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Hepatocellular carcinoma (HCC) is a relevant cause of cancer-related mortality worldwide. Around half of HCC patients will receive systemic therapies during their life span. The pivotal positive sorafenib trial and regulatory approval in 2007 was followed by a decade of negative studies with drugs leading to marginal anti-tumoral efficacy, toxicity, or trials with lack of enrichment strategies. This trend has changed during the period 2016-18, when several compounds such as lenvatinib (in first line) and regorafenib, cabozantinib, ramucirumab and nivolumab (in second-line) showed clinical benefit. These successes came at a cost of increasing the complexity of decision-making, and ultimately, impacting the design of future clinical trials. Nowadays, life expectancy with single active agents has surpassed the threshold of 1 year and the field is facing encouraging outcomes ∼2 years with sequential strategies. Overall survival (OS) remains as the main endpoint in phase III investigations, but as in other solid tumors, there is a clear need to define surrogate endpoints that both reliably recapitulate survival benefits and can be assessed prior additional efficacious drugs are administered. A thorough analysis of 21 phase III trials published in advanced HCC demonstrated a moderate correlation between progression-free survival (PFS) or time to progression (TTP) with OS (R=0.84 and R=0.83, respectively). Nonetheless, significant differences in PFS were only followed by differences in survival in 3 out of 7 phase III studies. In these later cases, the magnitude of benefit for PFS was HR ≤ 0.6, and thus this threshold is herein proposed as a potential surrogate endpoint of OS in advanced HCC. Conversely, PFS with a HR between 0.6-0.7, despite significant, was not associated with better survival, and thus these magnitudes are considered uncertain surrogates. In the current review, we discuss the reasons for positive or negative phase III trials in advanced HCC, and the strengths and limitations of clinical surrogate endpoints (PFS, TTP and objective response rate [ORR]) to predict survival.
This article was published in the following journal.
Name: Journal of hepatology
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Works about a study where participants are assigned to a treatment, procedure, or intervention by methods that are not random. Non-randomized clinical trials are sometimes referred to as quasi-experimental clinical trials or non-equivalent control group designs.
Works about randomized clinical trials that compare interventions in clinical settings and which look at a range of effectiveness outcomes and impacts.
Clinical trials that involve at least one test treatment and one control treatment, concurrent enrollment and follow-up of the test- and control-treated groups, and in which the treatments to be administered are selected by a random process, such as the use of a random-numbers table.
Clinical trials involving one or more test treatments, at least one control treatment, specified outcome measures for evaluating the studied intervention, and a bias-free method for assigning patients to the test treatment. The treatment may be drugs, devices, or procedures studied for diagnostic, therapeutic, or prophylactic effectiveness. Control measures include placebos, active medicines, no-treatment, dosage forms and regimens, historical comparisons, etc. When randomization using mathematical techniques, such as the use of a random numbers table, is employed to assign patients to test or control treatments, the trials are characterized as RANDOMIZED CONTROLLED TRIALS AS TOPIC.
Strategy for the analysis of RANDOMIZED CONTROLLED TRIALS AS TOPIC that compares patients in the groups to which they were originally randomly assigned.
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