Table 4.
Consensus recommendations on trial design for early-stage HCC
| Recommendation | Level of agreement |
|---|---|
| Target population | |
| Trials evaluating neoadjuvant or adjuvant strategies in early-stage HCC should include patients at high risk of recurrence after curative-intent treatment | Strong consensus (~95%) |
| In adjuvant trials, target population should include both candidates for resection and candidates for local ablation, and stratify for treatment prior to randomization | Majority agreement (64%) |
| Risk factors for poor outcome in the neoadjuvant-adjuvant setting are defined by the presence of any established clinical or pathological factor leading to recurrence: 1. Multifocality 2. Pathological findings (any of the following: microvascular invasion, satellitosis, poor differentiation degree)a 3. Preoperative AFP >400ng/ml 4. Tumour size >5cm |
1. Strong consensus (~95%) 2. Strong consensus (~95%) 3. Consensus (88%) 4. Majority agreement (70%) |
| Regarding pathological variables, although poor differentiation degree can be diagnosed with preoperative tumour biopsy, microvascular invasion and satellites require a surgical specimen; thus, these latter variables are appropriate for risk stratification in adjuvant trials | Strong consensus (~95%) |
| Risk status for neoadjuvant-adjuvant trials is defined as follows: high-risk status can be defined by the presence of at least two risk factors, whereas intermediate risk is established by one risk factor leading to recurrence | Majority agreement (52%) |
| It is recommended that a baseline tumour biopsy be obtained in neoadjuvant studies | Strong consensus (~95%) |
| In neoadjuvant trials, the recommended time span between randomization and surgery is ≤3 months | Strong consensus (100%) |
| End points | |
| RFS remains the primary end point recommended for adjuvant phase III trials in early-stage HCC | Consensus (88%) |
| EFS, defined as time from randomization to disease progression or toxicity precluding surgery, recurrence or death, is the primary end point recommended in neoadjuvant (plus adjuvant) phase III trials | Consensus (76%) |
| pCR or MPR are emerging as potential surrogate end points in neoadjuvant trials and should be prospectively validated for correlation with long-term survival outcomes | Strong consensus (100%) |
| OS may be considered and reported as secondary end point in adjuvant-neoadjuvant studies, although long survival after recurrence and treatment crossover can be confounding factors | Majority agreement (71%) |
| pCR, MPR and/or ORR are recommended as primary end points for phase II trials in the neoadjuvant setting; overall EFS or RFS are considered as key secondary end points | Consensus (82%) |
| A major pathological response is defined as ≥70–90%a tumour necrosis on histology (including quantification of viable tumour cells and the extent of necrosis); detailed pathological analyses are essential to accurately assess therapeutic efficacy, and should inform primary end points | Majority agreement (53%) |
| Radiological assessments using mRECIST and RECIST 1.1 should be used in neoadjuvant trials | Consensus (82%) |
| Early phase I trials should focus on safety and preliminary efficacy (assessed by ORR), and integrating biomarker analyses to clarify mechanisms and identify predictive markers | Strong consensus (100%) |
| In phase III neoadjuvant-adjuvant trials safety and toxicity should be a secondary end point | Strong consensus (100%) |
| Stopping rules at interim analysis in neoadjuvant and adjuvant trials require assessment of NPHs; in cases of NPHs, the measurement of clinical benefit in the primary end point (typically EFS or RFS) should be based on MaxCombo testing, and the magnitude of effect should be described by RMST at prespecified time horizons of 12, 24 and 36 months | Consensus (88%) |
| Interim analysis showing NPH require mature data to declare a positive trial; mature data are defined as data obtained either during double the follow-up of the control arm’s expected median time to the primary end point or from >60% of all randomized participants | Consensus (88%) |
| Stratification factors | |
| Stratification by prognostic factors is essential to ensure balanced risk profiles and enhance trial interpretability; a maximum of four factors — depending on the size of the study — is recommended, from amongst those risk factors voted in the Target population section, and type of therapy | Strong consensus (~95%) |
| Control arm | |
| Control arms in neoadjuvant and adjuvant trials should consist of current standards of care, such as active surveillance after curative resection or ablation, with clearly defined crossover conditions upon recurrence, when applicable | Strong consensus (~95%) |
| Surveillance protocols after resection or ablation in clinical trials should include contrast-enhanced CT or MRI and serum AFP measurements every 3 months for the first 2 years, then every 6 months for an additional 3 years | Strong consensus (~95%) |
| Surveillance protocols after resection or ablation in clinical trials should include chest imaging measurements every 6 months for 3 years | Majority agreement (65%) |
| Overall benefit assessment and regulatory issues | |
| Clinically meaningful outcomes from neoadjuvant and adjuvant trials require comprehensive interpretation that integrates efficacy (RFS or EFS, pathological response) with safety profiles, patient quality of life, the incidence and management of adverse events and trend in OS, thereby facilitating informed clinical decision-making and regulatory considerations | Consensus (88%) |
| In the neoadjuvant or adjuvant setting, treatment-related adverse events of grade 3 or 4 should be carefully considered when assessing the clinical benefit of a given regimen, although no threshold of grade 3 or 4 TRAEs should be pre-established | Majority agreement (71%) |
AFP, α-fetoprotein; EFS, event-free survival; HCC, hepatocellular carcinoma; MPR, major pathological response; mRECIST, modified RECIST; NPH, non-proportional hazard; ORR, objective response rate; OS, overall survival; pCR, pathological complete response; RECIST, Response Evaluation Criteria in Solid Tumors; RFS, recurrence-free survival; RMST, restricted mean survival time; TRAE, treatment-related adverse event.
a
If available.