Systemic Neoadjuvant and Adjuvant Therapies in the Management of Hepatocellular Carcinoma—A Narrative Review
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
3. Discussion
3.1. Preoperative Neoadjuvant Systemic Therapies
Experimental Arm | Comparison Arm | Patient Population | Phase | Primary Outcome(s) | Safety | Registration | Reference |
---|---|---|---|---|---|---|---|
Cabozantinib plus nivolumab | None | 15 patients with locally advanced/borderline resectable HCC | Ib | Number of adverse events Number of patients who completed preoperative treatment and proceeded to surgery | Grade 3 or higher treatment-related adverse events occurred in 2 patients | NCT03299946 | [14] |
Anti-PD-1 antibody (nivolumab, camrelizumab, pembrolizumab, or sintilimab) plus TKI (lenvatinib or apatinib) | None | 63 patients with unresectable or advanced HCC | Case series | Not applicable | 1 patient died from an immune-related adverse event | Not applicable | [15] |
Anti-PD-1 antibody (pembrolizumab, toripalimab, or sintilimab) plus TKI (lenvatinib or apatinib) | None | 10 patients with Child-Pugh class A and BCLC classification stage C | Case series | Not applicable | No patients experienced grade 3 or 4 treatment-related adverse events | Not applicable | [16] |
Nivolumab plus ipilimumab | None | 32 patients with early-stage, resectable HCC (17 enrolled and available for analysis at time of most recent publication) | Ib | Number of patients with an unplanned delay to surgery Safety and tolerability of nivolumab and ipilimumab | Grade 3 or treatment-related adverse events occurred in 1 patient | NCT03682276 EudraCT Number: 2018–000987-2 | [17] |
Dovitinib | None | 25 patients with early and intermediate-stage, resectable HCC | II | Objective response rate Intratumoral blood flow changes | Grade 3 or 4 treatment-related adverse events occurred in 22 patients | EU-CTR 2011-002445-36 | [19] |
Sorafenib | None | 30 patients with resectable HCC | II | Anti-tumor activity | Not reported | NCT01182272 | [20] |
3.2. Postoperative Adjuvant Systemic Therapies
3.3. Perioperative (Combined Preoperative Neoadjuvant and Postoperative Adjuvant) Systemic Therapies
Experimental Arm | Comparison Arm | Patient Population | Phase | Primary Outcome(s) | Safety | Registration | Reference |
---|---|---|---|---|---|---|---|
Neoadjuvant and adjuvant nivolumab | Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab plus ipilimumab | 30 patients with resectable HCC (27 enrolled) | II | Safety and tolerability of nivolumab with or without ipilimumab | Grade 3 or higher treatment-related adverse effects occurred in 3 (23%) of patients in the nivolumab arm and 6 (43%) patients in the nivolumab plus ipilimumab arm | NCT03222076 | [54] |
Neoadjuvant and adjuvant camrelizumab plus apatinib | None | 18 patients with resectable HCC | II | Major pathologic response (90% or greater tumor necrosis) | Grade 3 or higher treatment-related adverse effects occurred in 3 (16.7%) patients | NCT04297202 | [56] |
Cemepilimab | None | 21 patients with resectable HCC | II | Significant tumor necrosis (>70% or greater tumor necrosis) | Grade 3 or higher treatment-related adverse effects occurred in 7 (33.3%) patients | NCT03916627 | [57] |
4. Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Items | Specification |
---|---|
Date of search | 5 January 2023 |
Databases and other sources searched | PubMed, ClinicalTrials.gov |
Search terms used | Hepatocellular carcinoma, liver cancer, locoregional therapy, chemotherapy, targeted therapy, immunotherapy, randomized trials, controlled trials, phase I, phase II, phase III |
Inclusion and exclusion criteria | Trials were excluded if they were not completed, closed early, or did not report their outcome(s) in the form of a published abstract or manuscript |
Selection process | The authors conducted an independent search |
Experimental Arm | Comparison Arm | Patient Population | Phase | Primary Outcome(s) | Registration | Reference |
---|---|---|---|---|---|---|
Nivolumab plus ipilimumab | None | 40 patients with potential for curative surgical resection | II | Percentage of patients with tumor shrinkage > 10% | NCT03510871 | [21] |
Camrelizumab plus apatinib mesylate plus oxaliplatin | None | 15 participants with locally advanced, potentially resectable disease | II | Major pathological response (>90% tumor necrosis) | NCT04850040 | [22] |
Sorafenib plus capecitabine plus oxaliplatin | None | 15 participants with HCC confined to a single lobe and not suitable for surgery or locoregional therapies | II | Proportion of patients with resectable disease | NCT03578874 | [23] |
Sintilimab plus transarterial chemoembolization | None | 61 patients with BCLC stage A (not transplantable) or stage B (ineligible for resection) | II | Duration from treatment initiation to disease progression in patients who cannot undergo surgery, or to the date of relapse after surgery, or death | NCT04174781 | [24] |
Tislelizumab plus intensity modulated radiation therapy | None | 30 patients with resectable disease and portal vein tumor thrombus | II | Relapse-free survival | NCT04850157 | [24] |
Sorafenib plus laser ablation | Laser ablation | 40 patients with unresectable HCC containing one nodule larger than 4 cm in diameter | II | Complete tumor ablation rate, time-to-recurrence (in complete response group), time-to-progression (in partial response group) | NCT01507064 | [25] |
Atezolizumab plus bevacizumab plus stereotactic beam radiation therapy | None | 20 patients with resectable disease | I | Proportion of patients with grade 3 or 4 treatment-related adverse events | NCT04857684 | [26] |
Anlotinib hydrochloride plus TQB2450 (antibody against PD-L1) | None | 20 patients with resectable disease | Ib | Pathologic complete response rate, overall response rate | NCT04888546 | [27] |
Atezolizumab plus bevacizumab | None | 30 participants with resectable HCC | II | Pathologic complete response rate Safety/tolerability | NCT04721132 | [28] |
Experimental Arm | Comparison Arm | Patient Population | Phase | Primary Outcome | Safety | Registration | Reference |
---|---|---|---|---|---|---|---|
Sorafenib | No adjuvant therapy | 1114 patients with HCC who received curative-intent therapy with either resection or local ablation | III | RFS | Grade 3 or 4 drug-related adverse events occurred in 293 patients in sorafenib group vs. 51 in placebo group | NCT00692770 | [40] |
IFNα-2b | No adjuvant therapy | 150 patients with HCV-driven HCC who underwent resection | III | RFS | 9 (12%) patients in IFNα-2b group experienced toxicity resulting in dose reduction, 6 of whom stopped therapy | NCT00273247 | [41] |
IFNα-2b | No adjuvant therapy | 268 patients with HCV-driven HCC who underwent resection | III | RFS | Grade 3 or 4 adverse events related to fatigue (p = 0.035), leukopenia (p = 0.003), granulocytopenia (p < 0.001), and thrombocytopenia (p = 0.010) occurred in significantly more patients in IFNα-2b group | NCT00149565 | [42] |
Autologous cytokine-induced killer cells | No adjuvant therapy | 230 patients with HCC who received curative-intent therapy with either resection, RFA, or percutaneous ethanol injection | III | RFS | AEs occurred more frequently in the cellular therapy group (62% vs. 41%; p = 0.002) The rate of grade 3 or 4 AEs was comparable between groups (7.8% vs. 3.5%; p = 0.15) | NCT00699816 | [43] |
Experimental Arm | Comparison Arm | Patient Population | Phase | Primary Outcome | Registration | Reference |
---|---|---|---|---|---|---|
Atezolizumab plus bevacizumab | No adjuvant therapy | 668 patients with HCC who have undergone curative resection or ablation | III | RFS | NCT04102098 | [44] |
Durvalumab plus bevacizumab | Durvalumab | 908 patients with HCC who have undergone curative therapy with resection or ablation | III | RFS | NCT03847428 | [46] |
No adjuvant therapy | ||||||
Nivolumab | No adjuvant therapy | 545 patients with HCC who have undergone curative resection or ablation | III | RFS | NCT03383458 | [47] |
Pembrolizumab | No adjuvant therapy | 950 patients with HCC who have undergone curative resection or ablation | III | RFS, OS | NCT03867084 | [48] |
Camrelizumab plus rivoceranib (apatinib) | No adjuvant therapy | 687 patients with HCC who have undergone curative resection or ablation | III | RFS | NCT04639180 | [49] |
Camrelizumab plus rivoceranib (apatinib) | Camrelizumab | 250 patients with HCC who have undergone curative resection or ablation | II | RFS | NCT05367687 | [50] |
Donafenib plus tislelizumab | No adjuvant therapy | 32 patients with HCC who have undergone curative resection | II | 1-year RFS | NCT05545124 | [51] |
Tislelizumab plus sitravatinib | No adjuvant therapy | 40 patients with HCC who have undergone curative resection | II | 2-years RFS | NCT05407519 | [52] |
Donafenib and anti-PD-1 antibody (unspecified) | No adjuvant therapy | 30 patients with HCC who have undergone curative resection | I | 1-year RFS | NCT04418401 | [53] |
Experimental Arm(s) | Comparison Arm | Patient Population | Phase | Primary Outcome | Registration | Reference |
---|---|---|---|---|---|---|
Neoadjuvant tremelimumab plus durvalumab and adjuvant durvalumab | None | 28 patients with resectable HCC | II | Number of greater grade 3 or higher adverse events or immune-related adverse events that lead to treatment cessation | NCT05440864 | [58] |
Neoadjuvant nivolumab followed by electroporation and adjuvant nivolumab | None | 43 patients with resectable HCC | II | Local recurrence-free survival during 1-year follow-up | NCT03630640 | [59] |
Neoadjuvant atezolizumab followed by RFA and adjuvant atezolizumab plus bevacizumab | RFA alone | 202 patients with HCC eligible for ablation | II | Recurrence-free survival | NCT04727307 | [60] |
Neoadjuvant camrelizumab plus apatinib and adjuvant camrelizumab | Adjuvant camrelizumab | 78 patients with resectable HCC | II | 1-year tumor recurrence-free rate | NCT04930315 | [61] |
Neoadjuvant tislelizumab plus lenvatinib and adjuvant tislelizumab plus lenvatinib | N/A | 30 patients with resectable HCC | II | Safety as measured by the number of grade 3 and grade 4 adverse events that occurred when subjects participated in the study, feasibility as measured by rate of enrollment | NCT04834986 | [62] |
Neoadjuvant nivolumab and adjuvant nivolumab | Neoadjuvant nivolumab plus relatlimab and adjuvant nivolumab plus relatlimab | 20 patients with resectable HCC | I | Number of patients who complete neoadjuvant therapy and proceed to surgery | NCT04658147 | [63] |
Neoadjuvant pembrolizumab plus lenvatinib and adjuvant pembrolizumab | Neoadjuvant pembrolizumab or lenvatinib and adjuvant pembrolizumab | 60 patients with resectable HCC | II | Major pathological response rate, defined as the proportion of patients with less than 10% viable tumor | NCT05185739 | [64] |
Neoadjuvant toripalimab and adjuvant toripalimab | Neoadjuvant toripalimab plus lenvatinib and adjuvant toripalimab plus lenvatinib | 40 patients with resectable HCC | Ib/II | Pathological response rate | NCT03867370 | [65] |
Neoadjuvant toripalimab plus lenvatinib and adjuvant toripalimab | ||||||
Neoadjuvant tislelizumab and adjuvant tislelizumab | Neoadjuvant tislelizumab plus lenvatinib and adjuvant tislelizumab plus lenvatinib | 80 patients with resectable HCC | II | Disease-free survival | NCT04615143 | [66] |
Neoadjuvant atezolizumab plus bevacizumab and adjuvant atezolizumab plus bevacizuamb | None | 45 patients with potentially resectable HCC | II | Pathologic complete response rate, distinct immunophenotypes, and dynamic changes of tumor-infiltrating cells | NCT04954339 | [67] |
Neoadjuvant camrelizumab followed by TACE and adjuvant camrelizumab, plus apatinib | TACE | 290 patients with resectable HCC | None | Three-year event free-survival, major pathologic response rate (less than 50% residual tumor) | NCT04521153 | [68] |
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Chamseddine, S.; LaPelusa, M.; Kaseb, A.O. Systemic Neoadjuvant and Adjuvant Therapies in the Management of Hepatocellular Carcinoma—A Narrative Review. Cancers 2023, 15, 3508. https://doi.org/10.3390/cancers15133508
Chamseddine S, LaPelusa M, Kaseb AO. Systemic Neoadjuvant and Adjuvant Therapies in the Management of Hepatocellular Carcinoma—A Narrative Review. Cancers. 2023; 15(13):3508. https://doi.org/10.3390/cancers15133508
Chicago/Turabian StyleChamseddine, Shadi, Michael LaPelusa, and Ahmed Omar Kaseb. 2023. "Systemic Neoadjuvant and Adjuvant Therapies in the Management of Hepatocellular Carcinoma—A Narrative Review" Cancers 15, no. 13: 3508. https://doi.org/10.3390/cancers15133508