Cutaneous Side Effect Manifestations in NSCLC Patients with EGFR Mutation Who Received Gefitinib
This study showed that 10/11 patients experienced cutaneous side effects which confirmed the previous literature, Wang et al. , who revealed that 67.6% of lung carcinoma patients with unknown EGFR mutation status who received gefitinib in Taiwan experienced cutaneous side effects. According to Cohen et al. , the level of EGFR mutation was assumed to be associated with cutaneous side effects, because of the elevated EGFR inhibition in the skin tissue. Some patients were more susceptible to side effects of EGFR inhibition, due to DNA polimorphism of normal cells and carcinoma.
The most common cutaneous side effects findings in this study were xerosis cutis, followed by acneiform eruption, and paronychia (see Figs. 2, 3, 4). According to Roe, xerosis cutis developed in 100% of patients after 6 months consuming the EGFR inhibitor . This might have happened because, in normal conditions, it took 14 days for epidermal cells to reach the stratum corneum , and thus keratinocyte differentiation disorder due to EGFR inhibitor causing xerosis cutis was a late-onset side effect [14, 21].
Acneiform eruption in this study was found in almost every age group and was more common in male patients, as demonstrated by previous studies, due to the outdoor activities that exposed males to ultra violet (UV) light more than females . Ultra violet light exposure resulted in keratinocyte destruction through photoproducts and reactive oxygen species (ROS) formation. Hence, that effect might become worse when EGFR inhibition occurred simultaneously .
Inhibition of EGFR resulted in distortion of skin cell growth, epithelial cells differentiation, and skin protection function , including to UV exposure protection . Moreover, EGFR inhibition led to increased inflamatory chemokin expression which then recruited and resulted in inflammatory cells infiltration, especially in the follicle infundibulum .
Wang et al.  revealed the correlation between xerosis cutis and paronychia, and that xerosis cutis is a risk factor for paronychia, since xerosis cutis induced by the EGFR inhibitor might cause desquamation with subsequent sticking between the nail plate and the neighboring skin, inducing chronic irritation and inflammation . We confirmed this condition in our study that the patients who had paronychia also experienced xerosis cutis (see Fig. 4).
There were no other cutaneous side effects such as hair changes, mucositis, or drug hypersensitivity to gefitinib observed in our patients in this study. Similar results have been published in other studies of gefitinib treatment. Hair disorder has once been reported, by Santiago et al. , with one of seven patients who used erlotinib EGFR inhibitor experiencing hair growth and texture alteration. The hair became thin, brittle or curled. However, none of our participants used erlotinib.
Transepidermal Water Loss Value in NSCLC with EGFR Mutation Who Received Gefitinib
Mean patient TEWL value in this study increased compared to the normal value range 2.26 ± 1.36 g/m2/h, as a consequence of EGFR inhibition that might cause abnormal keratinocyte differentiation resulting in disturbances of the stratum corneum and sebaceous glands leading to the loss of the epidermal water-retaining function . Elevation of TEWL was also reported by Fabbrocini et al.  in 33 carcinoma patients who experienced EGFR inhibitor side effects (16.67 g/m2/h). However, our study differed from Fabroccini’s since we carried out stratification for each patient characteristic group.
Transepidermal water loss value measurement in our study participants (see Table 3) showed a higher value in male patients (11.64 g/m2/h) compared to females (10.68 g/m2/h). This might have resulted from several influencing factors, such as the use of topical products, exposure to chemicals (including frequency of exposure to solvents and detergents/surfactants), and the degree of skin damage which affected patients skin hydration state . Moreover, sweat and sebaceous gland activities were higher in males  and so might have increased the TEWL value . Similar results have been published by Reed et al. , who showed mean TEWL values in male patients of 5.1 ± 0.6 g/m2/h and in female patients of 4.8 ± 0.4 g/m2/h.
Transepidermal water loss value measurements classified by age group in our patients showed the highest value in the 40–44 years age group while the lowest one was in the >65 years age group. This happened because the participant with the highest TEWL value who experienced the most severe form of xerosis cutis was in the 40–44 years age group, while the one participant who did not experience skin disorder was included in the >65 years age group. This condition had an impact on the participants’ mean TEWL value in those age groups.
Classified by gefitinib consumption interval, the lowest TEWL value was found in patients using gefitinib for less than a month and the highest in the 5–6 months interval (see Table 3). As mentioned before, the only patient who had been using gefitinib for <1 month had not experienced any cutaneous effects which might also affect the TEWL value. On the other hand, one of two patients who has been on gefitinib therapy for 5–6 months experienced the most cutaneous side effects and had the highest TEWL value.
The limited number of samples in our study might not fully reflect the real population distribution of cutaneous side effects due to gefitinib treatment. Future studies should be conducted with longer observation times and records of both TEWL value measurements and cutaneous side effects from examinations in the pre- and post-gefitinib therapy period to provide better descriptions of EGFR inhibitior-induced cutaneous side effects.