Currently, both domestic and international guidelines and expert consensus regarding skin reactions induced by targeted drugs are available. However, the understanding of guideline content and recommended measures among clinical healthcare providers is far from satisfactory (23). Clinical managers should attach great importance to the knowledge needs of healthcare providers regarding targeted drugs, promptly conduct training to fill knowledge gaps, enabling them to master the symptom manifestations, predilection sites, development process, severity grading, treatment principles, and precautions of commonly used drugs for cutaneous toxicity caused by EGFRIs. This way, they can provide higher-quality healthcare services to cancer patients (12, 18, 23, 27). Acne-like rashes represent the earliest and most prevalent toxicity symptoms of EGFRIs (10). Approximately 60% of patients with rashes experience symptoms such as skin pruritus, xerosis, desquamation, a burning sensation, and pain (11), which frequently impact the daily existence and nocturnal slumber of cancer patients (25). Rashes are prone to occur in regions abundant in sebaceous glands (such as the head and face, particularly the nose, cheeks, nasolabial folds, and perioral areas, the “V”-shaped zone of the neck, the upper chest, and the back, etc.). When severe, the limbs can also be affected, and in extreme cases, the entire body can be involved (11, 25). Moreover, rashes caused by EGFRIs generally adhere to a well-defined clinical course. Rashes typically emerge within 1–2 weeks of treatment, peak at 4–6 weeks of treatment, and gradually wane 3–4 months subsequent to treatment (10, 16). The advancement of rashes typically traverses four distinct phases: during the first week, there is paresthesia (dysesthesia) accompanied by erythema and edema; from the first to the third week, red papules and pustules gradually materialize on the skin; from the third to the fourth week, purulent substances can surface on the skin and commence drying to form crusts; during the fourth week, there may be generalized erythema accompanied by scattered telangiectasia (12). Clinically, the diagnosis of cutaneous toxicity symptoms is typically based on a clear record of EGFRIs drug ingestion and pertinent skin clinical symptoms. Unless the clinical manifestations are atypical or the rashes are unresponsive to corresponding treatment, skin biopsy is generally not carried out to confirm cutaneous toxicity symptoms (11, 28). It is recommended that oncologists and dermatologists establish a collaborative team paradigm and enhance the referral and consultation regime. For patients whose cutaneous toxicity symptoms remain unimproved within 2 weeks of continuous treatment, those with moderate-to-severe cutaneous toxicity, and those with an atypical rash appearance or distribution, expert consultation is advisable. It is recommended to assemble a professional cutaneous toxicity team comprising oncology experts, dermatologists, pharmacy specialists, nursing teams, etc. (14, 16). Based on the type, severity, and location of cutaneous toxicity induced by EGFRIs, and in conjunction with the patient’s personal volition, individualized treatment can be administered to each cancer patient to assist them in effectively managing cutaneous toxicity symptoms (24, 25).

Peeters et al. (30) conducted a review of a panitumumab trial involving 463 cancer patients, thereby confirming that the clinical grading of cutaneous toxicity symptoms in cancer patients is associated with patient-reported health outcomes, quality of life, and survival. Acne-like rashes do not represent a contraindication to the continued administration of EGFRIs. A consistent positive correlation exists between the severity of rashes and anti-tumor activity (10, 22), and rashes may serve as a surrogate marker for the therapeutic efficacy of EGFRIs (12, 26). Cancer patients undergoing targeted therapy, often afflicted with malignant tumors and concurrently experiencing drug-related adverse reactions, are confronted with cutaneous toxicity symptoms. In particular, the dense rashes on the face significantly affect their self-image. The pruritic symptoms are generally pronounced, which frequently leads to patient irritability and excessive concern regarding treatment prognosis (31). This situation can potentially disrupt patients’ intimate and interpersonal relationships, even culminating in communication barriers and social isolation. In fact, rashes are non-infectious (28), self-limiting, and reversible (26). They tend to exhibit a pattern of repeated recurrence and remission throughout the treatment cycle, with their severity generally gradually diminishing (29). Typically, they subside within 4 weeks subsequent to the discontinuation of EGFRIs, without leaving any scars (11, 25). It is recommended that medical personnel apprise cancer patients and their families of the clinical manifestations, potential implications, treatment efficacy, and prognosis of cutaneous toxicity symptoms induced by EGFRIs (20, 23). Clearly communicate to cancer patients that EGFRI-induced cutaneous toxicity symptoms can be effectively managed at all possible stages and across all grades, thereby alleviating their psychological burden and enhancing their confidence in treatment (26). Lei and Chen (32) posited that following the administration of drugs to targeted patients, due to the absence of effective nursing management, patients lack an accurate understanding of the adverse reactions ensuing from drug intake and the corresponding countermeasures, resulting in poor medication compliance. This finding underscores the imperative for medical staff to prioritize the health education requirements of cancer patients in relation to targeted therapy. It is recommended that medical staff furnish relevant health education materials and information resources. During hospitalization, through means such as dedicated lectures on cutaneous toxicity symptoms, patient-experience exchange sessions, and the dissemination of educational brochures, and subsequent to patient discharge, via continuous nursing interventions such as telephone follow-up or WeChat-based follow-up, to facilitate cancer patients in enhancing their knowledge of EGFRIs and their self-skin-care capabilities (20, 22).

The cutaneous toxicity symptoms in cancer patients resulting from EGFRIs are associated with both drug-related factors (such as the type of EGFRIs, dosage, treatment duration, etc.) and patient-specific factors (including gender, smoking status, skin phototype, immune status, and history of exposure to cytotoxic drugs, etc.) (10, 12, 29). At present, EGFRIs are principally categorized into two main classes: tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) (33). Research has uncovered that the cutaneous toxicity reaction spectra of EGFR-TKIs and EGFR-mAbs bear resemblance; nevertheless, the occurrence rate of cutaneous toxicity symptoms is marginally higher in the case of EGFR-mAbs compared to EGFR-TKIs, with minute disparities in incidence among various drugs (34). These cutaneous toxicity symptoms commonly exhibit dose-dependence and frequently follow a pattern of recurring and remitting cycles over the course of treatment (10, 29). A retrospective research endeavor demonstrated that male cancer patients are more disposed to develop moderate-to-severe rashes, often resulting in the discontinuation of EGFRIs treatment, in contrast to their female counterparts (35). The correlation between age and the risk of cutaneous toxicity remains an enigma. One study indicated an association between patients aged 70 years or older and an elevated risk of severe rashes in non-small-cell lung cancer patients (36). In contrast, another study proposed a link between patients aged 70 years or younger and a higher incidence of grade 3 rashes in metastatic colon cancer patients (37). Currently, the evidence supporting the impact of age on cutaneous toxicity symptoms is scarce, and cancer patients of any age group are susceptible to these symptoms (10, 11). Smoking has the potential to stimulate the production of pigments within liver cells (11), which in turn accelerates the clearance rate of EGFRIs drugs (12), consequently increasing the maximum tolerated dose of EGFRIs in cancer patients. As a result, smokers typically experience less severe cutaneous toxicity symptoms compared to non-smokers (28). A study has revealed that moderate-to-severe rashes are almost solely observed in cancer patients with a skin phototype I or II (38), suggesting that the skin phototype represents a potential determinant influencing the cutaneous toxicity symptoms in cancer patients (11). Additionally, elements such as the immune status of cancer patients and the occurrence of genetic mutations like Kirsten rat sarcoma (KRAS) mutations can also impact their cutaneous toxicity manifestations (28). The utilization of cytotoxic drugs and concurrent radiotherapy in cancer patients is prone to impair the skin’s barrier function (20). Exposure of the skin to ultraviolet rays and inadequate moisturization might play a supplementary role in the progression and severity of rashes, thereby exacerbating the cutaneous toxicity symptoms of patients (11).

Assessment represents the initial step in symptom management. Healthcare providers should make a clinical diagnosis of cutaneous toxicity symptoms based on the EGFRIs medication history of cancer patients and the results of physical examinations (12). It is recommended that healthcare providers evaluate aspects such as the location, nature, severity, density, development process, triggering factors, presence of infection, patients’ subjective experiences, and reports and records of other adverse reactions of the cutaneous toxicity symptoms caused by EGFRIs (17, 20). Precise assessment of cutaneous toxicity symptoms is conducive to scientifically assisting clinical decision-making and formulating accurate treatment strategies. Currently, common skin assessment tools include CTCAE, MESTT, EGFRISTI, DLQI, Skindex, FACT-EGFRIs-18, etc. (14, 18, 20, 26). The Common Terminology Criteria for Adverse Events (CTCAE) is the most prevalent skin evaluation tool in current clinical trials and management reviews. It simply categorizes the cutaneous toxicity symptoms of EGFRIs based on the affected body surface area and symptoms (11). However, its limitations lie in its inability to reflect the sub-acute or chronic nature of cutaneous toxicity symptoms, and the patient-reported outcomes are not incorporated into the assessment of subjective symptoms and the impact on quality of life (12). Clinical healthcare providers should fully consider the objective circumstances of clinical practice when using this tool, select appropriate assessment items, and avoid omissions that could lead to incomplete reports (11). The MASCC EGFRI Skin Toxicity Tool-MESTT (39) was developed by the Multinational Association of Supportive Care in Cancer (MASCC). It has a strong correlation with the grading of CTCAE and can address the under-reporting and insufficient assessment of skin-related adverse events (18). The Epidermal Growth Factor Receptor Inhibitor Related Skin Toxicity Index (EGFRISTI) (40) determines the severity of cutaneous toxicity through numerical quantification. This tool is recommended for assessing the scope of cutaneous toxicity of EGFRIs (12). Furthermore, the Dermatology Life Quality Index (DLQI) (41), Skindex series scales (42, 43), and the Functional Assessment of Cancer Therapy-Epidermal Growth Factor Receptor Inhibitor-18 (FACT-EGFRIs-18) scale (44) are all patient-reported tools and belong to skin-related quality-of-life scales. They are recommended for use in the quality-of-life assessment of cancer patients after they have used EGFRIs. It is recommended that clinical healthcare providers assess cancer patients at least once every 2 weeks to promptly identify and intervene in cutaneous toxicity symptoms (26). If secondary skin infection in cancer patients is suspected, it is advisable to conduct bacterial and fungal cultures before using antibiotic treatment to determine the source of infection (23).

EGFR plays a crucial role in regulating skin inflammation, barrier function, and innate immunity (45). Affected by EGFRi drugs, the skin of cancer patients is more vulnerable compared to normal skin. Therefore, medical staff should guide them to minimize skin irritation (27). First, cancer patients should avoid over-cleaning their skin and avoid showering with water that is too cold or too hot. It is recommended to use lukewarm water at ≤40 °C (17). Second, cancer patients should avoid using skin-irritating substances such as soaps, detergents, or cosmetics containing ethanol and soap-based ingredients; over-the-counter acne-treatment drugs or topical preparations, etc. (16, 17). Ingredients such as ethanol and soap-based substances easily absorb the moisture in the skin, exacerbating the cutaneous toxicity symptoms of cancer patients (21). The rashes caused by EGFRIs are called acne-like rashes because their papules, nodules, and pustule-like skin lesions resemble acne, but they do not have the typical comedone characteristics of acne (12). If cancer patients use over-the-counter acne-treatment drugs or topical preparations such as α-hydroxy acids and benzoyl peroxide gel on their own, this may irritate and worsen the acne-like rashes, exacerbate skin dryness, and increase itching (26). Cancer patients should reduce going out in cold, dry, or hot weather; wear loose, soft cotton clothing and comfortable shoes and socks; and avoid sun exposure (13). Try to reduce the patient’s desire to scratch for itching as much as possible. Avoid excessive rubbing and scratching to prevent skin damage and subsequent infection. They can try rinsing the itchy area with lukewarm water and gently patting it dry, or relieve the itching by diverting their attention, such as listening to music or reading (15). Cancer patients should try to avoid waxing and plucking. Male patients should avoid using razors to shave. They can use electric shavers or non-abrasive shaving methods, such as simply trimming beards and hair with scissors, to prevent skin scratches (21).

Ultraviolet exposure can inhibit EGFR expression in skin keratinocytes and is one of the risk factors for cutaneous toxicity symptoms caused by EGFRIs, facilitating the occurrence or exacerbation of rashes (11). Medical staff should instruct cancer patients to take good personal sun protection measures, encourage them to stay away from sunlight, and reduce long-term outdoor activities from 10:00 to 15:00 h (29). Cancer patients can use physical sun protection methods such as wearing sun-protective clothing, hats, and using umbrellas (27), or use sunscreen to reduce potential skin damage caused by ultraviolet exposure. It is recommended that cancer patients use a broad-spectrum UVA/UVB sunscreen with a sun protection factor (SPF) of 30 or higher daily (12), and apply or reapply it to body parts exposed to sunlight within 1 h before going out and every 2 h outdoors (11, 17). In addition, cancer patients should regularly use emollient lotions or creams to effectively moisturize their skin and support post-sun repair. It is recommended to apply a gentle, moisturizing, hypoallergenic emollient that does not contain ethanol (12, 17). Medical skin care products containing ceramides or other physiological lipids and having skin–barrier–repair effects are preferred. For areas with relatively high oil secretion, such as the face, front of the neck, and back, cancer patients can choose a lightweight lotion and apply it twice daily. For areas prone to dryness, such as the extensor sides of the limbs, hands, and feet, cancer patients can choose a thick-textured moisturizing cream or ointment and apply it twice daily (29). Aloe vera gel has the effects of activating the vitality of skin cells, effectively locking in skin moisture, and nourishing the skin. Cancer patients can consider applying aloe vera gel topically twice daily to promote skin hydration (13).

Some experts have pointed out that compared with reactive treatment of cutaneous toxicity symptoms using antibiotics, prophylactic antibiotic treatment is linked to a reduced risk of rashes across all grades. Thus, a preemptive prevention strategy is anticipated to enhance the quality of life of cancer patients (12). It is recommended that medical staff, after analyzing the pros and cons and considering the patient’s personal wishes, think about using medications like antibiotics and low-potency corticosteroids for prevention in the first 6 weeks of EGFRIs treatment (11, 14, 16, 29). Tetracycline-class antibiotics such as doxycycline, minocycline, or oxytetracycline can be chosen and taken twice daily for a total of 6 weeks. In cases of intolerance or a relevant allergy history, alternative antibiotics include cephalosporin-class antibiotics such as cefadroxil, trimethoprim-sulfamethoxazole, all taken twice daily (11, 17, 22). Cancer patients can also opt to apply low-potency topical corticosteroids like hydrocortisone and alclometasone, either alone or in combination, twice daily to skin areas such as the face and chest (11, 17). This approach is especially suitable for cancer patients with a history of skin diseases such as psoriasis, eczema, and atopic dermatitis, and for high-risk groups whose skin tends to be dry and itchy (29).

For cancer patients with grades 1 and 2 cutaneous toxicity symptoms, the EGFRIs treatment should be continued. For those with grade 3 or higher cutaneous toxicity symptoms, the EGFRIs dosage should be discontinued or adjusted (19, 28, 29). In addition, cancer patients should use antibiotics, corticosteroids, and antihistamine drugs as per the doctor’s orders to treat cutaneous toxicity symptoms (11, 12, 17). Common topical corticosteroids include hydrocortisone, alclometasone, mometasone valerate, or fluocinonide cream, etc. Common topical antibiotics include clindamycin, dapsone gel, etc. It is recommended that all of the above-mentioned drugs be used twice daily for at least 2 weeks (11, 12). If medical staff reevaluate after 2 weeks and find that the symptoms have not improved or have worsened, oral tetracycline-class antibiotics such as doxycycline or minocycline can be used in combination, twice daily for 4–6 weeks. Systemic glucocorticoids can also be used for a short term to treat cutaneous toxicity symptoms (11, 12). Medical staff should suspect secondary viral or bacterial infections based on the morphology of skin lesions (such as yellow scabs or secretions, redness around the lesions) and the degree of purulent exudate. Before using antibiotics, the exudate should be cultured to determine an appropriate antimicrobial treatment plan (11, 23). In cases where cancer patients are intolerant or have a relevant history of allergies, alternative antibiotics include cephalexin, cefadroxil, trimethoprim-sulfamethoxazole, etc., all of which are taken twice daily (11, 17, 22). When cancer patients feel unbearably itchy, they can choose topical antipruritics such as menthol, pramoxine, doxepin cream, or take oral anti-histamine drugs to relieve the itching (17, 27). For daytime itching, non-sedating second-generation anti-histamine drugs such as loratadine are the first choice; for patients with unbearable itching at night that affects sleep, first-generation sedating anti-histamine drugs such as diphenhydramine and hydroxyzine can be considered. It is worth noting that antihistamine drugs should be used with caution in elderly cancer patients. Before use, medical staff must fully consider the interactions between drugs, especially when used in combination with central nervous system inhibitors (12). Generally, skin dryness symptoms can be effectively alleviated through daily moisturizing measures. However, when it is severe enough to cause cracking, in addition to daily moisturizing measures, drugs containing urea and glycerin can be used to promote skin smoothness. Cyanoacrylate preparations, salicylic acid ointment, or propylene glycol solution can be used for soaking to relieve skin pain and promote healing (18, 27).

In traditional Chinese medicine, the etiology and pathogenesis of EGFRI-induced cutaneous toxicity are mainly due to the cancer patients’ own insufficient constitution, making them vulnerable to pathogenic toxins. Additionally, they are affected by the special toxicity of EGFRI drugs. External pathogens invade the interstitial spaces of the skin. Unable to be drained internally or penetrated externally, they stagnate and transform into heat, consuming blood and injuring yin. Deficiency of blood generates wind and dryness, leaving the skin lacking nourishment (28). According to the different stages of pathogenic factors, traditional Chinese medicine treatment often focuses on dispersing the lung qi, clearing heat, cooling the blood, and removing blood stasis to relieve the excess symptoms. Patients with rashes are classified into four syndromes: wind-heat in the lung meridian, damp-heat in the stomach and intestines, yin deficiency with internal heat, and stasis-heat and phlegm accumulation (46). Various empirical oral formulas such as Xiaozhen Fang (47), Modified Yinqiao San (48), Jiawei Xiaofeng San (49), and Puxing Jiedu Tang (50) have been developed, achieving good curative effects in cancer patients. These formulas can reduce the incidence and severity of ECFRI-related rashes, improve the treatment effectiveness, and enhance the quality of life of patients (13, 20). Honeysuckle has the effect of clearing heat and detoxifying. Researchers soaked sterile gauze (4–6 layers) with Honeysuckle Liquid until it was just about to drip. Then, they applied it closely to the affected skin. The frequency of wet-dressing depends on the severity of the rash, generally 3–6 times daily, 20–30 min each time, with a suitable temperature of 38–40 °C. After continuous treatment for 1 week, it was found that the cutaneous toxicity symptoms of cancer patients using cetuximab were effectively relieved (51). A multi-center randomized controlled trial showed that Zhiyang Pingfu Ye has good antibacterial and anti-inflammatory effects. It can effectively reduce the severity of cutaneous toxicity symptoms caused by EGFRIs in cancer patients, with high patient satisfaction and clinical application value (52). In addition, topical preparations such as antibacterial moisturizers, drying gels, preservatives, and hydrocolloid dressings can also reduce the severity of cutaneous toxicity caused by EGFRIs (18, 20, 26).