 [3–37] | 0.006 | 9.0 [4–54] | 11.0 [5–24] | 10.0 [3–37] | 0.16 | |
| Albumin (g/L) | 42.0 [30–52] | 41.0 [36–49] | 40.5 [28–50] | 0.01 | 42.0 [30–50] | 41.0 [36–49] | 41.0 [28–50] | 0.27 | |
| AST (U/L) | 40.0 [16–186] | 43.0 [23–246] | 51.5 [23–246] | 0.009 | 40.0 [16–186] | 43.0 [23–246] | 53.0 [23–246] | 0.04 | |
| ALT (U/L) | 33.0 [11–133] | 41.0 [15–141] | 46.0 [16–224] | 0.24 | 33.5 [11–133] | 41.0 [15–141] | 47.0 [16–203] | 0.20 | |
| AFP (ng/mL) | 14.5 [1–158,188] | 24.0 [2–86,990] | 23.0 [1–41,401] | 0.79 | 9.0 [1.9–158,188] | 24.0 [2–86,990] | 29.0 [2–41,401] | 0.44 | |
| MELD score | 7.5 [6–14] | 7.5 [6–13] | 7.8 [6–17] | 0.03 | 7.5 [6–14] | 7.5 [6–13] | 8.09 [6–17] | 0.23 | |
| Tumour number | 1.0 [1–multiple] | 1.0 [1–multiple] | 3.0 [1–multiple] | <0.001 | 1.0 [1–multiple] | 1.0 [1–multiple] | 1.0 [1–multiple] | 0.12 | |
| Maximum tumour diameter (cm) | 6.0 [(2.3–18.0] | 6.5 [2.8–16.0] | 5.2 [0.5–14.5] | 0.01 | 6.0 [2.3–18.0] | 6.5 [2.8–16.0] | 6.2 [3.4–14.5] | 0.47 | |
| Total operating time (min) | 275.0 [71–1,045] | 281.0 [91–680] | – | 0.92 | 263.0 [90–735] | 281.0 [91–680] | – | 0.80 | |
| Blood loss (L) | 0.53 [0.01–8.0] | 0.88 [0.05–25.5] | – | 0.06 | 0.685 [0.1–3.2] | 0.88 [0.05–25.5] | – | 0.25 | |
| Laparoscopic liver resection | 0.87 | >0.99 | |||||||
| No | 81 (74.3) | 22 (75.9) | – | – | 45 (77.6) | 22 (75.9) | – | – | |
| Yes | 28 (25.7) | 7 (24.1) | – | – | 13 (22.4) | 7 (24.1) | – | – | |
| Resection | 0.04 | 0.10 | |||||||
| Major resection | 60 (55.0) | 22 (75.9) | 33 (56.9) | 22 (75.9) | |||||
| Minor resection | 49 (45.0) | 7 (24.1) | 25 (43.1) | 7 (24.1) | |||||
| Hospital stay (days) | 7.0 [2–60] | 6.0 [0–48] | – | 0.96 | 7.0 [2–48] | 6.0 [0–48] | – | 0.51 | |
| Hospital mortality (yes) | 1 (0.9) | 1 (3.4) | – | 0.89 | 0 (0.0) | 1 (3.4) | – | 0.33 | |
| Clavien-Dindo complication | – | – | |||||||
| IIIA | 7 (6.4) | 4 (13.8) | 0.36 | 3 (5.2) | 4 (13.8) | 0.33 | |||
| IIIB | 2 (1.8) | 0 (0.0) | >0.99 | 1 (1.7) | 0 (0.0) | >0.99 | |||
| IVA | 1 (0.9) | 0 (0.0) | >0.99 | 1 (1.7) | 0 (0.0) | >0.99 | |||
| IVB | 0 (0.0) | 0 (0.0) | – | 0 (0.0) | 0 (0.0) | – | |||
| V | 1 (0.9) | 1 (3.4) | 0.89 | 0 (0.0) | 1 (3.4) | 0.72 | |||
| Poorly differentiated | 0.05 | 0.20 | |||||||
| Yes | 24 (22.0) | 2 (6.9) | 17 (29.3) | 2 (6.9) | |||||
| No | 85 (78.0) | 27 (93.1) | 41 (70.3) | 27 (93.1) | |||||
| Microvascular invasion | 0.19 | 0.36 | |||||||
| Absent | 60 (55.0) | 12 (41.4) | 30 (51.7) | 12 (41.4) | |||||
| Present | 49 (45.0) | 17 (58.6) | 28 (48.3) | 17 (58.6) | |||||
Data are presented as median [range], n or n (%). AFP, alpha-fetoprotein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BCLC, Barcelona Clinic Liver Cancer; DM, diabetes mellitus; ECOG, Eastern Cooperative Oncology Group; INR, international normalized ratio; MELD, Model for End-Stage Liver Disease; NASH, non-alcoholic steatohepatitis; TACE, transarterial chemoembolization.
Table 2. BCLC-C patient baseline demographics, surgical and postoperative characteristics, and pathological examination results.
| Variables | Before matching | After matching | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Upfront resection (n=424) | Conversion (n=97) | TACE (n=337) | P value | Upfront resection (n=194) | Conversion (n=97) | TACE (n=97) | P value | ||
| Age (years) | 62.5 [19–89] | 62.0 [31–52] | 67.0 [20–94] | <0.001 | 62.5 [26–85] | 62.0 [31–52] | 62.0 [20–88] | 0.58 | |
| Sex | 0.33 | 0.22 | |||||||
| Male | 335 | 85 | 275 | 167 | 85 | 90 | |||
| Female | 89 | 12 | 62 | 27 | 12 | 7 | |||
| Aetiology | 0.003 | 0.19 | |||||||
| Hepatitis B | 322 (75.9) | 71 (73.2) | 215 (63.8) | 154 (79.4) | 81 (83.5) | 71 (73.2) | |||
| Hepatitis C | 14 (3.3) | 4 (4.1) | 21 (6.2) | 3 (1.5) | 4 (4.1) | 5 (5.2) | |||
| Hepatitis B and C | 2 (0.5) | 0 (0.0) | 3 (0.9) | 1 (0.5) | 0 (0.0) | 1 (1.0) | |||
| Alcoholic liver | 30 (7.1) | 7 (7.2) | 36 (10.7) | 13 (6.7) | 7 (7.2) | 12 (12.4) | |||
| NASH | 56 (13.2) | 5 (5.2) | 61 (18.1) | 23 (11.9) | 5 (5.2) | 8 (8.2) | |||
| Comorbid disease | 221 (52.1) | 50 (51.5) | 218 (64.7) | <0.001 | 96 (49.5) | 50 (51.5) | 56 (57.7) | 0.41 | |
| Heart | 189 (44.6) | 41 (42.3) | 176 (52.2) | 0.06 | 79 (40.7) | 41 (42.3) | 40 (41.2) | 0.97 | |
| Lung | 29 (6.8) | 7 (7.2) | 35 (10.4) | 0.20 | 12 (6.2) | 7 (7.2) | 7 (7.2) | 0.64 | |
| Renal | 8 (1.9) | 1 (1.0) | 12 (3.6) | 0.20 | 4 (2.1) | 1 (1.0) | 4 (4.1) | 0.35 | |
| DM | 100 (23.6) | 21 (21.6) | 88 (26.1) | 0.58 | 44 (22.7) | 21 (21.6) | 27 (27.8) | 0.54 | |
| ECOG | <0.001 | 0.42 | |||||||
| 0 | 27 (6.4) | 4 (4.1) | 4 (1.2) | 10 (5.2) | 4 (4.1) | 2 (2.1) | |||
| 1 | 397 (93.6) | 93 (95.9) | 333 (98.8) | 184 (94.8) | 93 (95.9) | 95 (97.9) | |||
| Child-Pugh class | <0.001 | 0.008 | |||||||
| A | 399 (94.1) | 94 (96.9) | 275 (81.6) | 177 (91.2) | 94 (96.9) | 82 (84.5) | |||
| B | 25 (5.9) | 3 (3.1) | 62 (18.4) | 17 (8.8) | 3 (3.1) | 15 (15.5) | |||
| Ascites | <0.001 | <0.001 | |||||||
| Absent | 408 (96.2) | 95 (97.9) | 282 (83.7) | 183 (94.3) | 95 (97.9) | 80 (82.5) | |||
| Present | 16 (3.8) | 2 (2.1) | 55 (16.3) | 11 (5.7) | 2 (2.1) | 17 (17.5) | |||
| Haemoglobin (g/dL) | 13.2 [6.6–19.3] | 12.7 [8.5–16.4] | 12.5 [6.7–19.0] | <0.001 | 13.1 [6.6–19.3] | 12.7 [8.5–16.4] | 12.5 [7.2–18.4] | 0.02 | |
| Platelet (×109/L) | 193.5 [20–742] | 189.0 [49–795] | 174.5 [28–590] | 0.009 | 191.5 [90–742] | 189.0 [49–795] | 169.0 [28–585] | 0.03 | |
| INR | 1.1 [0.8–1.4] | 1.1 [0.9–1.3] | 1.1 [0.8–2.3] | <0.001 | 1.1 [0.9–1.4] | 1.1 [0.9–1.3] | 1.1 (0.9–2.3) | 0.52 | |
| Bilirubin (μmol/L) | 10.0 [2–70] | 10.0 [3–33] | 14.0 [3–59] | <0.001 | 9.5 [2–34] | 10.0 [3–33] | 10.0 [3–34] | 0.45 | |
| Albumin (g/L) | 41.0 [23–53] | 40.0 [28–48] | 38.0 [35–321] | <0.001 | 40.0 [25–52] | 40.0 [28–48] | 39.0 [23–53] | 0.10 | |
| AST (U/L) | 49.0 [12–444] | 47.0 [17–1,848] | 67.0 [13–841] | <0.001 | 52.5 [13–444] | 47.0 [17–1,848] | 55.0 [21–307] | 0.26 | |
| ALT (U/L) | 41.0 [9–979] | 42.0 [11–515] | 45.0 [7–387] | 0.06 | 42.0 [10–696] | 42.0 [11–515] | 39.0 [8–387] | 0.95 | |
| AFP (ng/mL) | 59.0 [1–1,267,800] |
94.0 [1–431,204] |
63.0 [1–1,458,960] |
0.53 | 67.8 [1.8–1,367,800] |
94.0 [1–431,204] |
58.0 [1–572,380] |
0.89 | |
| MELD score | 7.5 [6–25] | 7.5 [6–17] | 8.5 [6–21] | <0.001 | 7.5 [6–22] | 7.5 [6–17] | 8.5 [6–21] | 0.02 | |
| Tumour number | 1.0 [1–multiple] | 1.0 [1–multiple] | 3.0 [1–multiple] | <0.001 | 1.0 [1–multiple] | 1.0 [1–multiple] | 1.0 [1–multiple] | 0.12 | |
| Maximum tumour diameter (cm) | 6.0 [2.3–18.0] | 6.5 [2.8–16.0] | 5.2 [0.5–14.5] | 0.01 | 6.0 [2.3–18.0] | 6.5 (2.8–16.0) | 6.2 [3.4–14.5] | 0.47 | |
| Total operating time (min) | 328.0 [34–1162] | 352.0 [69–1666] | – | 0.21 | 353.5 [103–1,162] | 352.0 [69–1,666] | – | 0.93 | |
| Blood loss (L) | 0.8 [0.02–36.83] | 0.95 [0.05–14.0] | – | 0.08 | 0.9 [0.02–36.83] | 0.95 [0.05–14.0] | – | 0.45 | |
| Laparoscopic liver resection | 0.39 | 0.06 | |||||||
| No | 352 (83.0) | 84 (86.6) | 164 (84.5) | 84 (86.6) | |||||
| Yes | 72 (17.0) | 13 (13.4) | 30 (15.5) | 13 (13.4) | |||||
| Resection | 0.04 | 0.30 | |||||||
| Major resection | 288 (67.9) | 76 (78.4) | 141 (72.7) | 76 (78.4) | |||||
| Minor resection | 136 (32.1) | 21 (21.6) | 53 (27.3) | 21 (21.6) | |||||
| Hospital stay (days) | 8.0 [2–229] | 9.0 [2–88] | – | 0.10 | 8.0 [2–229] | 9.0 [2–88] | – | 0.23 | |
| Hospital mortality (yes) | 6 (1.4) | 4 (4.1) | – | 0.18 | 1 (0.5) | 4 (4.1) | – | 0.08 | |
| Clavien-Dindo complication | – | – | |||||||
| IIIA | 53 (12.5) | 21 (21.6) | 0.02 | 29 (14.9) | 21 (21.6) | 0.15 | |||
| IIIB | 16 (3.8) | 11 (11.3) | 0.005 | 5 (2.6) | 11 (11.3) | 0.005 | |||
| IVA | 24 (5.7) | 9 (9.3) | 0.19 | 12 (6.2) | 9 (9.3) | 0.34 | |||
| IVB | 9 (2.1) | 3 (3.1) | 0.84 | 4 (2.1) | 3 (3.1) | 0.89 | |||
| V | 6 (1.4) | 4 (4.1) | 0.18 | 1 (0.5) | 4 (4.1) | 0.08 | |||
| Poorly differentiated | 0.11 | 0.04 | |||||||
| Yes | 94 (22.2) | 21 (21.6) | 51 (26.3) | 21 (21.6) | |||||
| No | 330 (77.8) | 76 (78.4) | 143 (73.7) | 76 (78.4) | |||||
| Microvascular invasion | 0.008 | 0.003 | |||||||
| Absent | 150 (35.4) | 49 (50.5) | 62 (32.0) | 49 (50.5) | |||||
| Present | 274 (64.6) | 48 (49.5) | 132 (68.0) | 48 (49.5) | |||||
Data are presented as median [range], n or n (%). AFP, alpha-fetoprotein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BCLC, Barcelona Clinic Liver Cancer; DM, diabetes mellitus; ECOG, Eastern Cooperative Oncology Group; INR, international normalized ratio; MELD, Model for End-Stage Liver Disease; NASH, non-alcoholic steatohepatitis; TACE, transarterial chemoembolization.
One hundred and eleven BCLC-B and 1,227 BCLC-C patients in total underwent therapy for conversion; conversion therapy modalities and change in tumour status are summarised for BCLC-B patients in Tables 3,4, and BCLC-C patients in Tables 5,6. Successful conversion was achieved in 29 BCLC-B and 97 BCLC-C patients, giving conversion rates of 26.1% and 7.9%.
Table 3. Conversion therapy modalities for BCLC-B with successful conversion followed by resection.
| Modalities | BCLC-B |
|---|---|
| Conversion | 29 (26.1) |
| TACE | 12 (41.4) |
| TACE + targeted therapy (bevacizumab) | 1 (3.4) |
| Systemic chemotherapy | – |
| Targeted therapy (lenvatinib) | 2 (6.9) |
| Immunotherapy (nivolumab) | 11 (37.9) |
| SBRT | 1 (3.4) |
| SIRT | – |
| START-FIT trimodal therapy | 2 (6.9) |
Data are presented as n (%). BCLC, Barcelona Clinic Liver Cancer; SBRT, stereotactic body radiation therapy; SIRT, selective internal radiation therapy; TACE, transarterial chemoembolization.
Table 4. BCLC-B tumour status pre- and post-conversion therapy.
| Variables | BCLC-B | P value | |
|---|---|---|---|
| Pre-conversion | Post-conversion | ||
| AFP (ng/mL) | 17.0 (2–107,960) | 14.0 (2–309,008) | 0.60 |
| Tumour size (cm) | 6.3 (2.5–14.7) | 6.5 (2.8–16.0) | 0.17 |
| Tumour number | 1.0 (1–multiple); 1.9±2.093 | 1.0 (1–multiple); 3.8±3.642 | 0.04 |
Data are presented as median (range) or mean ± standard deviation. AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer.
Table 5. Conversion therapy modalities for BCLC-C with successful conversion followed by resection.
| Modalities | BCLC-C |
|---|---|
| Conversion | 97 (7.9) |
| TACE | 71 (73.2) |
| TACE + targeted therapy (bevacizumab) | – |
| Systemic chemotherapy | 3 (3.1) |
| Targeted therapy (lenvatinib) | 9 (9.3) |
| Immunotherapy (nivolumab) | 11 (11.3) |
| SBRT | 3 (3.1) |
| SIRT | 1 (1.0) |
| START-FIT trimodal therapy | 5 (5.2) |
Data are presented as n (%). BCLC, Barcelona Clinic Liver Cancer; SBRT, stereotactic body radiation therapy; SIRT, selective internal radiation therapy; TACE, transarterial chemoembolization.
Table 6. BCLC-C tumour status pre- and post-conversion therapy.
| Variables | BCLC-C | P value | |
|---|---|---|---|
| Pre-conversion | Post-conversion | ||
| AFP (ng/mL) | 84.0 (1–431,204) | 48.0 (1–466,903) | 0.17 |
| Tumour size (cm) | 8.4 (1.0–19.0) | 8.5 (1–22.5) | 0.75 |
| Tumour number | 2.0 (1–multiple) | 2.0 (1–multiple) | 0.69 |
Data are presented as median (range). AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer.
Survival analysis showed that conversion therapy followed by resection had similar outcomes compared with upfront resection for both BCLC-B and BCLC-C stages. After matching, OS was comparable between conversion therapy and upfront resection for both BCLC-B and BCLC-C; 1-, 3-, and 5-year OS of upfront resection were 93.1%, 71.9% and 65.1% for BCLC-B and 79.5%, 54.2%, and 41.9% for BCLC-C respectively (P<0.001) (Figures 2,3).
Figure 2.
Survival outcomes in BCLC-B patients. BCLC, Barcelona Clinic Liver Cancer; DFS, disease-free survival; OS, overall survival; PSM, propensity score matching; TACE, transarterial chemoembolization.
Figure 3.
Survival outcomes in BCLC-C patients. BCLC, Barcelona Clinic Liver Cancer; DFS, disease-free survival; OS, overall survival; PSM, propensity score matching; TACE, transarterial chemoembolization.
Multivariate analysis, summarised in Tables 7,8, showed that pre-treatment AFP >400 ng/mL was associated with poorer OS in both BCLC-B [hazard ratio (HR) 6.553, 95% confidence interval (CI): 3.316–12.950, P<0.001] and BCLC-C (HR 1.504, 95% CI: 1.147–1.971, P<0.001) groups. Disease with multiple tumours was associated with poorer OS in the BCLC-B group (HR 1.238, 95% CI: 1.135–1.351, P<0.001). Pre-treatment AFP >400 ng/mL (HR 4.147, 95% CI: 2.085–8.249, P<0.001), blood loss (HR 1.168, 95% CI: 1.002–1.362, P=0.05), and multiple tumours (HR 1.167, 95% CI: 1.066–1.277, P=0.05) were also associated with poorer DFS in BCLC-B. For BCLC-C, poorer DFS was demonstrated with multiple tumours (HR 1.127, 95% CI: 1.083–1.173, P<0.001), involved resection margin (HR 2.051, 95% CI: 1.274–3.302, P=0.003), and venous infiltration (HR 1.523, 95% CI: 1.113–2.084, P=0.009). Interestingly, the BCLC-C conversion group showed better DFS than upfront resection (HR 0.729, 95% CI: 0.534–0.994, P=0.05).
Table 7. Univariate and multivariate analyses of potential prognostic factors affecting overall survival.
| Variables | BCLC-B overall survival | BCLC-C overall survival | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Univariate | Multivariate | Univariate | Multivariate | ||||||||
| HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | ||||
| Age | 1.002 (0.974–1.030) | 0.90 | – | – | 0.996 (0.985–1.008) | 0.54 | – | – | |||
| Sex | 1.567 (0.706–3.480) | 0.27 | – | – | 1.004 (0.686–1.470) | 0.98 | – | – | |||
| Comorbidity | 1.287 (0.725–2.283) | 0.39 | – | – | 0.939 (0.737–1.196) | 0.61 | – | – | |||
| Haemoglobin | 0.909 (0.775–1.066) | 0.24 | – | – | 0.936 (0.880–0.996) | 0.04 | – | – | |||
| Platelet | 1.002 (1.000–1.005) | 0.08 | 1.004 (1.002–1.007) | <0.001 | 1.002 (1.001–1.003) | 0.004 | 1.002 (1.001–1.003) | 0.003 | |||
| Creatinine | 1.002 (0.992–1.013) | 0.69 | – | – | 1.000 (0.998–1.002) | 0.88 | – | – | |||
| Albumin | 0.936 (0.873–1.004) | 0.06 | – | – | 0.945 (0.922–0.968) | <0.001 | – | – | |||
| INR | 2.257 (0.170–30.030) | 0.54 | – | – | 5.628 (2.148–14.742) | <0.001 | 3.783 (1.395–10.257) | 0.009 | |||
| AST | 1.007 (1.002–1.012) | 0.004 | – | – | 1.005 (1.003–1.007) | <0.001 | 1.004 (1.002–1.006) | 0.003 | |||
| ALT | 1.004 (0.997–1.010) | 0.25 | – | – | 1.003 (1.000–1.005) | 0.03 | – | – | |||
| Pre-treatment AFP (≤400 vs. >400 ng/mL) | 3.178 (1.807–5.592) | <0.001 | 6.553 (3.316–12.950) | <0.001 | 1.804 (1.403–2.319) | <0.001 | 1.504 (1.147–1.971) | <0.001 | |||
| MELD score | 1.032 (0.889–1.198) | 0.68 | – | – | 1.071 (1.017–1.128) | 0.01 | – | – | |||
| Tumour number | 1.163 (1.081–1.250) | <0.001 | 1.238 (1.135–1.351) | <0.001 | 1.127 (1.090–1.165) | <0.001 | – | – | |||
| Tumour size | 0.989 (0.909–1.075) | 0.79 | – | – | 1.016 (1.007–1.025) | <0.001 | – | – | |||
| Invasion of another organ other than gallbladder | 2.853 (0.689–11.818) | 0.15 | – | – | 1.476 (0.902–2.414) | 0.12 | – | – | |||
| Invasion of major branch | – | – | – | – | 2.313 (1.742–3.071) | <0.001 | – | – | |||
| Tumour rupture | 1.332 (0.182–9.735) | 0.78 | – | – | 0.898 (0.610–1.321) | 0.59 | – | – | |||
| Bilobar tumour | 2.247 (1.315–3.839) | <0.001 | – | – | 1.775 (1.384–2.276) | <0.001 | – | – | |||
| Treatment | <0.001 | <0.001 | <0.001 | <0.001 | |||||||
| Upfront | Ref | – | – | – | Ref | – | Ref | ||||
| Conversion | 1.070 (0.508–2.255) | 0.86 | 1.207 (0.548–2.658) | 0.64 | 0.868 (0.632–1.192) | 0.38 | 0.831 (0.602–1.147) | 0.26 | |||
| TACE | 3.882 (2.103–7.167) | <0.001 | 4.807 (2.434–9.492) | <0.001 | 2.581 (1.935–3.443) | <0.001 | 3.322 (2.453–4.500) | <0.001 | |||
AFP, alpha-fetoprotein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazard ratio; INR, international normalized ratio; MELD, Model for End-Stage Liver Disease; TACE, transarterial chemoembolization.
Table 8. Univariate and multivariate analyses of potential prognostic factors affecting disease-free survival.
| Variables | BCLC-B disease-free survival | BCLC-C disease-free survival | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Univariate | Multivariate | Univariate | Multivariate | ||||||||
| HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | ||||
| Age | 1.001 (0.972–1.031) | 0.93 | – | – | 0.994 (0.981–1.007) | 0.38 | – | – | |||
| Sex | 1.515 (0.639–3.595) | 0.35 | – | – | 1.049 (0.695–1.585) | 0.82 | – | – | |||
| Comorbidity | 1.279 (0.679–2.408) | 0.45 | – | – | 0.907 (0.691–1.192) | 0.48 | – | – | |||
| Haemoglobin | 1.079 (0.865–1.346) | 0.50 | – | – | 0.943 (0.881–1.010) | 0.10 | – | – | |||
| Platelet | 1.003 (1.000–1.006) | 0.03 | 1.005 (1.001–1.008) | 0.009 | 1.001 (0.999–1.002) | 0.40 | – | – | |||
| Creatinine | 0.993 (0.976–1.009) | 0.39 | – | – | 0.999 (0.996–1.002) | 0.47 | – | – | |||
| Albumin | 0.980 (0.899–1.068) | 0.65 | – | – | 0.958 (0.930–0.988) | 0.005 | – | – | |||
| INR | 0.362 (0.014–9.086) | 0.54 | – | – | 3.894 (0.986–15.377) | 0.05 | – | – | |||
| AST | 1.002 (0.996–1.009) | 0.47 | – | – | 1.005 (1.003–1.006) | <0.001 | 1.004 (1.002–1.006) | <0.001 | |||
| ALT | 0.998 (0.990–1.006) | 0.61 | – | – | 1.003 (1.001–1.006) | 0.02 | – | – | |||
| Pre-treatment AFP (≤400 vs. >400 ng/mL) | 3.264 (1.689–6.309) | <0.001 | 4.147 (2.085–8.249) | <0.001 | 1.461 (1.098–1.945) | 0.009 | – | – | |||
| MELD score | 0.801 (0.614–1.044) | 0.10 | – | – | 1.027 (0.955–1.104) | 0.47 | – | – | |||
| Resection (major vs. minor) | 0.738 (0.391–1.393) | 0.35 | – | – | 0.920 (0.673–1.258) | 0.60 | – | – | |||
| Laparoscopic liver resection | 1.522 (0.777–2.982) | 0.22 | – | – | 0.878 (0.599–1.286) | 0.50 | – | – | |||
| Blood loss | 1.135 (0.984–1.309) | 0.08 | 1.168 (1.002–1.362) | 0.05 | 1.032 (0.998–1.068) | 0.07 | – | – | |||
| Blood transfusion | 1.455 (0.758–2.793) | 0.26 | – | – | 1.425 (1.061–1.914) | 0.02 | – | – | |||
| Operation duration | 1.001 (0.999–1.003) | 0.31 | – | – | 1.001 (1.000–1.001) | 0.04 | – | – | |||
| Pringle manoeuvre | 0.669 (0.321–1.396) | 0.28 | – | – | 1.282 (0.954–1.723) | 0.10 | – | – | |||
| Overall complication | 1.079 (0.498–2.341) | 0.85 | – | – | 1.433 (1.067–1.924) | 0.02 | – | – | |||
| Hospital stay | 1.040 (1.008–1.072) | 0.01 | – | – | 1.001 (0.993–1.009) | 0.88 | – | – | |||
| Tumour number | 1.112 (1.023–1.208) | 0.01 | 1.167 (1.066–1.277) | 0.05 | 1.159 (1.116–1.204) | <0.001 | 1.127 (1.083–1.173) | <0.001 | |||
| Tumour size | 1.006 (0.922–1.098) | 0.90 | – | – | 1.012 (1.001–1.022) | 0.04 | – | – | |||
| Resection margin involved | 3.437 (0.820–14.397) | 0.09 | – | – | 2.295 (1.445–3.645) | <0.001 | 2.051 (1.274–3.302) | 0.003 | |||
| Short length of margin | 0.986 (0.620–1.569) | 0.95 | – | – | 0.865 (0.723–1.035) | 0.11 | – | – | |||
| Venous infiltration | 1.180 (0.651–2.142) | 0.59 | – | – | 2.006 (1.494–2.694) | <0.001 | 1.523 (1.113–2.084) | 0.009 | |||
| New Edmondson tumour differentiation | 1.111 (0.613–2.016) | 0.73 | – | – | 1.921 (1.426–2.588) | <0.001 | – | – | |||
| Invasion of another organ other than gallbladder | 3.821 (0.914–15.968) | 0.07 | – | – | 1.575 (0.913–2.715) | 0.10 | – | – | |||
| Tumour rupture | 0.859 (0.118–6.277) | 0.88 | – | – | 1.489 (1.048–2.176) | 0.04 | – | – | |||
| Bilobar tumour | 2.433 (1.301–4.551) | 0.005 | – | – | 1.584 (1.172–2.141) | 0.003 | – | – | |||
| Treatment | |||||||||||
| Upfront | Ref | – | – | – | Ref | – | – | – | |||
| Conversion | 1.168 (0.609–2.242) | 0.64 | – | – | 0.744 (0.550–1.006) | 0.06 | 0.729 (0.534–0.994) | 0.05 | |||
AFP, alpha-fetoprotein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazard ratio; INR, international normalized ratio; MELD, Model for End-Stage Liver Disease; TACE, transarterial chemoembolization.
BCLC-C showed a larger drop in AFP (from 84.0 to 48.0 ng/mL, P=0.17 compared to BCLC-B (from 17.0 to 14.0 ng/mL, P=0.60) before and after conversion therapy (Tables 4,6 and Figure 4). Pathological analysis of the resected specimens after conversion therapy showed necrosis only in 4 (13.8%) BCLC-B patients and 9 (9.5%) BCLC-C patients, suggesting no viable HCC lesion remained after conversion therapy. Conversion therapy was well-tolerated, and severe toxicity was uncommon. Treatment-related adverse events are summarised in Table 9.
Figure 4.
Serum AFP levels pre- and post-conversion therapy. AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer.
Table 9. Treatment-related adverse events.
| Adverse events | BCLC-B | BCLC-C | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Upfront resection (n=109) | Conversion therapy (n=29) | TACE | P value | Upfront resection (n=424) | Conversion therapy (n=97) | TACE | P value | ||
| Chest infection | 1 (0.9) | 1 (3.4) | – | 0.89 | 25 (5.9) | 2 (2.1) | – | 0.60 | |
| Pleural effusion | 3 (2.8) | 2 (6.9) | 1 (0.3) | 0.92 | 27 (6.4) | 10 (10.3) | – | 0.25 | |
| Wound complication (infection or dehiscence) | 3 (2.8) | 0 (0.0) | – | >0.99 | 13 (3.0) | 4 (4.1) | – | 0.84 | |
| Bleeding peptic ulcer | 1 (0.9) | 0 (0.0) | – | >0.99 | 1 (0.2) | 0 (0) | – | >0.99 | |
| Cardiac arrhythmia | 2 (1.8) | 2 (6.9) | – | 0.41 | 28 (6.6) | 8 (8.2) | – | 0.56 | |
| Myocardial infarction | – | – | – | – | 2 (0.5) | 0 (0.0) | – | >0.99 | |
| Deranged LFT | 1 (0.9) | 0 (0.0) | 17 (4.3) | >0.99 | 9 (2.1) | 4 (4.1) | 8 (1.2) | 0.44 | |
| Impaired RFT | – | – | 4 (0.9) | – | – | – | 2 (0.4) | – | |
| Portal vein thrombosis | 1 (0.9) | 0 (0.0) | – | >0.99 | 1 (0.2) | 1 (1.0) | – | 0.82 | |
| Hepatic artery dissection | – | – | 2 (0.5) | – | – | – | 1 (0.2) | – | |
| Subphrenic abscess | – | – | – | – | 5 (2.1) | 3 (3.1) | – | 0.36 | |
| Variceal bleeding | – | – | 3 (0.8) | – | – | – | 12 (1.8) | – | |
| Pulmonary embolism | – | – | – | – | 6 (1.4) | 1 (1.0) | – | >0.99 | |
| Disseminated intravascular coagulopathy | – | – | – | – | 1 (0.2) | 0 (0.0) | – | >0.99 | |
| Intestinal obstruction | – | – | – | – | 4 (0.9) | 1 (1.0) | – | >0.99 | |
| Respiratory failure | – | – | – | – | 3 (0.7) | 3 (3.1) | – | 0.15 | |
| Bile leakage | – | – | – | – | 8 (1.9) | 3 (3.1) | – | 0.72 | |
| Rash | – | 1 (3.4) | – | – | – | 3 (3.1) | – | – | |
| Thrombocytopenia | – | – | – | – | – | 1 (1.0) | – | – | |
| Ruptured HCC | – | 1 (3.4) | 1 (0.3) | – | – | – | 6 (0.9) | – | |
| Hyper/hypoglycaemia | – | – | – | – | – | 3 (3.1) | – | – | |
| Liver abscess | – | – | 2 (0.5) | – | – | 1 (1.0) | 13 (2.0) | – | |
| Confusion/hepatic encephalopathy | – | – | 2 (0.5) | – | – | – | 1 (0.2) | – | |
| Spontaneous bacterial peritonitis | – | – | – | – | – | – | 1 (0.2) | – | |
Data are presented as n (%). BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; LFT, liver function test; RFT, renal function test; TACE, transarterial chemoembolization.
This study highlights the potential of conversion therapy, particularly in advanced-stage disease, to select out responsive disease and achieve survival outcomes on par with candidates of upfront surgery.
Our findings echo results from comparable studies (16). Furthermore, combination therapy has yielded better outcomes than single modality regimens (12,17-22) that can be explained by their multi-dimensional targeting of tumour biology (10). TACE exhibits local control and has immunomodulatory effects together with SBRT that may act synergistically with immune checkpoint inhibitors to target micrometastases (23). In a reciprocal fashion, immunotherapy may also sensitise the tumour to radiotherapy and lead to better response with lower radiation doses (24). The START-FIT trial was a trimodal strategy to bring together the strengths of each modality, yielding promising rates of conversion (55%) and complete response (42%) (4).
There are limitations to this study. Firstly, this retrospective study at a single tertiary centre with a relatively smaller sample size may result in biases in patient selection and analysis. Nonetheless, PSM was used to minimise the effects of potential confounding factors and selection bias. The conversion therapy group also shows heterogeneity in the treatment regimen. While there have been systematic reviews (21), studies are still limited given the wide variety of treatments available. Targeted analysis of specific conversion regimens across multiple centres with long-term follow-up of survival outcomes would be beneficial.
Investigations are also warranted on predictive factors for conversion therapy success (25) and patient selection criteria. The Multicenter Evaluation of Reduction in Tumour Size before Liver Transplantation (MERITS-LT) consortium showed that success was related to the sum of the largest tumour diameters; with an 88% success rate for total tumour diameter less than 6 cm, in comparison to 81% for total tumour diameter greater than 7 cm (26). A 10-year study identified predictors for failure as tumour size greater than 7 cm at diagnosis, more than three tumours at diagnosis, and failure of decrease in AFP of at least 50% from maximum for AFP ≥20 ng/mL (27). This suggests that tumour burden in relation to AFP levels and total tumour size shows correlation with conversion success rate, and may be useful clinical indicators in the prediction of success and patient selection.
As surgical oncology continues to mature and gain traction in clinical practice, we envision that conversion therapy will expand to allow a wider population of patients to benefit from curative treatment for HCC and beyond. This study shows that there is potential in altering the trajectory of advanced-stage disease, where prognosis was previously most guarded for this group of patients; they may now stand to benefit the most from development in this area.
Conversion therapy is a promising strategy for initially inoperable tumours, yielding survival outcomes on par with upfront resectable tumours. Further studies are warranted to define a consensus on conversion regimen and selection criteria.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Informed consent was obtained from all patients for treatment and for usage of data for research purposes.
Footnotes
Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-68/coif). A.C.Y.C. serves as an unpaid editorial board member of HepatoBiliary Surgery and Nutrition. The other authors have no conflicts of interest to declare.
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