LAUSR

Traditional phase 1 trials for the development of cytotoxic agents are conducted in order to identify the ideal dose for later phase trials, where the maximum tolerated dose (MTD) is a critical component. The MTD is defined as the prespecified proportion of patients (e.g., 0.2 or 0.33) who present dose-limiting toxicity, usually corresponding to grade 3 or higher adverse reactions to the investigational agents (Fig. 1). Generally, the dose is escalated step by step, and a recommended dose for the next phase trial is set 1 step lower than the MTD [1]. This concept is based on the assumption that the higher the dose is the greater the antitumor effect is. It is also assumed that cancer cells are more susceptible to cytotoxic agents than are noncancerous cells due to the significant difference in replication frequency between the two. However, the assumption does not necessarily hold true in the era of molecularly targeted agents (MTA). Although a dose-response relationship also exists for MTA [2], the relationship is more complicated than that of cytotoxic drugs. For example, gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, inhibits cell growth in lung cancer cell lines carrying mutant EGFR in a dose-response fashion. However, this relationship was not observed in cell lines carrying wild-type EGFR [3]. Since the effect of MTA is highly specific to the structure of the target molecule, a small change in the structure results in total ineffectiveness. The relationship between dosage and toxicity is also more complicated in MTA in which some disabling AE may occur in later cycles, and a majority of patients experience dose reduction despite not presenting dose-limiting toxicity [4]. This difficulty in dose-ranging studies for MTA resulted in dose modifications in later phase trials. In addition to a larger diversity in the profile and onset period of AE compared to cytotoxic agents, investigators who engage in the development of MTA for hepatocellular carcinoma (HCC) also have to take into account impaired liver function. In this issue of Liver Cancer, Maruta et al. [5] explored the efficacy of lenvatinib for advanced HCC patients beyond the inclusion criteria of the phase-3 clinical trial using realReceived: March 26, 2020 Accepted: April 24, 2020 Published online: June 3, 2020