Comparative Analysis of Prevention versus Non-Prevention for Skin Toxicities on Clinical Outcomes in Non- Small Cell Lung Cancer (NSCLC) Patients Treated with Erlotinib: A 10-year Retrospective Cohort Study

Comparative Analysis of Prevention versus Non-Prevention for Skin Toxicities on Clinical Outcomes in Non- Small Cell Lung Cancer (NSCLC) Patients Treated with Erlotinib: A 10-year Retrospective Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparative Analysis of Prevention versus Non-Prevention for Skin Toxicities on Clinical Outcomes in Non- Small Cell Lung Cancer (NSCLC) Patients Treated with Erlotinib: A 10-year Retrospective Cohort Study Tanavij Pannoi, Chonnikarn Sunphakorn, Nattakan Detkaew, Parames Chernghom, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8138030/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: Erlotinib is an established first-line therapy for Epidermal Growth Factor Receptor ( EGFR ) mutant non-small cell lung cancer (NSCLC). However, dermatologic toxicities are common and lead to treatment interruption and reduced adherence. Evidence regarding the impact of prophylactic skin toxicity management on clinical effectiveness remains limited. Aim To compare the incidence and severity of skin toxicities, treatment modifications, and clinical outcomes between NSCLC patients receiving prophylactic skin toxicity and those without prophylactic during erlotinib therapy. Methods A retrospective cohort study was conducted among EGFR -mutant NSCLC patients treated with erlotinib at Surat Thani Hospital from 2015 to 2025. Patients were categorized into prevention and non-prevention groups based on receipt of prophylactic interventions. Associations with toxicity severity, objective response rate (ORR), and treatment discontinuation were evaluated using Chi-square tests, and multivariate logistic regression was performed to adjust for confounders. Propensity score matching (PSM) was applied for progression-free survival (PFS) and time to first skin toxicity. Kaplan–Meier estimates and log-rank tests were used for time-to-event analyses. Results A total of 265 patients were included. Severe toxicity was significantly lower in the prevention group (6.1% vs 25.0%, p = 0.011). Temporary and permanent erlotinib discontinuation were significantly lower in the prevention group (3.1% vs 42.9% and 48.2% vs 67.1%, p < 0.001 and p = 0.009, respectively). ORR was higher in the prevention group (63.1% vs 40.0%, p = 0.002). After PSM, PFS remained significantly longer in the prevention group (p = 0.00032), whereas time to first skin toxicity did not differ. Conclusion Prophylactic skin toxicity management reduces severe dermatologic events, decreases treatment interruption, improves ORR, and prolongs PFS without affecting rash onset. These findings support integrating structured prophylactic skin toxicity into routine erlotinib treatment. Erlotinib EGFR mutation Non-small cell lung cancer Skin toxicity Prophylactic management Dermatologic adverse events Figures Figure 1 Figure 2 Impact statements Prophylactic skin toxicity management reduced the severity of erlotinib-induced dermatologic adverse events, supporting the early identification and management of patients at risk of severe toxicity. Implementing preventive strategies minimized inappropriate erlotinib interruptions, thereby maintaining treatment continuity and contributing to improved objective response rates and progression-free survival. Clinically appropriate, proactive dermatologic care may enhance treatment adherence and overall therapeutic outcomes in patients with EGFR -mutant NSCLC receiving erlotinib. Introduction Lung cancer remains one of the leading causes of cancer-related mortality worldwide, accounting for approximately 18.7% of all cancer deaths and representing the highest mortality burden among all malignancies [ 1 ]. Non-small cell lung cancer (NSCLC) comprises 80–85% of lung cancer cases, whereas small cell lung cancer (SCLC) accounts for the remaining 15–20% [ 2 ]. According to the National Comprehensive Cancer Network (NCCN) Guidelines 2024, treatment strategies for NSCLC are stage-dependent. In early to locally advanced disease (stages 1A–3B), surgical resection remains the cornerstone of therapy, often complemented by adjuvant treatment for patients at high risk of recurrence. In contrast, the management of advanced-stage disease (stage 4) relies heavily on molecular profiling, including assessment of actionable genomic alterations such as Epidermal Growth Factor Receptor ( EGFR ) mutations, Anaplastic Lymphoma Kinase ( ALK ) rearrangements, and Programmed Death-Ligand 1 (PD-L1) expression [ 3 ]. Among these biomarkers, EGFR mutations, particularly exon 19 deletions and exon 21 L858R substitutions, are well-established predictors of response to EGFR tyrosine kinase inhibitors (TKIs). First-generation EGFR TKIs, such as erlotinib, have long been used as standard first-line therapy for patients with EGFR -mutant NSCLC [ 4 ]. In Thailand, erlotinib is included in the National List of Essential Medicines (NLEM) under category E(2), designating its use as initial treatment for advanced or metastatic NSCLC with confirmed EGFR mutation positivity [ 5 ]. This inclusion has substantially improved patient access to targeted therapy, particularly within the Universal Health Coverage Scheme (UC). Despite its clinical benefits, erlotinib is associated with notable adverse effects, particularly dermatologic toxicities, occurring in approximately 75–90% of patients. Severe dermatologic toxicities (grades 3–4) occur in about 10–20% of cases and have been shown to correlate with enhanced clinical outcomes. Studies suggest that the occurrence and severity of toxicity may serve as potential indicators of treatment efficacy, supporting the administration of erlotinib at the maximal tolerated dose [ 6 ]. For instance, patients experiencing non-severe dermatologic toxicities (grades 1–2) have shown significantly longer median overall survival (OS) than those without toxicity [ 7 ]. However, severe dermatologic toxicities can negatively impact patients’ quality of life (QoL) and may necessitate dose reductions, temporary discontinuation, or permanent discontinuation [ 8 , 9 ]. Studies report that up to 53% of patients with severe toxicities experience social avoidance, which further contributes to treatment non-adherence [ 9 ]. Additionally, severe toxicities are associated with an increased risk of disease flare following treatment discontinuation. Disease flare, characterized by rapid tumor progression after cessation of EGFR TKI therapy, has been observed in approximately 23% of patients, with a median time to flare of 8 days [ 10 ]. These findings highlight the critical need for strategies that not only manage but also prevent severe dermatologic toxicities, ensuring optimal treatment adherence and outcomes. Prevention strategies, including the preventive use of oral antibiotics, topical corticosteroids, and topical moisturizers, have been recommended to reduce the severity and incidence of EGFR TKI-induced skin toxicities [ 11 ]. Oral antihistamines are commonly used to reduce pruritus associated with EGFR-TKI-induced rashes and may also reduce rash severity when used preventively [ 12 , 13 ]. Although evidence for their preventive efficacy is limited, some studies suggest that early initiation of oral antihistamines could reduce rash progression [ 14 ]. However, further clinical trials are needed to confirm their role in rash prevention [ 15 ]. These interventions target the underlying pathophysiological mechanisms of skin toxicities, such as follicular inflammation, bacterial superinfection, and epidermal barrier dysfunction [ 16 ]. Previous studies have shown that prevention approaches can significantly reduce the severity of skin toxicities, thereby improving quality of life and supporting sustained treatment adherence [ 17 ]. However, evidence regarding the impact of preventive strategies on long-term clinical outcomes, such as survival, remains limited. Previous studies demonstrated that patients who received preemptive treatment for skin toxicity had a lower incidence of grade ≥ 2 rash, fewer panitumumab dose interruptions, and improved quality of life [ 18 ]. Nevertheless, clinical outcome data on the prevention of skin toxicities in patients receiving erlotinib remain limited. Aim This study aims to investigate the incidence and severity of dermatologic toxicities in NSCLC patients treated with erlotinib and to compare the clinical outcomes between those receiving prevention strategies for skin toxicity and those non prevention. The primary objectives are to assess the incidence and severity of skin toxicities. Secondary objectives include analyzing the impact of skin toxicity prevention on erlotinib objective response rate (ORR), erlotinib dose modifications, progression-free survival (PFS), and time to skin toxicity. Methods Study Design This retrospective cohort study evaluated the impact of skin toxicity prevention among NSCLC patients harbouring EGFR mutations who received erlotinib monotherapy at Surat Thani Hospital between May 1, 2015, and March 15, 2025. Eligible patients were adults (≥ 18 years) with a confirmed diagnosis of advanced-stage (stage IV) or recurrent NSCLC who received erlotinib therapy. Inclusion required documented EGFR mutation status and sufficient clinical records for assessing treatment outcomes and skin-related adverse events. Patients were excluded if they had a history of skin toxicity before initiating erlotinib, had previously received other EGFR-TKIs (e.g., gefitinib, afatinib, osimertinib) or anti-EGFR monoclonal antibodies (e.g., cetuximab, panitumumab), or if clinical data on treatment outcomes and adverse events were incomplete. Patients were categorized into a prevention group and a non-prevention group based on whether they received prophylactic interventions to mitigate skin toxicity before or at the initiation of erlotinib. Prophylactic measures included oral antihistamines, oral antibiotics, topical antibiotics, topical corticosteroids, and topical moisturizers, used either alone or in combination. Data Collection Data were extracted from electronic medical records and included baseline demographics [age, sex, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status (PS), and smoking history], cancer characteristics (disease stage, EGFR mutation subtype, line of treatment), and treatment-related variables (initial erlotinib dose, treatment duration, temporary and permanent discontinuation, concurrent medications, and concomitant interventions). Study Outcome Skin toxicity was defined as any dermatologic adverse event occurring during erlotinib therapy, including acneiform rash, xerosis, pruritus, paronychia, exfoliative dermatitis, maculopapular rash, or hand–foot syndrome. Adverse events were assessed and graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Toxicities were categorized as non-severe (grade 1–2) or severe (grade 3–5) based on their clinical impact. Treatment response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete and partial responses were defined as objective responses, whereas stable disease and progressive disease were classified as non-responders. Progression-free survival (PFS) was defined as the interval from the initiation of erlotinib therapy to radiologically confirmed disease progression or death from any cause. The primary outcomes were the incidence and severity of skin toxicity. Secondary outcomes included the objective response rate (ORR), the frequency of temporary and permanent discontinuation of erlotinib due to skin toxicity, progression-free survival, and time to skin toxicity. Statistical Analysis All statistical analyses were performed using SPSS version 23.0 (IBM Corp., Armonk, NY, USA) and R software version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria). Baseline characteristics were summarised using frequencies and percentages for categorical variables and means with standard deviations (SD) or medians with interquartile ranges (IQR) for continuous variables. Group comparisons were conducted using the Chi-square test for categorical variables and the independent t-test or Mann–Whitney U test for continuous variables, based on distributional assumptions. Associations between skin toxicity prevention and categorical outcomes—including overall skin toxicity, toxicity severity, treatment discontinuation, and objective response rate (ORR)—were analysed using Chi-square tests. Multivariate logistic regression was employed to adjust for sex, age, BMI, ECOG performance status, smoking status, staging, EGFR mutation, and line of treatment. Odd ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of the associations between skin toxicity prevention and the study outcomes. Propensity score matching (PSM) was applied for time-to-event outcomes, specifically progression-free survival (PFS) and time to first skin toxicity. PSM was performed in R using the MatchIt package. Propensity scores were estimated using logistic regression based on prespecified covariates (age, sex, ECOG performance status, smoking history, EGFR type, and lines of treatment). Nearest-neighbor matching without replacement was performed using a 0.001 caliper to ensure close matches and limit residual bias. Covariate balance before and after matching was assessed using standardized mean differences (SMD). After matching, time-to-event analyses were performed using the Kaplan–Meier method. Between-group differences in PFS were assessed using the log-rank test, with 95% confidence intervals for survival estimates calculated using the Greenwood method. Time to first skin toxicity was evaluated using Kaplan–Meier curves with predefined follow-up windows (≤ 6 months, ≤ 1 year, ≤ 5 years). Log-rank tests were used to compare the prevention and non-prevention groups for each time interval. Censoring was indicated by tick marks in all survival plots. All statistical tests were two-sided, and p-values < 0.05 were considered statistically significant. The required sample size was estimated using two approaches. First, a Z-test for two independent proportions was applied using rash incidence rates reported for EGFR-TKI therapy [ 19 ]. A previous study reported skin rash incidences of 84.4% in the minocycline prophylaxis group (32 patients) and 57.5% in the control group (106 patients) [ 20 ]. Based on these proportions, a minimum of 28 and 85 participants per group was required to achieve 80% power with a two-sided α of 0.05, yielding a total sample size of 113 patients. Second, sample size estimation for progression-free survival (PFS) was performed using Schoenfeld’s method for survival analysis [ 21 ]. A previous study reported a median PFS of 714 days (95% CI 411–1247) in the minocycline group and 420 days (95% CI 343–626) in the control group, corresponding to a hazard ratio (HR) of 0.44 (95% CI 0.27–0.73; p = 0.0014) [ 20 ]. Using a two-sided log-rank test with α = 0.05 and 80% power, the required sample size was estimated at 48 patients per group, for a total of 96 participants. Ethics approval This study was approved by the Surat Thani Hospital Human Research Ethics Committee (REC 67–0112). Result Baseline Characteristics A total of 265 patients with NSCLC were included, with 195 in the prevention group and 70 in the non-prevention group. The median follow-up duration was 15.0 months (IQR 8.0 to 33.0). Sex distribution, age, BMI, smoking status, disease stage, EGFR mutation subtype, and treatment line were comparable between groups (all p > 0.05). However, ECOG performance status (ECOG PS) differed significantly (p = 0.026): in the prevention group, 56.9% had ECOG PS 1, 37.9% had PS 2, and 4.1% had PS 3, whereas in the non-prevention group, 47.1% had PS 1, 35.7% had PS 2, 12.9% had PS 3, and 1.4% had PS 4 (Table 1 ). Table 1 Baseline characteristics of the patients enrolled in the study. Before Matching (N = 265) After Matching (N = 96) Parameter Skin toxicity prevention N (%) Skin toxicity non-prevention N (%) Skin toxicity prevention N (%) Skin toxicity non-prevention N (%) Standardized Mean Difference (SMD) Number of patients 195 (73.6) 70 (26.4) 48(50.0) 48(50.0) Sex < 0.001 Male 73 (37.4) 28 (40.0) 15 (31.2) 15 (31.2) Female 122 (62.6) 42 (60.0) 33(68.8) 33(68.8) Age (years) (Mean ± SD) 65.6 ± 11.3 66.8 ± 12.3 65.52 ± 11.6 67.06 ± 12.4 0.128 BMI (kg/m 2 ) (Mean ± SD) 21.5 ± 5.1 21.1 ± 5.1 22.06 ± 7.7 21.45 ± 5.2 0.094 ECOG PS 0.208 0 2 (1.0) 2 (2.9) 0 (0.0) 1 (2.1) 1 111 (56.9) 33 (47.1) 26 (54.2) 26 (54.2) 2 74 (37.9) 25 (35.7) 20 (41.7) 19 (39.6) 3 8 (4.1) 9 (12.9) 2 (4.2) 2 (4.2) 4 0 (0) 1 (1.4) 0 (0.0) 0 (0.0) Smoking status 0.112 Non-smoker 99 (50.8) 34 (48.6) 26 (54.2) 28 (58.3) Current smoker 4 (2.1) 4 (5.7) 1 (2.1) 1 (2.1) Ex-smoker 7 (3.6) 4 (5.7) 3 (6.2) 2 (4.2) Second-hand smoker 4 (2.1) 0 (0) 0 (0.0) 0 (0.0) Unknown 81 (41.5) 28 (40.0) 18 (37.5) 17 (35.4) Staging < 0.001 III 7 (3.6) 3 (4.3) 1 (2.1) 1 (2.1) IV 188 (96.4) 67 (95.7) 47 (97.9) 47 (97.9) EGFR mutation subtype 0.090 Exon 19 deletion 120 (61.5) 44 (62.9) 32 (66.67) 34 (70.8) Exon 21 L858R 72 (36.9) 23 (32.9) 16 (33.3) 14 (29.2) Exon 21 L861Q 1 (0.5) 2 (2.9) 0 (0.0) 0 (0.0) Exon 18 G719x 2 (1.0) 1 (1.4) 0 (0.0) 0 (0.0) Line of treatment 0.129 First line 169 (86.7) 53 (75.7) 39 (81.2) 39 (81.2) Second line 22 (11.3) 13 (18.6) 7 (14.6) 8 (16.7) Third line 4 (2.1) 4 (5.7) 2 (4.2) 1 (2.1) BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group performance status; SD, standard deviation; SMD, standardized mean difference; N, number of patients. All patients received erlotinib 150 mg once daily. No CYP3A4 or CYP1A2 inhibitors or inducers were used during treatment. Liver and renal function remained stable, with no parameters requiring dose adjustment. Serum creatinine values did not exceed 1.5 times the upper limit of normal, and ALT and AST levels remained below three times the upper limit of normal. Incidence and Severity of Skin Toxicity The overall incidence of skin toxicity was comparable between the two groups: 115 patients (59.0%) in the prevention group and 36 patients (51.4%) in the non-prevention group (p = 0.325). Among the 151 patients who developed skin toxicity, the distribution of toxicity grades differed significantly (p = 0.003): grade 1 occurred in 66.1% vs 58.3%, grade 2 in 27.8% vs 16.7%, and grade 3 in 6.1% vs 25.0% in the prevention and non-prevention groups, respectively (Table 2 ). When the results were grouped by severity, non-severe toxicity (grades 1–2) was more frequent in the prevention group (93.9% vs 75.0%), whereas severe toxicity (grade 3) was less common (6.1% vs 25.0%, p = 0.003). Severe toxicity also remained significantly lower in the prevention group compared with the non-prevention group after multivariate analysis (OR 0.22, 95% CI 0.07 to 0.71, p = 0.011). Table 2 Incidence of skin toxicities and erlotinib dose adjustment in the prevention and non-prevention groups. (N = 265) Parameter Prevention N (%) Non –prevention N (%) P value ± No skin toxicity 80 (41.0) 34 (48.6) 0.325 Skin toxicity 115 (59.0) 36 (51.4) • Grade 1 76 (66.1) 21 (58.3) 0.003* • Grade 2 32 (27.8) 6 (16.7) • Grade 3 7 (6.1) 9 (25.0) Response 123 (63.1) 28 (40.0) 0.001* Non-response 72 (36.9) 42 (60.0) Temporary discontinuation 6 (3.1) 30 (42.9) < 0.001* Permanent discontinuation 94 (48.2) 47 (67.1) 0.005* N, number of patients; ±, Chi-square test; *, Statistically significant. Erlotinib Dose Modification and Objective Response Rate Both temporary and permanent erlotinib discontinuation were significantly lower in the prevention group (3.1% vs 42.9%, p < 0.001; and 48.2% vs 67.1%, p = 0.005, respectively) (Table 2 ). After multivariate analysis, the prevention group also had significantly lower rates of temporary and permanent discontinuation compared with the non-prevention group (OR 0.04, 95% CI 0.01 to 0.10, p < 0.001; and OR 0.44, 95% CI 0.23 to 0.82, p = 0.009, respectively). Among patients who developed skin toxicity (N = 151), temporary and permanent discontinuation also remained significantly lower in the prevention group (5.2% vs 47.2%, p < 0.001, and 47.0% vs 66.7, p = 0.030, respectively), with both outcomes remaining statistically significant in the multivariate analysis (OR 0.04, 95% CI 0.01 to 0.14, p < 0.001; and OR 0.36, 95% CI 0.15 to 0.84, p = 0.018, respectively). The erlotinib objective response rate (ORR) was significantly higher in the prevention group, with 123 patients (63.1%) achieving a treatment response compared with 28 patients (40.0%) in the non-prevention group (p = 0.001). This association also remained statistically significant after multivariate analysis (OR 2.62, 95% CI 1.41 to 4.87, p = 0.002) (Table 2 ). Comparison of Prevention Regimens Patients receiving prophylactic interventions were categorized into oral antihistamine, topical agent, and combination regimen groups. The incidence of skin toxicity, toxicity grade, toxicity severity, temporary discontinuation rate, permanent discontinuation rate, and ORR did not differ significantly among these prevention strategies (Table 3 ). Table 3 Association between skin toxicity prevention regimen and skin toxicity outcomes Category All grade skin toxicity (N = 265) P value ± Skin toxicity No skin toxicity Prevention regimen Oral antihistamine alone 72 (62.6) 49 (61.3) 0.955 Topical agent alone a 21 (18.3) 16 (20.0) Combination regimen b 22 (19.1) 15 (18.8) Category Skin toxicity grading (N = 151) P value ± Grade 1 Grade 2 Grade 3 Prevention regimen Oral antihistamine alone 54 (71.1) 15 (46.9) 3 (42.9) 0.054 Topical agent alone a 10 (13.2) 10 (31.3) 1 (14.3) Combination regimen b 12 (15.8) 7 (21.9) 3 (42.9) Category Skin toxicity severity (N = 151) P value ± Non-severe (Grade 1,2) Severe (Grade 3) Prevention regimen Oral antihistamine alone 69 (63.9) 3 (42.9) 0.256 Topical agent alone a 20 (18.5) 1 (14.3) Combination regimen b 19 (17.6) 3 (42.9) a, steroids or moisturizer or antibiotic; b, oral antihistamine combination with one topical agent (steroids or moisturizer or antibiotic); ± Chi-square test, * Statistically significant Survival Outcomes Progression-free survival (PFS) differed significantly between patients who received prophylactic skin toxicity management before erlotinib therapy and those who did not. Kaplan–Meier estimates showed a higher PFS probability in the prevention group throughout follow-up. At 12 months, approximately 75% of patients receiving prophylaxis remained progression-free compared with 45% among those without prophylaxis, and this difference persisted over time. The log-rank test indicated a statistically significant difference between groups (p = 0.00032) (Fig. 1 ). The separation of survival curves suggests that patients who received proactive dermatologic management maintained disease control for a longer duration during erlotinib therapy. We compared the time to first skin toxicity between patients who received prophylactic skin toxicity management and those who did not. Across all observation windows (≤ 6 months, ≤ 1 year, and ≤ 5 years), the Kaplan–Meier curves demonstrated similar time-to-rash distributions between the two groups. At 6 months, the proportion of patients who remained rash-free was comparable in the prevention and non-prevention groups, and the log-rank test showed no statistically significant difference (p = 0.47). A similar pattern was observed when extending follow-up to 1 year (p = 0.36) and up to 5 years (p = 0.31) (Fig. 2 ). These findings indicate that prophylactic management did not substantially alter the timing of rash onset during erlotinib therapy. Overall, although the total incidence of skin toxicity was similar between groups, the prevention strategy was associated with a higher frequency of non-severe toxicity and a markedly lower frequency of severe toxicity. In contrast, the non-prevention group experienced significantly higher rates of temporary and permanent erlotinib discontinuation due to skin toxicity, along with a lower objective response rate. Moreover, patients who received proactive dermatologic management maintained disease control for a longer duration during erlotinib therapy. Discussion Our study provides strong evidence supporting the clinical benefits of prophylactic skin toxicity management in patients receiving erlotinib. Although the overall incidence of skin toxicity did not differ significantly between groups, patients who received preventive measures experienced a markedly higher proportion of non-severe toxicity and a substantially lower rate of severe toxicity (p = 0.011). Prevention was also strongly associated with reduced temporary and permanent discontinuation of erlotinib treatment due to skin toxicity (p < 0.001 and p = 0.009, respectively). In addition, the prevention group demonstrated a significantly higher objective response rate (ORR) and longer median progression-free survival (PFS) compared with the non-prevention group (p = 0.002 and p = 0.00029, respectively). These findings highlight the multifaceted impact of prophylactic management on both treatment tolerability and therapeutic effectiveness. Although the overall incidence of skin toxicity was similar between groups, the higher frequency of non-severe events in the prevention group should be interpreted as a favourable outcome. Prophylactic interventions—including oral antihistamines, oral antibiotics, topical antibiotics, topical corticosteroids, moisturizers, or combination approaches—when initiated at the onset of therapy, may attenuate the progression of dermatologic adverse events, keeping them within mild and manageable grades. This is clinically meaningful because non-severe toxicities rarely necessitate treatment interruption, thereby supporting treatment continuity and maintaining drug exposure. The predominance of non-severe toxicity in the prevention group aligns with previous evidence demonstrating that early intervention minimizes discomfort, preserves quality of life, and reduces the likelihood of treatment disruption [ 7 , 18 ]. The lower rate of severe skin toxicities observed in the prevention group suggests that early interventions may be effective in attenuating rash progression, even if they do not prevent rash onset entirely. These findings are consistent with previous studies demonstrating the effectiveness of prevention strategies in reducing the severity of EGFR inhibitor-associated dermatologic toxicities [ 18 , 22 ]. The STEPP trial, which enrolled patients with metastatic colorectal cancer receiving panitumumab, reported a significant reduction in ≥ grade 2 skin toxicities with pre-emptive intervention compared to reactive management (29% vs. 62%) [ 23 ]. Similarly, the J-STEPP trial, conducted in Japanese patients with colorectal cancer treated with panitumumab, showed a comparable trend, with a lower rate of ≥ grade 2 rash in the prevention group (39.5% vs. 59.1%) [ 18 ]. Likewise, the Pan Canadian Rash Trial emphasized the importance of reducing skin toxicity severity to preserve the quality of life and maintain adherence to EGFR-TKI therapy [ 24 ]. These data support the view that the goal of prevention is not necessarily to eliminate rash but rather to reduce its clinical burden. This study demonstrated that prevention strategies significantly reduced both temporary and permanent discontinuation of erlotinib due to skin toxicity. Patients in the prevention group had a notably lower incidence of temporary (3.1% vs. 42.9%) and permanent discontinuation (48.2% vs. 67.1%) compared to the non-prevention group, with results remaining statistically significant after subgroup analysis further confirmed these findings among patients who developed skin toxicities. These results highlight the importance of early preventive management to maintain treatment continuity and minimize interruptions. These findings from previous studies have demonstrated the benefits of prevention strategies. The STEPP trial reported that patients receiving pre-emptive skin toxicity had a lower incidence of ≥ grade 2 rash, fewer dose interruptions, and improved quality of life [ 23 ]. Similarly, the J-STEPP trial found that those in the prevention group experienced a longer time for dose modification and fewer skin-related discontinuations [ 18 ]. A previous study also showed that prophylactic oral antibiotics were associated with fewer dose reductions and treatment delays in patients treated with EGFR-TKIs [ 25 ]. These findings reinforce the clinical value of implementing prevention strategies to reduce the need for treatment modifications due to skin toxicities, supporting their incorporation into standard practice for patients receiving EGFR-TKIs. In terms of treatment efficacy, the prevention group showed a significantly higher objective response rate (ORR) than the non-prevention group. These findings support the clinical benefit of implementing skin toxicity prevention strategies to enhance treatment efficacy. Notably, our results present stronger evidence than earlier studies. For instance, the STEPP trial reported only a slight difference in ORR between the prevention and reactive groups (15% vs. 11%), with nearly identical disease control rates (65% vs. 64%) [ 23 ]. Similarly, the J-STEPP trial showed no significant difference in ORR between the prevention (13.3%) and non-prevention (18.2%) groups [ 18 ]. Another study reported a higher ORR in the prevention group (36.0%) than in the control group (7.7%) [ 26 ]. However, this difference was not statistically significant, potentially because the temporary and permanent treatment discontinuation rates did not differ between groups, which may have influenced the overall treatment response. Notably, after propensity score matching, the prevention group showed a consistently higher probability of remaining progression-free throughout follow-up. At 12 months, approximately 75% of patients receiving prophylaxis remained progression-free compared with 45% in the non-prevention group, and this separation persisted over time. The log-rank test confirmed a statistically significant difference between groups (p = 0.00032). These findings indicate that prophylactic management of EGFR-TKI–related skin toxicities may improve tolerability and enhance treatment durability. In contrast, earlier randomized trials did not demonstrate similar benefits. The STEPP trial reported comparable median PFS between prevention and reactive management groups (4.7 vs. 4.1 months, HR = 1.0, 95% CI 0.6–1.6) [ 23 ], and the J-STEPP trial likewise observed no significant difference (3.6 vs. 3.6 months, HR = 1.20, 95% CI 0.78–1.84; p = 0.413) [ 18 ]. The more pronounced PFS benefit in our study may be explained by the significantly higher rates of treatment continuity, lower rates of both temporary and permanent discontinuation, and improved tumor response among patients receiving prophylaxis. Despite this advantage in PFS, prophylactic management did not alter the timing of dermatologic toxicity onset. Time-to-first skintoxicity analyses—conducted across 6-month, 1-year, and 5-year observation windows—showed no significant differences between groups. These findings suggest that while prophylactic strategies effectively reduce the severity of EGFR-TKI–induced skin reactions, they do not delay their onset. This mechanistic distinction supports the notion that prophylaxis mitigates the progression of inflammation rather than preventing the initial cutaneous response to EGFR inhibition. A key strength of this study is its comprehensive assessment of both toxicity severity and treatment modification patterns in a real-world population of EGFR -mutant NSCLC patients receiving erlotinib. The use of propensity score matching further enhances the robustness of the findings by accounting for potential confounding in time-to-event outcomes. Additionally, the subgroup analysis restricted to patients who developed skin toxicity provided additional confirmation of the protective effect of prophylaxis in reducing severe events and minimizing treatment interruption. Nevertheless, several limitations should be acknowledged. First, the retrospective single-centre design may introduce selection bias, and unmeasured confounders cannot be fully excluded despite PSM. The number of participants after matching was much reduced, though the balance of covariates between the 2 groups was acceptable. Second, although multiple prophylactic strategies were evaluated, patient adherence to these interventions was not captured and may have influenced their effectiveness. Third, the study did not analyse quality-of-life outcomes, which represent an important aspect of dermatologic toxicity management. Future prospective multicentre studies incorporating patient-reported outcomes and adherence monitoring are warranted to validate these findings and refine optimal prophylactic regimens. Conclusion This study provides compelling evidence that prophylactic skin toxicity management significantly reduces the severity of EGFR-TKI–related dermatologic adverse events, decreases the need for temporary and permanent treatment discontinuation, and is associated with higher objective response rates and prolonged progression-free survival. Although prophylaxis did not alter the timing of rash onset, its impact on rash severity and treatment continuity suggests substantial clinical value. These findings support integrating structured prophylactic skin care into routine practice for patients initiating erlotinib therapy. Further prospective trials are needed to confirm these results and establish standardized prevention protocols. Declarations Conflicts of interest: The authors declare no conflicts of interest. Funding: This research was financially supported by Walailak University. Author Contribution Tanavij Pannoi: Conceptualization, Methodology, Investigation, Formal analysis, Writing - Original Draft, Visualization, Writing - Review & Editing, Chonnikarn Sunphakorn and Nattakan Detkaew: Conceptualization, Investigation, Final Review & Editing, Mohitosh Biswas: Conceptualization, Methodology, Investigation, Formal analysis, Writing - Original Draft, Final Review & Editing, Parames Chernghom, Kulfamee Nimor, Papatchaya Tongsai, and Panjarat Suknukul: Conceptualization, Methodology, Investigation, Final Review & Editing, Teerapat Majam: Conceptualization, Methodology, Validation, Formal analysis, Writing - Original Draft, Visualization, Writing - Review & Editing. TP was the first author, and TM was the corresponding author. All authors contributed to the article and approved the submitted version. Acknowledgement The authors would like to thank all participants in the study. Data Availability The datasets generated and analyzed during the current study are not publicly available due to patient confidentiality and institutional data protection policies but are available from the corresponding author on reasonable request. References World Health Organization. Global cancer statistics 2024: WHO Cancer Report. 2024. Available from: https://www.who.int American Cancer Society. Lung cancer facts and Figs. 2024. ACS Annual Report. 2024. Available from: https://www.cancer.org National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. NCCN Guidelines. 2025. Available from: https://www.nccn.org Passaro A, Leighl N, Blackhall F, Popat S, Kerr K, Ahn MJ, et al. ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer. Ann Oncol. 2022;33(5):466–87. Epub 2022 Feb 14. PMID: 35176458. 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Randomized controlled trial on the skin toxicity of panitumumab in Japanese patients with metastatic colorectal cancer: HGCSG1001 study; J-STEPP. Future Oncol. 2015;11(4):617 – 27. 10.2217/fon.14.251 . PMID: 25686117. Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale (NJ): Lawrence Erlbaum Associates; 1988. Tone M, Iwahori K, Shiroyama T, Futami S, Naito Y, Fukushima K, et al. Impact of minocycline on outcomes of EGFR-mutant non-small cell lung cancer patients treated with EGFR-TKIs. Sci Rep. 2023;13(1):8313. 10.1038/s41598-023-35519-4 . PMID: 37221285; PMCID: PMC10204024. Schoenfeld DA. Sample-size formula for the proportional-hazards regression model. Biometrics. 1983;39(2):499–503. PMID: 6354290. Melosky B, Hirsh V. Management of Common Toxicities in Metastatic NSCLC Related to Anti-Lung Cancer Therapies with EGFR-TKIs. Front Oncol. 2014;4:238. 10.3389/fonc.2014.00238 . PMID: 25279350; PMCID: PMC4165207. Lacouture ME, Mitchell EP, Piperdi B, Pillai MV, Shearer H, Iannotti N, et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-Emptive Skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28(8):1351–7. 10.1200/JCO.2008.21.7828 . Epub 2010 Feb 8. PMID: 20142600. Melosky B, Anderson H, Burkes RL, Chu Q, Hao D, Ho V, et al. Pan Canadian Rash Trial: A Randomized Phase III Trial Evaluating the Impact of a Prophylactic Skin Treatment Regimen on Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-Induced Skin Toxicities in Patients With Metastatic Lung Cancer. J Clin Oncol. 2016;34(8):810–5. Epub 2015 Nov 16. PMID: 26573073. Califano R, Tariq N, Compton S, Fitzgerald DA, Harwood CA, Lal R, Lester J, McPhelim J, Mulatero C, Subramanian S, Thomas A, Thatcher N, Nicolson M. Expert Consensus on the Management of Adverse Events from EGFR Tyrosine Kinase Inhibitors in the UK. Drugs. 2015;75(12):1335–48. 10.1007/s40265-015-0434-6 . PMID: 26187773; PMCID: PMC4532717. Yamada M, Iihara H, Fujii H, Ishihara M, Matsuhashi N, Takahashi T, Yoshida K, Itoh Y. Prophylactic Effect of Oral Minocycline in Combination with Topical Steroid and Skin Care Against Panitumumab-induced Acneiform Rash in Metastatic Colorectal Cancer Patients. Anticancer Res. 2015;35(11):6175–81. PMID: 26504047. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8138030","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":546948407,"identity":"b24138c1-5f49-45e1-852e-589cff5f8df1","order_by":0,"name":"Tanavij Pannoi","email":"","orcid":"","institution":"Walailak University","correspondingAuthor":false,"prefix":"","firstName":"Tanavij","middleName":"","lastName":"Pannoi","suffix":""},{"id":546948408,"identity":"cd8c6172-161e-43d6-8484-c26e26ea2bd3","order_by":1,"name":"Chonnikarn Sunphakorn","email":"","orcid":"","institution":"Surat Thani 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1","display":"","copyAsset":false,"role":"figure","size":26326,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves for progression-free survival (PFS) in patients receiving erlotinib with and without prophylactic skin toxicity management. The prevention group had a higher probability of remaining progression-free over time than the non-prevention group. Shaded regions represent 95% confidence intervals. Censoring is indicated by tick marks. The difference between groups was evaluated using the log-rank test (p = 0.00032).\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8138030/v1/abb8aa19e09bcbc671bbe88f.png"},{"id":96288408,"identity":"c65ff1a2-e9d2-477d-9201-0369353710b4","added_by":"auto","created_at":"2025-11-19 12:12:03","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":441166,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier plots of time to skin toxicity among patients receiving erlotinib with and without prophylactic skin toxicity management, evaluated at ≤ 6 months, ≤ 1 year, and ≤ 5 years. Shaded areas indicate 95% confidence intervals. Between-group differences were assessed using log-rank tests.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8138030/v1/a5aa0cb0c5743ba12fedd3c9.jpeg"},{"id":96369239,"identity":"57ed7f1e-c116-4e0e-846c-d64c5336c9f1","added_by":"auto","created_at":"2025-11-20 10:20:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1577151,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8138030/v1/bb57e697-fbd1-4b2f-9470-70b2a3353e8c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparative Analysis of Prevention versus Non-Prevention for Skin Toxicities on Clinical Outcomes in Non- Small Cell Lung Cancer (NSCLC) Patients Treated with Erlotinib: A 10-year Retrospective Cohort Study","fulltext":[{"header":"Impact statements","content":"\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eProphylactic skin toxicity management reduced the severity of erlotinib-induced dermatologic adverse events, supporting the early identification and management of patients at risk of severe toxicity.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eImplementing preventive strategies minimized inappropriate erlotinib interruptions, thereby maintaining treatment continuity and contributing to improved objective response rates and progression-free survival.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eClinically appropriate, proactive dermatologic care may enhance treatment adherence and overall therapeutic outcomes in patients with \u003cem\u003eEGFR\u003c/em\u003e-mutant NSCLC receiving erlotinib.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eLung cancer remains one of the leading causes of cancer-related mortality worldwide, accounting for approximately 18.7% of all cancer deaths and representing the highest mortality burden among all malignancies [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Non-small cell lung cancer (NSCLC) comprises 80–85% of lung cancer cases, whereas small cell lung cancer (SCLC) accounts for the remaining 15–20% [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. According to the National Comprehensive Cancer Network (NCCN) Guidelines 2024, treatment strategies for NSCLC are stage-dependent. In early to locally advanced disease (stages 1A–3B), surgical resection remains the cornerstone of therapy, often complemented by adjuvant treatment for patients at high risk of recurrence. In contrast, the management of advanced-stage disease (stage 4) relies heavily on molecular profiling, including assessment of actionable genomic alterations such as \u003cem\u003eEpidermal Growth Factor Receptor\u003c/em\u003e (\u003cem\u003eEGFR\u003c/em\u003e) mutations, \u003cem\u003eAnaplastic Lymphoma Kinase\u003c/em\u003e (\u003cem\u003eALK\u003c/em\u003e) rearrangements, and Programmed Death-Ligand 1 (PD-L1) expression [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAmong these biomarkers, \u003cem\u003eEGFR\u003c/em\u003e mutations, particularly exon 19 deletions and exon 21 L858R substitutions, are well-established predictors of response to EGFR tyrosine kinase inhibitors (TKIs). First-generation EGFR TKIs, such as erlotinib, have long been used as standard first-line therapy for patients with \u003cem\u003eEGFR\u003c/em\u003e-mutant NSCLC [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In Thailand, erlotinib is included in the National List of Essential Medicines (NLEM) under category E(2), designating its use as initial treatment for advanced or metastatic NSCLC with confirmed \u003cem\u003eEGFR\u003c/em\u003e mutation positivity [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. This inclusion has substantially improved patient access to targeted therapy, particularly within the Universal Health Coverage Scheme (UC).\u003c/p\u003e\u003cp\u003eDespite its clinical benefits, erlotinib is associated with notable adverse effects, particularly dermatologic toxicities, occurring in approximately 75–90% of patients. Severe dermatologic toxicities (grades 3–4) occur in about 10–20% of cases and have been shown to correlate with enhanced clinical outcomes. Studies suggest that the occurrence and severity of toxicity may serve as potential indicators of treatment efficacy, supporting the administration of erlotinib at the maximal tolerated dose [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. For instance, patients experiencing non-severe dermatologic toxicities (grades 1–2) have shown significantly longer median overall survival (OS) than those without toxicity [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eHowever, severe dermatologic toxicities can negatively impact patients’ quality of life (QoL) and may necessitate dose reductions, temporary discontinuation, or permanent discontinuation [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Studies report that up to 53% of patients with severe toxicities experience social avoidance, which further contributes to treatment non-adherence [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Additionally, severe toxicities are associated with an increased risk of disease flare following treatment discontinuation. Disease flare, characterized by rapid tumor progression after cessation of EGFR TKI therapy, has been observed in approximately 23% of patients, with a median time to flare of 8 days [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. These findings highlight the critical need for strategies that not only manage but also prevent severe dermatologic toxicities, ensuring optimal treatment adherence and outcomes.\u003c/p\u003e\u003cp\u003ePrevention strategies, including the preventive use of oral antibiotics, topical corticosteroids, and topical moisturizers, have been recommended to reduce the severity and incidence of EGFR TKI-induced skin toxicities [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Oral antihistamines are commonly used to reduce pruritus associated with EGFR-TKI-induced rashes and may also reduce rash severity when used preventively [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Although evidence for their preventive efficacy is limited, some studies suggest that early initiation of oral antihistamines could reduce rash progression [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, further clinical trials are needed to confirm their role in rash prevention [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. These interventions target the underlying pathophysiological mechanisms of skin toxicities, such as follicular inflammation, bacterial superinfection, and epidermal barrier dysfunction [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Previous studies have shown that prevention approaches can significantly reduce the severity of skin toxicities, thereby improving quality of life and supporting sustained treatment adherence [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eHowever, evidence regarding the impact of preventive strategies on long-term clinical outcomes, such as survival, remains limited. Previous studies demonstrated that patients who received preemptive treatment for skin toxicity had a lower incidence of grade ≥ 2 rash, fewer panitumumab dose interruptions, and improved quality of life [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Nevertheless, clinical outcome data on the prevention of skin toxicities in patients receiving erlotinib remain limited.\u003c/p\u003e\n\u003ch3\u003eAim\u003c/h3\u003e\n\u003cp\u003eThis study aims to investigate the incidence and severity of dermatologic toxicities in NSCLC patients treated with erlotinib and to compare the clinical outcomes between those receiving prevention strategies for skin toxicity and those non prevention. The primary objectives are to assess the incidence and severity of skin toxicities. Secondary objectives include analyzing the impact of skin toxicity prevention on erlotinib objective response rate (ORR), erlotinib dose modifications, progression-free survival (PFS), and time to skin toxicity.\u003c/p\u003e"},{"header":"Methods","content":"\u003ch2\u003eStudy Design\u003c/h2\u003e\u003cp\u003eThis retrospective cohort study evaluated the impact of skin toxicity prevention among NSCLC patients harbouring \u003cem\u003eEGFR\u003c/em\u003e mutations who received erlotinib monotherapy at Surat Thani Hospital between May 1, 2015, and March 15, 2025. Eligible patients were adults (≥ 18 years) with a confirmed diagnosis of advanced-stage (stage IV) or recurrent NSCLC who received erlotinib therapy. Inclusion required documented \u003cem\u003eEGFR\u003c/em\u003e mutation status and sufficient clinical records for assessing treatment outcomes and skin-related adverse events.\u003c/p\u003e\u003cp\u003ePatients were excluded if they had a history of skin toxicity before initiating erlotinib, had previously received other EGFR-TKIs (e.g., gefitinib, afatinib, osimertinib) or anti-EGFR monoclonal antibodies (e.g., cetuximab, panitumumab), or if clinical data on treatment outcomes and adverse events were incomplete.\u003c/p\u003e\u003cp\u003ePatients were categorized into a prevention group and a non-prevention group based on whether they received prophylactic interventions to mitigate skin toxicity before or at the initiation of erlotinib. Prophylactic measures included oral antihistamines, oral antibiotics, topical antibiotics, topical corticosteroids, and topical moisturizers, used either alone or in combination.\u003c/p\u003e\u003ch3\u003eData Collection\u003c/h3\u003e\u003cp\u003eData were extracted from electronic medical records and included baseline demographics [age, sex, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status (PS), and smoking history], cancer characteristics (disease stage, \u003cem\u003eEGFR\u003c/em\u003e mutation subtype, line of treatment), and treatment-related variables (initial erlotinib dose, treatment duration, temporary and permanent discontinuation, concurrent medications, and concomitant interventions).\u003c/p\u003e\u003ch3\u003eStudy Outcome\u003c/h3\u003e\u003cp\u003eSkin toxicity was defined as any dermatologic adverse event occurring during erlotinib therapy, including acneiform rash, xerosis, pruritus, paronychia, exfoliative dermatitis, maculopapular rash, or hand–foot syndrome. Adverse events were assessed and graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Toxicities were categorized as non-severe (grade 1–2) or severe (grade 3–5) based on their clinical impact.\u003c/p\u003e\u003cp\u003eTreatment response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete and partial responses were defined as objective responses, whereas stable disease and progressive disease were classified as non-responders. Progression-free survival (PFS) was defined as the interval from the initiation of erlotinib therapy to radiologically confirmed disease progression or death from any cause. The primary outcomes were the incidence and severity of skin toxicity. Secondary outcomes included the objective response rate (ORR), the frequency of temporary and permanent discontinuation of erlotinib due to skin toxicity, progression-free survival, and time to skin toxicity.\u003c/p\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eAll statistical analyses were performed using SPSS version 23.0 (IBM Corp., Armonk, NY, USA) and R software version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria). Baseline characteristics were summarised using frequencies and percentages for categorical variables and means with standard deviations (SD) or medians with interquartile ranges (IQR) for continuous variables. Group comparisons were conducted using the Chi-square test for categorical variables and the independent t-test or Mann–Whitney U test for continuous variables, based on distributional assumptions. Associations between skin toxicity prevention and categorical outcomes—including overall skin toxicity, toxicity severity, treatment discontinuation, and objective response rate (ORR)—were analysed using Chi-square tests. Multivariate logistic regression was employed to adjust for sex, age, BMI, ECOG performance status, smoking status, staging, \u003cem\u003eEGFR\u003c/em\u003e mutation, and line of treatment. Odd ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of the associations between skin toxicity prevention and the study outcomes.\u003c/p\u003e\u003cp\u003ePropensity score matching (PSM) was applied for time-to-event outcomes, specifically progression-free survival (PFS) and time to first skin toxicity. PSM was performed in R using the MatchIt package. Propensity scores were estimated using logistic regression based on prespecified covariates (age, sex, ECOG performance status, smoking history, EGFR type, and lines of treatment). Nearest-neighbor matching without replacement was performed using a 0.001 caliper to ensure close matches and limit residual bias. Covariate balance before and after matching was assessed using standardized mean differences (SMD).\u003c/p\u003e\u003cp\u003eAfter matching, time-to-event analyses were performed using the Kaplan–Meier method. Between-group differences in PFS were assessed using the log-rank test, with 95% confidence intervals for survival estimates calculated using the Greenwood method. Time to first skin toxicity was evaluated using Kaplan–Meier curves with predefined follow-up windows (≤ 6 months, ≤ 1 year, ≤ 5 years). Log-rank tests were used to compare the prevention and non-prevention groups for each time interval. Censoring was indicated by tick marks in all survival plots. All statistical tests were two-sided, and p-values \u0026lt; 0.05 were considered statistically significant.\u003c/p\u003e\u003cp\u003eThe required sample size was estimated using two approaches. First, a Z-test for two independent proportions was applied using rash incidence rates reported for EGFR-TKI therapy [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. A previous study reported skin rash incidences of 84.4% in the minocycline prophylaxis group (32 patients) and 57.5% in the control group (106 patients) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Based on these proportions, a minimum of 28 and 85 participants per group was required to achieve 80% power with a two-sided α of 0.05, yielding a total sample size of 113 patients. Second, sample size estimation for progression-free survival (PFS) was performed using Schoenfeld’s method for survival analysis [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. A previous study reported a median PFS of 714 days (95% CI 411–1247) in the minocycline group and 420 days (95% CI 343–626) in the control group, corresponding to a hazard ratio (HR) of 0.44 (95% CI 0.27–0.73; p = 0.0014) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Using a two-sided log-rank test with α = 0.05 and 80% power, the required sample size was estimated at 48 patients per group, for a total of 96 participants.\u003c/p\u003e\u003ch2\u003eEthics approval\u003c/h2\u003e\u003cp\u003e This study was approved by the Surat Thani Hospital Human Research Ethics Committee (REC 67–0112).\u003c/p\u003e"},{"header":"Result","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003eBaseline Characteristics\u003c/h2\u003e\u003cp\u003eA total of 265 patients with NSCLC were included, with 195 in the prevention group and 70 in the non-prevention group. The median follow-up duration was 15.0 months (IQR 8.0 to 33.0). Sex distribution, age, BMI, smoking status, disease stage, \u003cem\u003eEGFR\u003c/em\u003e mutation subtype, and treatment line were comparable between groups (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). However, ECOG performance status (ECOG PS) differed significantly (p\u0026thinsp;=\u0026thinsp;0.026): in the prevention group, 56.9% had ECOG PS 1, 37.9% had PS 2, and 4.1% had PS 3, whereas in the non-prevention group, 47.1% had PS 1, 35.7% had PS 2, 12.9% had PS 3, and 1.4% had PS 4 (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline characteristics of the patients enrolled in the study.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eBefore Matching (N\u0026thinsp;=\u0026thinsp;265)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eAfter Matching (N\u0026thinsp;=\u0026thinsp;96)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eParameter\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eSkin toxicity\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eprevention\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eN (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eSkin toxicity\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003enon-prevention\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eN (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003eSkin toxicity\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eprevention\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eN (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eSkin toxicity\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003enon-prevention\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eN (%)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003eStandardized Mean Difference (SMD)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNumber of patients\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e195 (73.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e70 (26.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e48(50.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e48(50.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e73 (37.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28 (40.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15 (31.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e15 (31.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e122 (62.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e42 (60.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e33(68.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e33(68.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge (years) (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e65.6\u0026thinsp;\u0026plusmn;\u0026thinsp;11.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e66.8\u0026thinsp;\u0026plusmn;\u0026thinsp;12.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e65.52\u0026thinsp;\u0026plusmn;\u0026thinsp;11.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e67.06\u0026thinsp;\u0026plusmn;\u0026thinsp;12.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.128\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBMI (kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e) (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21.5\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21.1\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e22.06\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e21.45\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.094\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eECOG PS\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.208\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (1.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (2.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (2.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e111 (56.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e33 (47.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e26 (54.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e26 (54.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e74 (37.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25 (35.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20 (41.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e19 (39.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (4.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 (12.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (4.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (4.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (1.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSmoking status\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.112\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-smoker\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99 (50.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e34 (48.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e26 (54.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e28 (58.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCurrent smoker\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (2.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (5.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (2.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (2.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEx-smoker\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (3.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (5.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (6.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2 (4.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSecond-hand smoker\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (2.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e81 (41.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28 (40.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e18 (37.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e17 (35.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eStaging\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIII\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (3.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (4.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (2.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (2.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e188 (96.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e67 (95.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e47 (97.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e47 (97.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEGFR\u003c/b\u003e \u003cb\u003emutation\u0026nbsp;subtype\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.090\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExon 19 deletion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e120 (61.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e44 (62.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e32 (66.67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e34 (70.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExon 21 L858R\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e72 (36.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23 (32.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16 (33.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e14 (29.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExon 21 L861Q\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (0.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (2.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExon 18 G719x\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (1.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (1.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLine of treatment\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.129\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFirst line\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e169 (86.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e53 (75.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e39 (81.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e39 (81.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSecond line\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22 (11.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (18.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7 (14.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e8 (16.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThird line\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (2.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (5.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (4.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (2.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003eBMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group performance status; SD, standard deviation; SMD, standardized mean difference; N, number of patients.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eAll patients received erlotinib 150 mg once daily. No CYP3A4 or CYP1A2 inhibitors or inducers were used during treatment. Liver and renal function remained stable, with no parameters requiring dose adjustment. Serum creatinine values did not exceed 1.5 times the upper limit of normal, and ALT and AST levels remained below three times the upper limit of normal.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eIncidence and Severity of Skin Toxicity\u003c/h2\u003e\u003cp\u003eThe overall incidence of skin toxicity was comparable between the two groups: 115 patients (59.0%) in the prevention group and 36 patients (51.4%) in the non-prevention group (p\u0026thinsp;=\u0026thinsp;0.325). Among the 151 patients who developed skin toxicity, the distribution of toxicity grades differed significantly (p\u0026thinsp;=\u0026thinsp;0.003): grade 1 occurred in 66.1% vs 58.3%, grade 2 in 27.8% vs 16.7%, and grade 3 in 6.1% vs 25.0% in the prevention and non-prevention groups, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). When the results were grouped by severity, non-severe toxicity (grades 1\u0026ndash;2) was more frequent in the prevention group (93.9% vs 75.0%), whereas severe toxicity (grade 3) was less common (6.1% vs 25.0%, p\u0026thinsp;=\u0026thinsp;0.003). Severe toxicity also remained significantly lower in the prevention group compared with the non-prevention group after multivariate analysis (OR 0.22, 95% CI 0.07 to 0.71, p\u0026thinsp;=\u0026thinsp;0.011).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cb\u003eIncidence of skin toxicities and erlotinib dose adjustment in the prevention and non-prevention groups. (N\u0026thinsp;=\u0026thinsp;265)\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParameter\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePrevention\u003c/p\u003e\u003cp\u003eN (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNon \u0026ndash;prevention\u003c/p\u003e\u003cp\u003eN (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP value\u003csup\u003e\u0026plusmn;\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo skin toxicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e80 (41.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e34 (48.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.325\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSkin toxicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e115 (59.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e36 (51.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026bull; Grade 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e76 (66.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e21 (58.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.003*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026bull; Grade 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e32 (27.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6 (16.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026bull; Grade 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7 (6.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e9 (25.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eResponse\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e123 (63.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e28 (40.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.001*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-response\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e72 (36.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e42 (60.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTemporary discontinuation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6 (3.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e30 (42.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePermanent discontinuation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e94 (48.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e47 (67.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.005*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eN, number of patients; \u0026plusmn;, Chi-square test; *, Statistically significant.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eErlotinib Dose Modification and Objective Response Rate\u003c/h2\u003e\u003cp\u003eBoth temporary and permanent erlotinib discontinuation were significantly lower in the prevention group (3.1% vs 42.9%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; and 48.2% vs 67.1%, p\u0026thinsp;=\u0026thinsp;0.005, respectively) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). After multivariate analysis, the prevention group also had significantly lower rates of temporary and permanent discontinuation compared with the non-prevention group (OR 0.04, 95% CI 0.01 to 0.10, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; and OR 0.44, 95% CI 0.23 to 0.82, p\u0026thinsp;=\u0026thinsp;0.009, respectively).\u003c/p\u003e\u003cp\u003eAmong patients who developed skin toxicity (N\u0026thinsp;=\u0026thinsp;151), temporary and permanent discontinuation also remained significantly lower in the prevention group (5.2% vs 47.2%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, and 47.0% vs 66.7, p\u0026thinsp;=\u0026thinsp;0.030, respectively), with both outcomes remaining statistically significant in the multivariate analysis (OR 0.04, 95% CI 0.01 to 0.14, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; and OR 0.36, 95% CI 0.15 to 0.84, p\u0026thinsp;=\u0026thinsp;0.018, respectively).\u003c/p\u003e\u003cp\u003eThe erlotinib objective response rate (ORR) was significantly higher in the prevention group, with 123 patients (63.1%) achieving a treatment response compared with 28 patients (40.0%) in the non-prevention group (p\u0026thinsp;=\u0026thinsp;0.001). This association also remained statistically significant after multivariate analysis (OR 2.62, 95% CI 1.41 to 4.87, p\u0026thinsp;=\u0026thinsp;0.002) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eComparison of Prevention Regimens\u003c/h2\u003e\u003cp\u003e Patients receiving prophylactic interventions were categorized into oral antihistamine, topical agent, and combination regimen groups. The incidence of skin toxicity, toxicity grade, toxicity severity, temporary discontinuation rate, permanent discontinuation rate, and ORR did not differ significantly among these prevention strategies (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAssociation between skin toxicity prevention regimen and skin toxicity outcomes\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eCategory\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e\u003cp\u003eAll grade skin toxicity (N\u0026thinsp;=\u0026thinsp;265)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eP value\u003csup\u003e\u0026plusmn;\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eSkin toxicity\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eNo skin toxicity\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevention regimen\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOral antihistamine alone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e72 (62.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e49 (61.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.955\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTopical agent alone \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e21 (18.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e16 (20.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCombination regimen \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e22 (19.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e15 (18.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eCategory\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eSkin toxicity grading (N\u0026thinsp;=\u0026thinsp;151)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eP value\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026plusmn;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eGrade 1\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e\u003cb\u003eGrade 2\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003eGrade 3\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePrevention regimen\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOral antihistamine alone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e54 (71.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e15 (46.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (42.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.054\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTopical agent alone \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 (13.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e10 (31.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (14.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCombination regimen \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 (15.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e7 (21.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (42.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eCategory\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eSkin toxicity severity (N\u0026thinsp;=\u0026thinsp;151)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eP value\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026plusmn;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cb\u003eNon-severe \u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(Grade 1,2)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e\u003cb\u003eSevere\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(Grade 3)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePrevention regimen\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOral antihistamine alone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e69 (63.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e3 (42.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.256\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTopical agent alone \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e20 (18.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e1 (14.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCombination regimen \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e19 (17.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003e3 (42.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003ea, steroids or moisturizer or antibiotic; b, oral antihistamine combination with one topical agent (steroids or moisturizer or antibiotic); \u003csup\u003e\u0026plusmn;\u003c/sup\u003e Chi-square test, \u003cb\u003e*\u003c/b\u003e Statistically significant\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eSurvival Outcomes\u003c/h2\u003e\u003cp\u003eProgression-free survival (PFS) differed significantly between patients who received prophylactic skin toxicity management before erlotinib therapy and those who did not. Kaplan\u0026ndash;Meier estimates showed a higher PFS probability in the prevention group throughout follow-up. At 12 months, approximately 75% of patients receiving prophylaxis remained progression-free compared with 45% among those without prophylaxis, and this difference persisted over time. The log-rank test indicated a statistically significant difference between groups (p\u0026thinsp;=\u0026thinsp;0.00032) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The separation of survival curves suggests that patients who received proactive dermatologic management maintained disease control for a longer duration during erlotinib therapy.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eWe compared the time to first skin toxicity between patients who received prophylactic skin toxicity management and those who did not. Across all observation windows (\u0026le;\u0026thinsp;6 months, \u0026le; 1 year, and \u0026le;\u0026thinsp;5 years), the Kaplan\u0026ndash;Meier curves demonstrated similar time-to-rash distributions between the two groups. At 6 months, the proportion of patients who remained rash-free was comparable in the prevention and non-prevention groups, and the log-rank test showed no statistically significant difference (p\u0026thinsp;=\u0026thinsp;0.47). A similar pattern was observed when extending follow-up to 1 year (p\u0026thinsp;=\u0026thinsp;0.36) and up to 5 years (p\u0026thinsp;=\u0026thinsp;0.31) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). These findings indicate that prophylactic management did not substantially alter the timing of rash onset during erlotinib therapy.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eOverall, although the total incidence of skin toxicity was similar between groups, the prevention strategy was associated with a higher frequency of non-severe toxicity and a markedly lower frequency of severe toxicity. In contrast, the non-prevention group experienced significantly higher rates of temporary and permanent erlotinib discontinuation due to skin toxicity, along with a lower objective response rate. Moreover, patients who received proactive dermatologic management maintained disease control for a longer duration during erlotinib therapy.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study provides strong evidence supporting the clinical benefits of prophylactic skin toxicity management in patients receiving erlotinib. Although the overall incidence of skin toxicity did not differ significantly between groups, patients who received preventive measures experienced a markedly higher proportion of non-severe toxicity and a substantially lower rate of severe toxicity (p\u0026thinsp;=\u0026thinsp;0.011). Prevention was also strongly associated with reduced temporary and permanent discontinuation of erlotinib treatment due to skin toxicity (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and p\u0026thinsp;=\u0026thinsp;0.009, respectively). In addition, the prevention group demonstrated a significantly higher objective response rate (ORR) and longer median progression-free survival (PFS) compared with the non-prevention group (p\u0026thinsp;=\u0026thinsp;0.002 and p\u0026thinsp;=\u0026thinsp;0.00029, respectively). These findings highlight the multifaceted impact of prophylactic management on both treatment tolerability and therapeutic effectiveness.\u003c/p\u003e\u003cp\u003eAlthough the overall incidence of skin toxicity was similar between groups, the higher frequency of non-severe events in the prevention group should be interpreted as a favourable outcome. Prophylactic interventions\u0026mdash;including oral antihistamines, oral antibiotics, topical antibiotics, topical corticosteroids, moisturizers, or combination approaches\u0026mdash;when initiated at the onset of therapy, may attenuate the progression of dermatologic adverse events, keeping them within mild and manageable grades. This is clinically meaningful because non-severe toxicities rarely necessitate treatment interruption, thereby supporting treatment continuity and maintaining drug exposure. The predominance of non-severe toxicity in the prevention group aligns with previous evidence demonstrating that early intervention minimizes discomfort, preserves quality of life, and reduces the likelihood of treatment disruption [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe lower rate of severe skin toxicities observed in the prevention group suggests that early interventions may be effective in attenuating rash progression, even if they do not prevent rash onset entirely. These findings are consistent with previous studies demonstrating the effectiveness of prevention strategies in reducing the severity of EGFR inhibitor-associated dermatologic toxicities [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The STEPP trial, which enrolled patients with metastatic colorectal cancer receiving panitumumab, reported a significant reduction in \u0026ge;\u0026thinsp;grade 2 skin toxicities with pre-emptive intervention compared to reactive management (29% vs. 62%) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Similarly, the J-STEPP trial, conducted in Japanese patients with colorectal cancer treated with panitumumab, showed a comparable trend, with a lower rate of \u0026ge;\u0026thinsp;grade 2 rash in the prevention group (39.5% vs. 59.1%) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Likewise, the Pan Canadian Rash Trial emphasized the importance of reducing skin toxicity severity to preserve the quality of life and maintain adherence to EGFR-TKI therapy [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. These data support the view that the goal of prevention is not necessarily to eliminate rash but rather to reduce its clinical burden.\u003c/p\u003e\u003cp\u003eThis study demonstrated that prevention strategies significantly reduced both temporary and permanent discontinuation of erlotinib due to skin toxicity. Patients in the prevention group had a notably lower incidence of temporary (3.1% vs. 42.9%) and permanent discontinuation (48.2% vs. 67.1%) compared to the non-prevention group, with results remaining statistically significant after subgroup analysis further confirmed these findings among patients who developed skin toxicities. These results highlight the importance of early preventive management to maintain treatment continuity and minimize interruptions. These findings from previous studies have demonstrated the benefits of prevention strategies. The STEPP trial reported that patients receiving pre-emptive skin toxicity had a lower incidence of \u0026ge;\u0026thinsp;grade 2 rash, fewer dose interruptions, and improved quality of life [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Similarly, the J-STEPP trial found that those in the prevention group experienced a longer time for dose modification and fewer skin-related discontinuations [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. A previous study also showed that prophylactic oral antibiotics were associated with fewer dose reductions and treatment delays in patients treated with EGFR-TKIs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. These findings reinforce the clinical value of implementing prevention strategies to reduce the need for treatment modifications due to skin toxicities, supporting their incorporation into standard practice for patients receiving EGFR-TKIs.\u003c/p\u003e\u003cp\u003eIn terms of treatment efficacy, the prevention group showed a significantly higher objective response rate (ORR) than the non-prevention group. These findings support the clinical benefit of implementing skin toxicity prevention strategies to enhance treatment efficacy. Notably, our results present stronger evidence than earlier studies. For instance, the STEPP trial reported only a slight difference in ORR between the prevention and reactive groups (15% vs. 11%), with nearly identical disease control rates (65% vs. 64%) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Similarly, the J-STEPP trial showed no significant difference in ORR between the prevention (13.3%) and non-prevention (18.2%) groups [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Another study reported a higher ORR in the prevention group (36.0%) than in the control group (7.7%) [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. However, this difference was not statistically significant, potentially because the temporary and permanent treatment discontinuation rates did not differ between groups, which may have influenced the overall treatment response.\u003c/p\u003e\u003cp\u003eNotably, after propensity score matching, the prevention group showed a consistently higher probability of remaining progression-free throughout follow-up. At 12 months, approximately 75% of patients receiving prophylaxis remained progression-free compared with 45% in the non-prevention group, and this separation persisted over time. The log-rank test confirmed a statistically significant difference between groups (p\u0026thinsp;=\u0026thinsp;0.00032). These findings indicate that prophylactic management of EGFR-TKI\u0026ndash;related skin toxicities may improve tolerability and enhance treatment durability. In contrast, earlier randomized trials did not demonstrate similar benefits. The STEPP trial reported comparable median PFS between prevention and reactive management groups (4.7 vs. 4.1 months, HR\u0026thinsp;=\u0026thinsp;1.0, 95% CI 0.6\u0026ndash;1.6) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], and the J-STEPP trial likewise observed no significant difference (3.6 vs. 3.6 months, HR\u0026thinsp;=\u0026thinsp;1.20, 95% CI 0.78\u0026ndash;1.84; p\u0026thinsp;=\u0026thinsp;0.413) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The more pronounced PFS benefit in our study may be explained by the significantly higher rates of treatment continuity, lower rates of both temporary and permanent discontinuation, and improved tumor response among patients receiving prophylaxis.\u003c/p\u003e\u003cp\u003eDespite this advantage in PFS, prophylactic management did not alter the timing of dermatologic toxicity onset. Time-to-first skintoxicity analyses\u0026mdash;conducted across 6-month, 1-year, and 5-year observation windows\u0026mdash;showed no significant differences between groups. These findings suggest that while prophylactic strategies effectively reduce the \u003cem\u003eseverity\u003c/em\u003e of EGFR-TKI\u0026ndash;induced skin reactions, they do not delay their onset. This mechanistic distinction supports the notion that prophylaxis mitigates the progression of inflammation rather than preventing the initial cutaneous response to EGFR inhibition.\u003c/p\u003e\u003cp\u003eA key strength of this study is its comprehensive assessment of both toxicity severity and treatment modification patterns in a real-world population of \u003cem\u003eEGFR\u003c/em\u003e-mutant NSCLC patients receiving erlotinib. The use of propensity score matching further enhances the robustness of the findings by accounting for potential confounding in time-to-event outcomes. Additionally, the subgroup analysis restricted to patients who developed skin toxicity provided additional confirmation of the protective effect of prophylaxis in reducing severe events and minimizing treatment interruption.\u003c/p\u003e\u003cp\u003eNevertheless, several limitations should be acknowledged. First, the retrospective single-centre design may introduce selection bias, and unmeasured confounders cannot be fully excluded despite PSM. The number of participants after matching was much reduced, though the balance of covariates between the 2 groups was acceptable. Second, although multiple prophylactic strategies were evaluated, patient adherence to these interventions was not captured and may have influenced their effectiveness. Third, the study did not analyse quality-of-life outcomes, which represent an important aspect of dermatologic toxicity management. Future prospective multicentre studies incorporating patient-reported outcomes and adherence monitoring are warranted to validate these findings and refine optimal prophylactic regimens.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study provides compelling evidence that prophylactic skin toxicity management significantly reduces the severity of EGFR-TKI\u0026ndash;related dermatologic adverse events, decreases the need for temporary and permanent treatment discontinuation, and is associated with higher objective response rates and prolonged progression-free survival. Although prophylaxis did not alter the timing of rash onset, its impact on rash severity and treatment continuity suggests substantial clinical value. These findings support integrating structured prophylactic skin care into routine practice for patients initiating erlotinib therapy. Further prospective trials are needed to confirm these results and establish standardized prevention protocols.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eConflicts of interest:\u003c/h2\u003e\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e\u003cp\u003eThis research was financially supported by Walailak University.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eTanavij Pannoi: Conceptualization, Methodology, Investigation, Formal analysis, Writing - Original Draft, Visualization, Writing - Review \u0026amp; Editing, Chonnikarn Sunphakorn and Nattakan Detkaew: Conceptualization, Investigation, Final Review \u0026amp; Editing, Mohitosh Biswas: Conceptualization, Methodology, Investigation, Formal analysis, Writing - Original Draft, Final Review \u0026amp; Editing, Parames Chernghom, Kulfamee Nimor, Papatchaya Tongsai, and Panjarat Suknukul: Conceptualization, Methodology, Investigation, Final Review \u0026amp; Editing, Teerapat Majam: Conceptualization, Methodology, Validation, Formal analysis, Writing - Original Draft, Visualization, Writing - Review \u0026amp; Editing. TP was the first author, and TM was the corresponding author. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors would like to thank all participants in the study.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and analyzed during the current study are not publicly available due to patient confidentiality and institutional data protection policies but are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organization. Global cancer statistics 2024: WHO Cancer Report. 2024. 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PMID: 26504047.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Erlotinib, EGFR mutation, Non-small cell lung cancer, Skin toxicity, Prophylactic management, Dermatologic adverse events","lastPublishedDoi":"10.21203/rs.3.rs-8138030/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8138030/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eIntroduction:\u003c/b\u003e\u003c/p\u003e\u003cp\u003eErlotinib is an established first-line therapy for \u003cem\u003eEpidermal Growth Factor Receptor\u003c/em\u003e (\u003cem\u003eEGFR\u003c/em\u003e) mutant non-small cell lung cancer (NSCLC). However, dermatologic toxicities are common and lead to treatment interruption and reduced adherence. Evidence regarding the impact of prophylactic skin toxicity management on clinical effectiveness remains limited.\u003c/p\u003e\u003cp\u003e\u003cb\u003eAim\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTo compare the incidence and severity of skin toxicities, treatment modifications, and clinical outcomes between NSCLC patients receiving prophylactic skin toxicity and those without prophylactic during erlotinib therapy.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA retrospective cohort study was conducted among \u003cem\u003eEGFR\u003c/em\u003e-mutant NSCLC patients treated with erlotinib at Surat Thani Hospital from 2015 to 2025. Patients were categorized into prevention and non-prevention groups based on receipt of prophylactic interventions. Associations with toxicity severity, objective response rate (ORR), and treatment discontinuation were evaluated using Chi-square tests, and multivariate logistic regression was performed to adjust for confounders. Propensity score matching (PSM) was applied for progression-free survival (PFS) and time to first skin toxicity. Kaplan\u0026ndash;Meier estimates and log-rank tests were used for time-to-event analyses.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA total of 265 patients were included. Severe toxicity was significantly lower in the prevention group (6.1% vs 25.0%, p\u0026thinsp;=\u0026thinsp;0.011). Temporary and permanent erlotinib discontinuation were significantly lower in the prevention group (3.1% vs 42.9% and 48.2% vs 67.1%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and p\u0026thinsp;=\u0026thinsp;0.009, respectively). ORR was higher in the prevention group (63.1% vs 40.0%, p\u0026thinsp;=\u0026thinsp;0.002). After PSM, PFS remained significantly longer in the prevention group (p\u0026thinsp;=\u0026thinsp;0.00032), whereas time to first skin toxicity did not differ.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e\u003cp\u003eProphylactic skin toxicity management reduces severe dermatologic events, decreases treatment interruption, improves ORR, and prolongs PFS without affecting rash onset. These findings support integrating structured prophylactic skin toxicity into routine erlotinib treatment.\u003c/p\u003e","manuscriptTitle":"Comparative Analysis of Prevention versus Non-Prevention for Skin Toxicities on Clinical Outcomes in Non- Small Cell Lung Cancer (NSCLC) Patients Treated with Erlotinib: A 10-year Retrospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-19 12:11:58","doi":"10.21203/rs.3.rs-8138030/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ac1397fa-b5ec-482c-b2f6-d33af6a797f4","owner":[],"postedDate":"November 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-11T17:14:03+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-19 12:11:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8138030","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8138030","identity":"rs-8138030","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}