Retrospective clinical study analysis of skin adverse reactions related to epidermal growth factor receptor inhibitors.

Background: Epidermal growth factor receptor inhibitors (EGFRIs) represent a cornerstone in the targeted therapy of malignant tumors. While effective, dermatological adverse events (dAEs) associated with EGFRIs pose a significant challenge, often necessitating treatment discontinuation due to their severity and potential to impede the continuity of cancer therapy. Despite extensive research, the specific mechanisms and predictors of these adverse events remain poorly understood, particularly in diverse populations. This gap in knowledge underscores the need for targeted studies to better predict and manage these events, enhancing patient outcomes and adherence to life-saving therapies. Methods: This observational study was conducted at The First Affiliated Hospital of Guangxi Medical University, covering cancer patients treated with EGFRIs from 2020 to 2022. We analyzed clinical data including patient demographics, treatment specifics, and the development and timing of dAEs. The study employed SPSS 26.0 software for data analysis, focusing on the incidence of dAEs and factors influencing their occurrence. We used Kaplan-Meier and Cox regression methods to establish a predictive model for dAEs, tracking their onset and impact on treatment continuity. Results: In our study of 120 patients treated with EGFR inhibitors at The First Affiliated Hospital of Guangxi Medical University, we found a high prevalence of dAEs, with 84.2% of patients experiencing such effects. The most common manifestations were papulopustular rashes, observed as pustules in 52.5% and papules in 57.4% of cases, followed by nail lesions in 62.4% of patients, oral or other mucosal ulcers in 34.7%, and hair changes in 26.7%. The median incubation time (MIT) for dAEs was 5 weeks. We identified drug type, ethnicity, and occupation as statistically significant risk factors (P<0.05 for all) that influenced the MIT, which the Cox regression model further identified as protective factors. Nomograms were developed to assess the risk of dAEs, although it is important to note that these models have only been internally validated, lacking external validation data at this stage. Conclusions: The study highlights the high incidence of EGFRIs-associated dAEs, with specific dermatological manifestations posing significant challenges in cancer therapy. The identification of drug type, ethnicity, and occupation as influential factors on the MIT for dAEs informs clinical decisions. Our prediction model serves as a practical tool for evaluating the risk of developing dAEs over time, aiming to optimize patient management and mitigate treatment interruptions.

EGFR-TKIs - induced cardiotoxicity in NSCLC: incidence, evaluation, and monitoring.

The advent of targeted drug therapy has greatly changed the treatment landscape of advanced non-small cell lung cancer(NSCLC), but the cardioxic side effects of targeted drug anti-cancer therapy seriously affect the prognosis of NSCLC, and it has become the second leading cause of death in cancer patients. Therefore, early identification of the cardiotoxic side effects of targeted drugs is crucial for the prevention and treatment of cardiovascular diseases. The cardiotoxic side effects that may be caused by novel targeted drugs epidermal growth factor receptor inhibitors, including thromboembolic events, heart failure, cardiomyopathy, arrhythmia and hypertension, are discussed, and the mechanisms of their respective adverse cardiovascular reactions are summarized, to provide useful recommendations for cardiac management of patients with advanced lung cancer to maximize treatment outcomes for lung cancer survivors. Clinicians need to balance the risk-benefit ratio between targeted therapy for malignant tumors and drug-induced cardiotoxicity, and evaluate and monitor TKIs-induced cardiotoxicity through electrocardiogram, cardiac imaging, biomarkers, etc., so as to remove the susceptibility risk factors as soon as possible and provide a reference for the clinical use of such drugs in the treatment of malignant tumors.

Erythema dyschromicum perstans-like eruptions induced by epidermal growth factor receptor inhibitors in patients with lung cancer.

INTRODUCTION: Cutaneous adverse reactions to epidermal growth factor receptor inhibitors (EGFRi) are some of the most common side effects that patients experience. However, cutaneous adverse reactions that cause dyspigmentation in patients have been rarely reported. Erythema dyschromicum perstans (EDP) is a rare pigmentary condition that causes ashy-grey hyperpigmented macules and patches, with a few cases reported from EGFRi in the literature. The disfiguration caused by this condition may negatively impact patients' quality of life. Our study aimed to describe the clinical characteristics of EDP induced by EGFRi to better recognize and manage the condition. METHODS: We conducted a multicenter retrospective review at three academic institutions to identify patients with EDP induced by EGFRi from 2017 to 2023 and included sixteen patients in our study. RESULTS: The median age of patients was 66 years old, with 63% female and 37% male (Table 1). The majority of our patients were Asian (88%). All patients had non-small cell lung cancer and most patients received osimertinib. Median time to EDP was 6 months. The most common areas of distribution were the head/neck region, lower extremities, and upper extremities. Various topical ointments were trialed; however, approximately less than half had improvement in their disease and most patients had persistent EDP with no resolution. All patients desired treatment except one with EDP on the tongue, and there was no cancer treatment discontinuation or interruption due to EDP. Table 1 Patient demographics and clinical characteristics of 16 patients with EDP induced by EGFRi Case no Demographics: age, race, and sex Fitzpatrick skin type Cancer type EGFR therapy Concomitant photosensitive drug(s) Time to EDP (months) Clinical features Distribution Symptoms Treatments and clinical course EDP status from most recent follow up 1 47 y/o Asian male III Stage IV NSCLC Erlotinib None Unknown Brown-blue-gray hyperpigmented patches Bilateral shins Left thigh Xerosis Pruritus Triamcinolone 0.1% ointment for 4 months, improvement of blue discoloration Tacrolimus 0.1% BID for 9 months, improvement but no resolution Ongoing 2 62 y/o Asian female IV Stage IV NSCLC Osimertinib None 4 Gray-brown hyperpigmented patches Bilateral arms Back Forehead Neck Right shin None Tacrolimus 0.1% ointment for 1 year with minor improvement Ongoing 3 69 y/o Asian female IV Stage IV NSCLC Osimertinib None 4 Gray-brown macules and patches Chest Face Forehead Bilateral legs None Tacrolimus 0.1% ointment for 10 months, no improvement Ongoing 4 79 y/o White male II Stage IV NSCLC Osimertinib None 15 Mottled grey-blue hyperpigmented patches and plaques with mild scaling Bilateral arms Back Forehead Neck None Photoprotection, no improvement Ongoing 5 69 y/o Asian female III Stage IV NSCLC Osimertinib Ibuprofen 4 Blue-grey hyperpigmented macules and patches Abdomen Bilateral arms None Tacrolimus 0.1% ointment for 7 months, no improvement Ongoing 6 65 y/o Asian male III Stage IV NSCLC Osimertinib None 20 Hyperpigmented blue gray macules and patches Helix Bilateral shins None Photoprotection, no improvement Ongoing 7 66 y/o Asian female IV Stage IV NSCLC Erlotinib TMP-SMX 6 Ashy grey-brown thin plaques Back Forehead None 2.5% hydrocortisone ointment for 8 months, resolved Resolved 8 82 y/o Asian male III Stage III NSCLC Erlotinib Simvastatin 20 Ash-grey hyperpigmented patches Dorsal feet Forehead Scalp None Photoprotection Ongoing 9 57 y/o Asian female III Stage II NSCLC Erlotinib None 1 Bue-grey discoloration Tongue None No intervention Ongoing 10 51 y/o Asian female III Stage IV NSCLC Osimertinib None 9 Blue-grey hyperpigmented macules and patches Bilateral arms Axillae Groin Neck Trunk None 2.5% hydrocortisone ointment, triamcinolone 0.1% ointment, photoprotection with mild improvement Ongoing 11 67 y/o Asian male III Stage IV NSCLC Osimertinib None 7 Gray-blue macules and patches with mild background erythema and scaling Bilateral arms Ears Face Bilateral shins None Triamcinolone 0.1% ointment, protection for 6 months with mild improvement Ongoing 12 75 y/o Asian female IV Stage III NSCLC Osimertinib TMP-SMX 3 Gray-blue hyperpigmented patches Bilateral arms Abdomen Back Face Bilateral shins Pruritus Triamcinolone 0.1% and betamethasone 0.01% with relief of pruritus, lesions unchanged Triluma cream 6 months, mild improvement Ongoing 13 42 y/o Asian male IV Stage IV NSCLC Afatinib TMP-SMX 24 Grey-brown hyperpigmented patches Back Face None Hydroquinone 4% cream for 2 years with mild improvement Ongoing 14 74 y/o White female III Stage II NSCLC Osimertinib Atorvastatin 4 Grey-brown hyperpigmented patches Bilateral legs Trunk None Photoprotection Ongoing 15 64 y/o Asian female IV Stage IV NSCLC Osimertinib None 3 Gray-brown hyperpigmentation Abdomen Bilateral arms Back Bilateral legs Pruritus Triamcinolone 0.1% cream; No change, minimal concern to patient Ongoing 16 52 y/o Asian female IV Stage IV NSCLC Osimertinib None 42 Gray hyperpigmented patches with digitate shape Abdomen Bilateral flanks None Triamcinolone 0.1% cream Ongoing NSCLC, non-small cell lung cancer, TMP-SMX, Trimethoprim/Sulfamethoxazole CONCLUSIONS: We highlight the largest case series describing EDP from EGFR inhibitors, which mostly affected Asian patients with lung malignancy and on EGFR tyrosine kinase inhibitors. Clinicians should be able to recognize this condition in their patients and assess how it is affecting their quality of life, and refer to dermatology to help with management.

Panitumumab-Induced Periorbital Dermatitis: A Case Report.

Panitumumab is a recombinant, fully humanized immunoglobulin G2 monoclonal antibody targeting the epidermal growth factor receptor (EGFR). It is approved for the first- and second-line treatment of advanced wild-type KRAS colorectal cancer. Although common cutaneous side effects include acneiform dermatitis, folliculitis, and xerosis, ocular toxicities have occasionally been reported. Herein, we report the case of an 81-year-old Thai female with chemorefractory advanced stage sigmoid colon cancer who developed isolated periorbital dermatitis following treatment with panitumumab plus modified FOLFOX6. The cutaneous adverse reaction recurred after subsequent infusions; however, it was alleviated by topical therapy. To our knowledge, panitumumab-induced periorbital dermatitis is exceptionally rare. To raise awareness of potential periocular cutaneous side effects in patients taking EGFR inhibitors, the published literature regarding periorbital dermatitis induced by these agents has also been reviewed in this article. Periorbital dermatitis should be considered as a potential cutaneous reaction following panitumumab administration, and should be promptly treated.

New-onset keratitis associated with epidermal growth factor receptor-based targeted therapies in Han Chinese patients with lung cancer: A multi-center cohort study.

PURPOSE: To determine the risk and incidence of keratitis following treatment with epidermal growth factor receptor inhibitors (EGFRi) and subtypes of EGFRi-associated keratitis. METHODS: This multi-center cohort study included EGFRi-treated patients and non-users with lung cancer between 2010 and 2023. EGFRi included first-generation agent gefitinib and erlotinib, second-generation agent afatinib, and third-generation agent osimertinib. The primary outcome was new-onset keratitis. Cox proportional hazard models with multivariable adjustment were applied to determine the effect of EGFRi on keratitis over time. Subgroup analyses were conducted, stratified by agents of EGFRi. Sub-outcome analyses were performed to identify the subtypes of EGFRi-associated keratitis. RESULTS: A total of 1549 EGFRi-treated patients and 6146 non-users were included. 38 (2.5%) EGFRi-treated patients developed keratitis. The incidence of keratitis in EGFRi-treated patients was significantly higher than that in controls (incidence rate, IR, per 1000 person-years = 14.7 vs 4.49, p < 0.0001). EGFRi-treated patients presented with an increased risk for keratitis (adjusted hazard ratio, aHR = 3.14, 95% CI = 1.85-5.35, p < 0.001). Erlotinib (aHR = 2.64, 95% CI = 1.35-5.15, p = 0.004), afatinib (aHR = 4.42, 95% CI = 2.17-9.02, p < 0.001), and osimertinib (aHR = 4.67, 95% CI = 1.60-13.64, p = 0.005), but not gefitinib (aHR = 2.30, 95% CI = 0.96-5.55, p = 0.063), significantly contributed to the risk of keratitis. Subtypes of EGFRi-associated keratitis included corneal ulcer (IR = 2.31 vs 0.166, p < 0.0001) and keratoconjunctivitis (IR = 9.27 vs 2.91, p < 0.0001). None of the EGFRi-treated patients developed perforated corneal ulcer, interstitial and deep keratitis, or corneal neovascularization. CONCLUSION: Treatment with EGFRi was associated with an increased risk of keratitis. Ocular toxicity of EGFRi was highest for third-generation agents, followed by second-generation agents, and then first-generation agents.

Ligand and structure based hierarchical virtual screening cascade for finding novel epidermal growth factor receptor inhibitors.

The epidermal growth factor receptor (EGFR) tyrosine kinase plays an important role in tumor formation and growth by mediating cell growth and other physiological processes. Therefore, EGFR is a promising target for the treatment of cancer. In this work, we combined ligand-based and structure-based virtual screening methods to identify novel EGFR inhibitors from a library of more than 103 thousand compounds. We first obtained hundreds of compounds with similar physiochemical properties through 3D molecular shape and electrostatic similarity screening with potent inhibitors AEE788 and Afatinib as queries. Next, we identified compounds with strong binding affinities to the EGFR pocket through molecular docking, which makes good use of the structure information of the receptor. After molecular scaffold analysis, our bioassay confirmed 13 compounds with EGFR inhibitory activity and three compounds had IC50 values below 1000 nM. In addition, we collected 5371 EGFR inhibitors from online databases, and clustered them into 7 groups by K-means method using their ECFP4 fingerprints as input. Each cluster had typical molecular fragments and corresponding activity characteristics, which could guide the design of EGFR inhibitors, and we concluded that the fragments from some of the hits are indicated in the highly active scaffolds.

Risk factors for thromboembolism during first-line treatment of patients with unresectable advanced or recurrent colorectal cancer: a retrospective short study.

BACKGROUND: While cancer is a risk factor for developing thromboembolism, so is the use of molecularly targeted therapies. This study aimed to determine whether thromboembolism incidence differed between vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitor use in patients with unresectable advanced or recurrent colorectal cancer, and to compare the risk of thromboembolism caused by cancer and the use of molecular targeted therapy drugs. MAIN BODY: We retrospectively evaluated patients with unresectable advanced or recurrent colorectal cancer who were treated with a cytotoxic anticancer drug and a VEGF or EGFR inhibitor combination between April 2016 and October 2021. Patients were compared in terms of the regimen administered, thromboembolism occurrence during the first-line treatment period, patient background, and clinical laboratory values. Of the 179 included patients, 12 of 134 (8.9%) in the VEGF-inhibitor group and 8 of 45 (17.8%) in the EGFR-inhibitor group developed thromboembolism, with no significant difference between the groups (P = 0.11). There was no significant difference in time to thromboembolism between patients in the VEGF- inhibitor group and patients in the EGFR-inhibitor group (P = 0.206). The cutoff value determined by a receiver operating characteristic analysis for the occurrence of thromboembolism was one point. Multivariate analysis using the occurrence of thromboembolism as the response variable identified at least one risk factor for thromboembolism (odds ratio = 4.17, P = 0.006, 95% confidence interval = 1.51-11.50). Molecular targeted therapies were not identified as a risk factor. CONCLUSIONS: Although the small sample size, there was no difference in the incidence of thromboembolism between the two molecular-targeted therapies in first-line treatment of patients with unresectable advanced or recurrent colorectal cancer. Our results suggest that risk factors for thromboembolism may be more strongly influenced by cancer itself than by the use of molecularly targeted therapies.

Efficacy and safety of antiangiogenic agents or chemotherapy plus EGFR-TKIs in advanced non-small cell lung cancer: A systematic review and network meta-analysis.

BACKGROUND: The combination of antiangiogenic agents with epidermal growth factor receptor inhibitors (EGFR-TKIs) and chemotherapy with EGFR-TKIs are the most common combination treatment options in epidermal growth factor receptor (EGFR) positive non-small cell lung cancer (NSCLC). This network meta-analysis was performed to evaluate the differences between them. METHODS: We searched the PubMed, EMBASE and the Cochrane Controlled Trials Register up to August 2022. The primary outcomes were progression-free survival (PFS) and objective response rate (ORR). The secondary endpoints were overall survival (OS), disease control rate (DCR) and adverse events (AEs). The data of hazard ratio (HR) or risk ratio (RR) with their corresponding 95% confidence intervals (CIs) were extracted in the studies. A network meta-analysis (NMA) was used to indirectly compare the efficacy and safety of antiangiogenic agents plus EGFR-TKIs and chemotherapy plus EGFR-TKIs. RESULTS: Pooled data of included studies were demonstrated that chemotherapy plus EGFR-TKIs had a benefit in ORR compared to antiangiogenic agents plus EGFR-TKIs in patients with EGFR mutated NSCLC (RR = 1.1, 95% CI: 1.0-1.2). However, there were no significant differences in PFS, OS and DCR between in the two group (PFS: HR = 1.0, 95% CI: 0.74-1.6; OS: HR = 0.78, 95% CI: 0.45-1.5; DCR: RR = 1.0, 95% CI: 0.94-1.1). The common treatment-related AEs in the two groups were relatively manageable. CONCLUSION: Based on the efficacy and safety, the combination of chemotherapy with EGFR-TKIs is considered the best combination treatment options in advanced NSCLC with EGFR mutation.

Acupuncture in the Treatment of Panitumumab Skin Toxicity: A Case Report.

BACKGROUND: Inflammatory skin rash resulting from treatment with epidermal growth factor receptor inhibitors may cause physical and mental disabling to patients treated for their oncologic condition and may, in some cases, lead to the cessation of biological treatment. CASE REPORT: In this case report, acupuncture treatment was provided to a patient with metastatic colorectal carcinoma who developed skin toxicity from panitumumab including rash, itching, and skin inflammation. Itching, infection, and inflammation symptoms improved significantly following acupuncture, subsequently relapsed following treatment cessation, and improved once again following reintroduction of acupuncture. CONCLUSION: Acupuncture may be effective in alleviating panitumumab-related skin inflammatory symptoms.

Dermatologic toxicities in epidermal growth factor receptor: a comprehensive pharmacovigilance study from 2013 to 2023.

Epidermal growth factor receptor inhibitors (EGFRIs) induced cutaneous toxicity is a common adverse event (AE), although it is not as severe as major cancers, we still need to pay enough attention to them. Therefore, it is necessary to evaluate the diversity of EGFRI class drugs. The objective of this study was to conduct a scientific and systematic investigation into the correlation between EGFRI and cutaneous toxicities. The data accessed from the FDA adverse event reporting system database (FAERS) encompass a time frame spanning from January 2013 to March 2023. By utilizing reporting odds ratios (RORs), information components (ICs), proportional reporting ratios (PRRs), and chi-squared (χ2), the relationship between drugs and adverse reactions was evaluated through disproportionality analysis. Within the FAERS database, a total of 29,559 skin adverse events were recorded. A robust indication of the correlation between EGFRI and elderly patients (≥65 years) was identified. Among EGFRIs, erlotinib accounted for the largest proportion of skin adverse events (39.72%). Rash, dry skin, and pruritus ranked top among all preferred terms, and signals such as rash, skin lesions, and acneiform dermatitis were detected in every single drug. Clinicians should guide patients customize the treatment plan for each patient.

Topical Zhiyang Pingfu Liquid for Moderate to Severe Skin Rash Associated With EGFRIs: A double-blinded randomized controlled trial.

BACKGROUND: Skin rash is the most common adverse effect associated with epidermal growth factor receptor inhibitors (EGFRIs). The study has observed the efficacy and safety of Zhiyang Pingfu Liquid in the treatment of EGFRIs-related moderate and severe rash. METHODS: Patients suffering from EGFRIs-related moderate to severe rash were enrolled and then randomly divided into the treatment group and the control group, receiving Zhiyang Pingfu Liquid and placebo liquid respectively combined with minocycline and methylprednisolone recommended by guideline for 14 days. Changes in rash grades were observed, as well as the dosage of minocycline. Blood routine examination and liver and kidney function were evaluated to observe the safety of Zhiyang Pingfu Liquid. The total response of rash included complete response (CR) and partial response (PR). And the effective rate of rash was the percentage of CR and PR in the total cases. RESULTS: A total of 54 out of 58 patients finished the study with 27 patients in each group. The effective rates of rash among the treatment group and the control group were 81.48% and 55.56% after 14 days treatment (P = .040). The treatment group had a lower dosage of minocycline compared with the control group. The median total dose of oral minocycline administration was 1000 mg in the treatment group and 1400 mg in the control group. CONCLUSION: Zhiyang Pingfu Liquid can effectively improve the moderate and severe EGFRIs-induced rash, and reduce the use of minocycline, as well as the side reactions brought by minocycline. However, larger randomized controlled trials are needed to verify these findings. CLINICAL TRIAL REGISTRATION: The trial was registered on the Chinese Clinical Trial Registry, the registration number is ChiCTR1800017053.

Red light emitting diode as an adjuvant treatment for epidermal growth factor receptor inhibitors-induced paronychia.

We evaluated the efficacy and safety of red light LED as an adjuvant treatment for epidermal growth factor receptor inhibitor-induced paronychia. Eight patients were recruited in this randomized, single-blinded controlled trial. They were randomized to receive red-light on one hand or foot 2-3 times/week for 6 weeks while the contralateral side served as controls. The standard treatments were continued. Erythema and lesion elevation observed by Anthera® 3D, severity and pain scores were obtained at weeks 0, 2, 4, 6, and 8. The red light group showed significantly lower erythema, severity, and pain scores at weeks 4, 6, and 8. The elevation was significantly lower in the red light group at every follow-up visit. No adverse events occurred. Red light therapy may be an option as adjunctive treatment for EGFRi-induced paronychia.

Incidence of Adverse Cutaneous Reactions to Epidermal Growth Factor Receptor Inhibitors in Patients with Non-Small-Cell Lung Cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors are routinely used in advanced non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, their use is associated with gastrointestinal and cutaneous toxicities, including acneiform eruptions, pruritus, xerosis, nail and hair changes. Aside from reducing patients' quality of life, such cutaneous reactions have a considerable impact on the oncologic treatment given that dose reduction or even drug discontinuation may be necessary, especially for the severe forms. OBJECTIVES: To assess the incidence, impact on treatment and management of EGFR inhibitor-related cutaneous reactions in patients with NSCLC. METHODS: We conducted a prospective observational study on 87 consecutive patients with advanced NSCLC treated with EGFR-tyrosine kinase inhibitors from January to December 2019. Patients who developed mucocutaneous reactions were evaluated and treated by both oncologists and dermatologists, and underwent dermatologic follow-up until resolution of the cutaneous reaction. Demographic and clinical data were collected for each patient, and the severity of the cutaneous reaction was graded using the Common Terminology Criteria for Adverse Events. RESULTS: Seventy-one patients (81.6%) developed cutaneous reactions. The number of cutaneous reactions per patient was 1 in 37%, 2 in 41% and 3 or more in 22%. The most common cutaneous reactions included acneiform eruptions (56.3%), xerosis ± asteatotic eczema (48.3%), nail changes (39.1%), mucositis (29.9%), pruritus (24.1%) and hair changes (12.6%). Afatinib was associated with a higher rate of nail changes and mucositis (p < 0.01 and p < 0.005, respectively) compared to other agents, while no patient-related predictive factors were identified. Dose reduction was performed in 18% of patients. Multidisciplinary management involving dermatologists allowed to resume the drug in all patients who had discontinued it due to the cutaneous reactions. CONCLUSIONS: A multidisciplinary approach to EGFR inhibitor-related cutaneous reactions is advantageous and can reduce the need to discontinue oncologic treatment.

Gefitinib induced severe hyponatremia: A case report.

INTRODUCTION: Evolution of targeted molecular therapies has greatly improved patient survival in cancer. Gefitinib is an oral, reversible, epidermal growth factor receptor inhibitor used in advance non-small cell lung cancer. Skin rashes and diarrhea are common adverse effects associated with gefitinib. However, electrolytes disorders are rarely reported with gefitinib, particularly hyponatremia. CASE REPORT: We describe a 65-year-old male with metastatic non-small cell lung cancer treated with gefitinib for the last three weeks. He presented to our hospital with complaints of acute onset drowsiness. On evaluation of drowsiness, patient was diagnosed with severe hyponatremia.Management and outcome: After ruling out other common causes of hyponatremia, gefitinib was attributed as a cause of hyponatremia. Gefitinib was immediately stopped and IV hypertonic saline (3% sodium chloride) was started due to severe symptomatic hyponatremia. After seven days of cessation of gefitinib, he became asymptomatic with normalisation of serum sodium levels. DISCUSSION: Hyponatremia in cancer patients is associated with poor prognosis and prolonged hospital stay. Possibility of gefitinib-induced hyponatremia should be considered in order to achieve early diagnosis and prevent significant mortality in cancer patients.

Dermatological side effects of targeted antineoplastic therapies: a prospective study.

INTRODUCTION: Epidermal growth factor receptor inhibitors (EGFRs) are chemotherapeutic agents used in multiple solid organ malignity. These medications have common dermatological side effects, particularly papulopustular (PPL) lesions. The management of the diagnosis and treatment processes for such side effects may facilitate the continuation of chemotherapy and enhance the patient's quality of life. OBJECTIVE: The objective of this study is to report the cutaneous side effects of EGFR inhibitors and to share treatment methods for such side effects. MATERIALS AND METHODS: In this prospective study, 59 patients using EGFR due to breast and colorectal carcinoma at the oncology unit of Haseki Training and Research Hospital were assessed. The patients for whom EGFR was initiated were examined at the beginning of the treatment at weeks 1 and 2, their demographic characteristics were recorded, and the patients who developed a skin rash were followed up from the onset of the lesion. The PPL side effects that developed in the patients and other dermatological findings were recorded. The PPL side effects were graded, and the treatment plans were reported. The study was conducted between February 2016 and February 2018 under the approval of the local ethical committee. RESULTS: The mean age of the 59 patients (47 females, 12 males) taking EGFR inhibitors was 52.4 ± 12.0 (range: 29-84). Forty-five patients had early stage and 14 patients had advanced stage carcinoma. Fourteen patients had colorectal carcinoma, three patients had renal cancer, and 42 patients had breast cancer. Forty-two patients were using trastuzumab (single therapy in 29 patients and combined therapy in 13 patients), five patients were using cetuximab, three patients were using sunitinib, eight patients were using panitumumab, and six patients were using pertuzumab. In 22 patients, PPL side effects were observed in the skin; it was G1 in 19 patients and G2 in three patients. In seven patients who developed acneiform side effects, systemic doxycycline was used, and in others, topical tetracycline and clindamycin were used. Except for one patient using trastuzumab, all patients has lesions on the face, upper trunk, and back. One patient exhibited an atypical rash, which was diagnosed as a granulomatous follicular reaction. Xerosis was present in two cases, and paronychia, pyogenic granuloma, trichomegaly, and madarosis were observed in one patient each. The patients who developed an acneiform rash were treated with topical and systemic antibiotics, light keratolytics, and emollients. The skin side effects of all patients were mild to moderate, and all patients completed the chemotherapy process. An acneiform skin rash and other dermatological side effects are common with EGFR inhibitors. To treat these side effects, emollients, topical steroids, and local, systemic antibiotics are recommended. Clindamycin may be preferred as a topical treatment, and doxycycline may be preferred as a systematic treatment.

Efficacy and Safety of Epidermal Growth Factor Receptor (EGFR) Inhibitors Plus Antiangiogenic Agents as First-Line Treatments for Patients With Advanced EGFR-Mutated Non-small Cell Lung Cancer: A Meta-Analysis.

Background: Tyrosine kinase inhibitors (TKIs) are standard treatment options for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Increasing clinical investigations have explored the value of EGFR-TKIs plus antiangiogenic drugs as the first-line treatment for EGFR-mutated NSCLC. Methods: We systematically searched PubMed, Cochrane Library, and EMBASE for randomized controlled trials (RCTs) investigating EGFR-TKIs administered with or without antiangiogenic agents for advanced EGFR-mutated NSCLC. The latest RCT that was presented orally at the 2019 European Society for Medical Oncology Congress was obtained online. The endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rates (DCRs), and grade 3 or higher adverse events (AEs). Results: We included seven articles on five trials with 1,226 patients. The interventions for the experimental group were the first-generation EGFR-TKI erlotinib combined with bevacizumab (four studies) or ramucirumab (one study), and erlotinib monotherapy (four studies) or erlotinib plus placebo (one study) for the control group. All studies reached their primary study endpoints (i.e., PFS). Compared to erlotinib monotherapy, erlotinib plus antiangiogenic agents remarkably prolonged PFS [hazard ratio (HR) = 0.59, 95% confidence interval (CI) = 0.51-0.69, P = 0.000]; however, ORR, DCR, and OS were similar between the two groups. The overall grade 3-5 AEs increased in combination group (OR = 5.772, 95% CI = 2.38-13.94, P = 0.000), particularly the incidence of diarrhea (OR = 2.51, 95% CI = 1.21-5.23, P = 0.014), acneiform (OR = 1.815, 95% CI = 1.084-3.037, P = 0.023), hypertension (OR = 6.77, 95% CI = 3.62-12.66, P = 0.000), and proteinuria (OR = 13.48, 95% CI = 4.11-44.22, P = 0.000). Additionally, subgroup analysis demonstrated that Asian patients could significantly benefit from combination therapy (HR = 0.59, 95% CI = 0.50-0.69, P = 0.000). Patients with exon 19 deletions (HR = 0.61, 95% CI = 0.49-0.75, P = 0.000) and 21 Leu858Arg mutations (HR = 0.59, 95% CI = 0.47-0.73, P = 0.000) had almost equivalent PFS benefits when treated with double-blocking therapy. Patients with brain metastases at baseline in the combination group had a trend toward better PFS (HR = 0.55, 95% CI = 0.30-1.01, P = 0.001). Conclusions: Erlotinib plus bevacizumab or ramucirumab in EFGR-mutated NSCLC first-line setting yielded remarkable PFS benefits; however, this was accompanied by higher AEs. Epidermal growth factor receptor-TKI plus antiangiogenic agent therapy may be considered a new option for advanced EGFR-mutated NSCLC patients.

The Addition of EGFR Inhibitors in Neoadjuvant Therapy for KRAS-Wild Type Locally Advanced Rectal Cancer Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Patients with locally advanced rectal cancer (LARC) are at higher risk of local and distant recurrence and are thus more vulnerable to metastatic diseases. Neoadjuvant chemoradiotherapy (nCRT) and subsequent curative resection with total mesorectal excision (TME) followed by adjuvant chemotherapy have been recommended by the National Comprehensive Cancer Network (NCCN) guidelines as standard of care for LARC patients. However, the efficacy of the addition of epidermal growth factor receptor (EGFR) inhibitors in kirsten rat sarcoma viral oncogene (KRAS)-wild type LARC patients remains uncertain. MATERIALS: PubMed, Embase, and Web of Science were searched to retrieve records on the application of EGFR inhibitors in a neoadjuvant setting for LARC patients. pCR was used as surrogate endpoint to perform data synthesis in a single-arm setting. RESULTS: Ten cohorts covering 540 subjects were eligible in this systematic review. The pooled pCR rate for EGFR inhibitors was 15% (95% confidence interval (95% CI), 11-20%; I2 = 55.2%); the pooled estimates of Grade 3/4 diarrhea, Grade 3/4 hand-foot syndrome, Grade 3/4 acneiform rash were 17% (95% CI, 4-34%; I2 = 93.3%), 2% (95% CI, 0-5%; I2 = 13.7%), and 15% (95% CI, 9-22%; I2 = 65.4%), respectively. CONCLUSION: The addition of EGFR inhibitors in the nCRT for KRAS-wild type LARC patients provides comparable efficacy and acceptable safety. However, the results should be interpreted cautiously due to the small amount of relevant data and need further confirmation by more future studies.

A comparative study on erlotinib & gefitinib therapy in non-small cell lung carcinoma patients.

Background & objectives: Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have been evaluated in patients with advanced non-small cell lung cancer (NSCLC). Erlotinib and gefitinib are the first-generation EGFR-TKIs for patients with NSCLC. However, there is a paucity of studies comparing the effectiveness of these two drugs. Hence, this study was aimed to compare the effectiveness and safety of erlotinib and gefitinib in NSCLC patients. Methods: This study included 71 NSCLC patients who received EGFR-TKIs between 2013 and 2016. Adverse drug reaction of both erlotinib (n=37) and gefitinib (n=34) was determined and graded according to Common Terminology Criteria for Adverse Events grading system. Effectiveness was measured using response evaluation criteria in solid tumours and progression-free survival (PFS). Pharmacoeconomic analysis was performed by cost-effective analysis. Results: When comparing safety profile, both the drugs had similar adverse events except for dermal side effects such as acneiform eruption (51.4%), rash (54.05%) and mucositis (59.5%) for erlotinib and 20.6, 26.5 and 29.4 per cent for gefitinib, respectively. The PFS of the two drugs was compared to differentiate the effectiveness of erlotinib and gefitinib. There was no significant difference between the effectiveness of the two drugs. The pharmacoeconomic analysis showed that gefitinib was more cost-effective than erlotinib. Interpretation & conclusions: This study showed that erlotinib and gefitinib had similar effectiveness but gefitinib had a better safety profile compared to erlotinib. Therefore, gefitinib could be considered a better option for NSCLC patients compared to erlotinib. However, further studies need to be done with a large sample to confirm these findings.

Immunotherapies and Targeted Therapies in the Treatment of Metastatic Colorectal Cancer.

Colorectal cancer (CRC) is the third leading cause of cancer deaths, and while mortality has largely improved in the developed world, five-year survival for metastatic disease remains dismally low at only 15%. Fortunately, nearly a dozen targeted therapies and immunotherapies have been FDA approved in the past decade for certain patient profiles with metastatic CRC (mCRC), and many others are under development. Checkpoint inhibitors such as pembrolizumab have proven effective at extending survival for mismatch repair (MMR)-deficient and high microsatellite instability (MSI) mCRC patients. In combination with chemotherapy in first- and second-line treatment, antiangiogenic (anti-vascular endothelial growth factor (anti-VGEF)) agent bevacizumab has been shown to increase mCRC survival. Anti-epidermal growth factor receptor (anti-EGFR) agents panitumumab and cetuximab, in combination with chemotherapy, have also prolonged survival among KRAS and all RAS wild-type mCRC patients. Among these patients, anti-EGFR therapy has been found to be more efficacious than bevacizumab. Improved selectivity has allowed small-molecule receptor tyrosine kinase (RTK) inhibitors to target VEGF and EGFR with greater efficacy and tolerability. Combinations of immunotherapies, RTKs, monoclonal antibodies, and cytotoxic drugs are being investigated to provide broad-spectrum protection against relapse by simultaneously targeting many cancer hallmarks. Lastly, human epidermal growth factor receptor 2 (HER2) therapy has shown promise for HER2-positive mCRC patients, though larger clinical trials are required to secure FDA approval.

Management of skin toxicities during panitumumab treatment in metastatic colorectal cancer.

BACKGROUND: Anti-epidermal growth factor receptor therapy is associated with skin adverse events not previously reported with conventional chemotherapy. Prophylactic actions are recommended, but routine clinical management of these toxicities and their impact on quality of life remain unknown. AIM: To assess the dermatological toxicities reported after panitumumab initiation, their impact on the quality of life and the clinical practices for their management. METHODS: Patients included in this prospective multicenter observational study were over 18 years of age and began treatment with panitumumab for wild-type KRAS metastatic colorectal cancer. The incidence of dermatological toxicities, clinical practices for their management and impact on quality of life were recorded during a 6-mo follow-up. RESULTS: Overall, 229 patients (males, 57.6%; mean age, 66.2 years) were included. At day 15, 59.3% of patients had dermatological toxicity; the rate peaked at month 2 (74.7%) and decreased at month 6 (46.5%). The most frequent dermatological toxicities were rash/acneiform rash, xerosis and skin cracks. At least one preventive treatment was administered to 65.9% of patients (oral antibiotics, 84.1%; emollients, 75.5%; both, 62.9%). The rates of patients who received at least one curative treatment peaked at month 2 (63.4%) and decreased at month 6 (44.8%). The impact of the dermatological toxicities on quality of life was limited as assessed with Dermatology Life Quality Index scores and inconvenience visual analogic scale score. The rates of topical corticosteroids administration and visits to specialists were low. CONCLUSION: The rates of the different skin toxicities peaked at various times and were improved at the end of follow-up. Nevertheless, their clinical management could be optimized with a better adherence to current recommendations. The impact of skin toxicities on patient's quality of life appeared to be limited.