Determining the recommended dose of traditional cytotoxic antitumor agents usually occurs at or near their maximum-tolerated dose (1–3). The recommended dose for epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is established at an optimal biological dose, which minimizes the risk of adverse events (AEs) without compromising efficacy (4–6). However, previous dose-finding studies did not factor in body size or body surface area (BSA). A significant portion of EGFR-mutated patients are female and the majority may have low BSA (7–9). Therefore, these patients may require a dose reduction in daily clinical practice due to AEs or low BSA. However, limited information is available regarding the association between low BSA and TKI dose reduction and efficacy (10,11). Furthermore, the efficacy of TKIs has not been elucidated in patients undergoing a dose reduction due to severe AEs. In the present study, the efficacy of TKIs was evaluated in patients undergoing a dose reduction due to AEs and in those with a low BSA in clinical practice.

A fixed dose of EGFR-TKIs achieved a significant improvement in PFS with acceptable AE profiles in previous clinical trials (14,15). The first-choice treatments for advanced NSCLC patients with EGFR mutation include gefitinib, erlotinib or afatinib (14,15). However, TKI efficacy in the clinical setting, particularly in patients undergoing a dose reduction due to toxicity or low BSA, remains to be elucidated. Whether a strictly fixed dose of TKIs, as determined by dose-finding studies, would exhibit the same efficacy in patients undergoing a dose reduction as in those without also remains to be elucidated. Therefore, the RR, DCR, PFS and OS in patients with and those without a dose reduction of TKIs were determined in our previous study (11). However, the study included heterogeneity in the EGFR mutation status, TKIs used, and second or later line of TKI treatment. To eliminate the effect on the results of unknown factors associated with them, the present study was performed using a database of patients treated with first-line erlotinib. Dose reduction of erlotinib for the reason of low BSA and poor PS occurred in 14 (63.6%) of the patients: 6 (27.3%) had initial dose reduction, 6 (27.3%) had dose reduction in their clinical courses, and 2 (9.1%) exhibited both. In previous studies assessing TKI treatments, either in clinical trials or clinical practice, the population of female patients with NSCLC was higher compared to that in the general population (7–9,16). The present study identified no disadvantage regarding TTF from a dose reduction in patients receiving first-line erlotinib, even when considering BSA. Although these findings were obtained from a small number of patients in a retrospective study, no definitive conclusions could be drawn on how dose reduction would affect patients with AEs and those with low BSA. Therefore, these results be should be interpreted carefully, rather than overlooking them as anecdotal findings. The most appropriate dosage of erlotinib for such patients should possibly be recalculated, in order to obtain maximum efficacy with an acceptable toxicity profile.

To the best of our knowledge, only two previous studies have evaluated the effect of BSA on the efficacy of TKIs; the study by Ichihara et al (10) and our previous study (11). The former study investigated the potential effect of BSA on the PFS and OS of patients with advanced EGFR-mutated NSCLC who were treated with gefitinib (10) and identified that BSA affected the outcome of gefitinib therapy, with a higher BSA being associated with worse PFS (10). The main focus of the study by Ichihara et al (10) was treatment efficacy in patients with a high BSA. By contrast, the present study aimed to assess the effects of dose reduction in patients with AEs, as well as in patients with a low BSA. The PFS of patients with low BSA with treatment interruption or reduced dose was either equal to or superior to that of all low-BSA patients (10), consistent with our previous study (11) and the present results. Ichihara et al (10) hypothesized that dose reduction in patients due to AEs may be those with relatively high blood concentrations of the agent, due to factors including drug metabolism. This hypothesis requires confirmation in future studies.

The effect of BSA on OS was also investigated. There was no association between OS and BSA in the study by Ichihara et al (10). In our previous study, there was no apparent difference in OS between patients with BSA <1.5 m² and those >1.5 m² receiving treatment with either gefitinib or erlotinib (11). The OS in patients without dose reduction appeared to be longer compared to patients with dose reduction, with no statistical significance (11). Ichihara et al (10) suggested that this was possibly the effect of preceding and/or subsequent therapies on OS, and >70% of the patients received chemotherapy following disease progression post-gefitinib monotherapy, therefore, post-progression therapy may have hindered any difference in PFS between the high- and low-BSA subgroups. Further cytotoxic antitumor chemotherapy was not indicated in the majority of the low-BSA patients, as observed in our previous study, which may also be an explanation (11). In the present study, taking BSA into consideration, there was no significant disadvantage in the ID level and LTD level for patients with low BSA. These results suggested that the degree of dose reduction conducted in daily practice for low BSA, poor PS and severe AEs has little influence on the survival rate.

There are certain limiting factors for the analysis of the present data set: Small sample size, retrospective design, reasons for dose reduction, and exclusion of patients with discontinuation of erlotinib without any dose reduction. Another major limitation was that pharmacokinetic data were not included in this analysis. Whether BSA differences cause inter-patient pharmacokinetic variability, resulting in the observed difference in TTF remains to be elucidated, possibly by a pharmacokinetics-pharmacodynamics study. The blood concentration of cytotoxic agents is closely associated with their efficacy (17–19), and similarly, the blood concentration of TKIs appears to be associated with their efficacy (20,21).

The present results suggested that dose reduction of erlotinib with ID/BSA >80 mg/m², and LTD/BSA >50 mg/m² may not be associated with survival disadvantage. Dose-reduction estimation studies for TKIs may be crucial, particularly for low-BSA patients. Heterogeneity in these factors, such as low BSA, poor PS and severe AEs, should be taken into consideration. Prospective studies, followed by confirmation in retrospective ones, which investigate the incidence of dose reduction in patients with AEs and those with low BSA may be important for common clinical practice. This approach may further elucidate the clinical meaning of TKI dose reduction in such patients.