Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors

INTRODUCTION — Acneiform eruption is the prototypical cutaneous adverse reaction associated with all epidermal growth factor receptor (EGFR) inhibitors, which include monoclonal antibodies and oral small molecules used for the treatment of certain advanced or metastatic cancers, such as non-small cell lung cancer (afatinib, erlotinib, gefitinib, osimertinib, mobocertinib, necitumumab, amivantamab), pancreatic cancer (erlotinib), breast cancer (lapatinib, neratinib), colon cancer (cetuximab, panitumumab), and head and neck cancer (cetuximab). Acneiform eruption is also one of the most frequent adverse effects of inhibitors of the EGFR downstream mitogen-activated protein kinase kinase (MEK) signaling pathways MEK1 and MEK2 (eg, trametinib, cobimetinib, binimetinib, selumetinib), especially when used as monotherapy [1-3].

Although not life threatening, acneiform eruption affects cosmetically sensitive areas, causes pain and pruritus, and may impair the patient's quality of life and adherence to cancer therapies [4].

The acneiform eruption secondary to EGFR/MEK inhibitors will be reviewed in this topic. Other cutaneous adverse reactions to EGFR inhibitors and other molecularly targeted therapy or conventional chemotherapy agents are discussed separately. (See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy" and "Cutaneous adverse effects of conventional chemotherapy agents".)

EPIDEMIOLOGY

Incidence — All-grade acneiform eruptions occur in up to 90 percent of patients treated with EGFR or MEK inhibitors, with approximately 10 to 20 percent of patients developing severe (grade 3 or 4) eruption (table 1) [1,2,5-7]. Patients of any age may be affected [8,9].

Risk factors for severe rash — Potential risk factors for the development of severe EGFR inhibitor-related acneiform rash include age, sex, skin phototype, ultraviolet (UV) exposure, and combination with other treatment modalities (eg, conventional cytotoxic chemotherapy agents, radiotherapy) [10]:

●Age – In patients with advanced non-small cell lung cancer treated with erlotinib, age ≥70 is associated with an increased risk of severe (grade ≥3 (table 1)) rash [8,11]. However, in a study of patients treated with cetuximab for metastatic colon cancer, age ≤70 and male sex were associated with a higher rate of grade 3 eruption [9].

●Skin phototype – In a retrospective study of patients treated with erlotinib, grade 3 to 4 rash (table 1) occurred almost exclusively in patients with skin phototype I/II (table 2) [12].

●Sex – A retrospective study of 67 patients revealed that males were more likely to discontinue EGFR inhibitors because of rash when compared with females [13].

●Sun exposure – The frequent localization of the acneiform eruption to sun-exposed areas, such as the face and the "V" area of the neck and upper chest, suggests that UV radiation may act as a cofactor in the development or severity of the skin eruption. However, in a randomized trial, the daily application of a sunscreen with a sun protection factor (SPF) of 60 did not prevent or reduce the severity of the skin reaction [14].

●Combination therapy – In a meta-analysis of nine trials (5333 patients), the incidence of grade ≥3 rash (table 1) was higher in patients treated with cetuximab in combination with a variety of conventional cytotoxic agents than in patients treated with cetuximab alone [10].

●Smoking – Among patients with non-small cell lung cancer, smoking during therapy with erlotinib is associated with a lower incidence of skin eruption [15]. A possible mechanism is the induction of the liver cytochrome P450 3A4 with subsequent enhanced clearance of the drug [15,16]. This mechanism is supported by the observation that patients who are active smokers tolerate higher doses of erlotinib [16].

PATHOGENESIS — Direct inhibition of the EGFR and induction of an inflammatory response are critical steps in the development of the primary, papulopustular lesion [17]. However, the underlying molecular mechanisms are incompletely understood, as is the role of commensal skin microorganisms.

Direct receptor inhibition — In the epidermis, the EGFR is preferentially expressed in undifferentiated, actively proliferating basal and suprabasal keratinocytes; outer layers of the hair follicle; and pilosebaceous glands [18,19]. Coupled to various intracellular signaling pathways, EGFR plays a critical role in maintaining epidermal homeostasis through regulation of keratinocyte proliferation, differentiation, migration, and survival [20]. The intracellular signaling pathways may include RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), stress-activated protein kinase (SAPK), and Janus kinase/signal transducer and activator of transcription (JAK/STAT).

Direct receptor inhibition by tyrosine kinase inhibitors (TKIs) or monoclonal antibodies downregulates the level of the phosphorylated EGFR in basal and suprabasal keratinocytes and the outer layer of hair follicles, resulting in [21-25]:

●Diminished proliferation of basal keratinocytes, evidenced by the reduced expression of the proliferation marker Ki67 and increased expression of the negative growth regulator p27

●Growth arrest and apoptosis of keratinocytes

●Increased expression of terminal differentiation markers keratin 1 and STAT3 in the basal keratinocytes, reflecting premature and accelerated differentiation

●Decreased migration of differentiating keratinocytes through the epidermis due to enhanced cell attachment, mediated by increased expression of desmoglein 2

Inflammatory response — Exposure of epithelial cells to EGFR inhibitors induces upregulation of interleukin (IL) 1 and tumor necrosis factor (TNF)-alpha and increases synthesis of other inflammatory chemokines and cytokines (eg, monocyte chemoattractant protein 1 [CCL2], RANTES [CCL5], T lymphocyte-recruiting CCL18, CCL3, CCL27, and CXCL14) [26], resulting in the formation of an early infiltrate of CD45RO⁺ T lymphocytes, Langerhans cells, macrophages, and TNF-related apoptosis-inducing ligand (TRAIL)-positive cells with dendritic morphology [17,21,27,28].

Keratinocyte-derived cytokines appear to be the major force recruiting macrophages, mast cells, and granulocytes [26]. This hypothesis is supported by the finding that patients treated with erlotinib have elevated levels of serum CCL27 compared with normal controls [26]. The eventual influx of neutrophils contributes to the inflammation, manifesting as superficial perifolliculitis or suppurative folliculitis [21,28].

In addition, an increased number of total and highly degranulated mast cells has been demonstrated in lesional skin [26]. Macrophages may also play an important pathogenetic role, since in mouse models, their local depletion resulted in amelioration of cutaneous eruption [29].

The inflammatory response may also be secondary to altered growth and differentiation of follicular epithelium, which results in keratotic plugging, rupture of follicular infundibulum, and influx of neutrophils [28]. This theory is supported by the observation that abnormal pilosebaceous units are present in both affected and unaffected skin of patients exposed to EGFR inhibitors [27]. In mouse models, an initial alteration in hair follicles and pilosebaceous units is followed by inflammatory changes [30,31].

Role of microorganisms — In vitro investigations demonstrated the ability of erlotinib to inhibit the expression of human beta-defensin-3, cathelicidin LL37, and ribonuclease 7, which are critical components of the innate antimicrobial defense system. Furthermore, diminished expression of claudin-1, a tight junction protein, is significantly reduced in lesional skin of EGFR inhibitor-treated patients, which may contribute to the disruption of the epidermal barrier and increase the risk of cutaneous infections [26].

In mouse models, it has been shown that when EGFR is inhibited or absent, the opening of the follicular ostia during hair eruption allows for the penetration of commensal microorganisms into the hair follicle, which initiates an inflammatory reaction [32]. A study using gene expression profiling of biopsy samples of lesional skin found that EGFR/MEK inhibitors interact with the commensal bacterium Cutibacterium acnes within the microbiome of pilosebaceous follicles to induce IL-36-gamma expression in keratinocytes and, subsequently, IL-8-mediated neutrophil recruitment and inflammation [33].

Colonization with Staphylococcus aureus may be seen early in the course of the cutaneous eruption [26]. Secondary infection with S. aureus may also have a role in the late phase of the rash, sometimes after several months of therapy [34].

Role of ultraviolet radiation exposure — The frequent localization of the acneiform eruption to sun-exposed areas, such as the face and the "V" area of the neck and upper chest, suggests that ultraviolet (UV) radiation may act as a cofactor in the development or severity of skin eruption. Preclinical data also implicate EGFR as an important mediator of keratinocyte proliferation and survival in response to exposure to UV radiation. Inhibition of EGFR in cultured keratinocytes prior to UV radiation exposure has been shown to decrease cell survival and enhance apoptosis/necrosis following UV irradiation compared with cells exposed only to UV radiation [17,35]. However, in a randomized trial, the daily application of a sunscreen with a sun protection factor (SPF) of 60 did not prevent or reduce the severity of the skin reaction [14].

HISTOPATHOLOGY — The most frequently affected structures include hair follicles (61 percent), epidermis (52 percent), and sebaceous glands (45 percent) [27]. The two major histopathologic patterns are a superficial perifolliculitis, characterized by neutrophilic infiltrate surrounding the hyperkeratotic and/or ectatic follicular infundibula, and a florid, neutrophilic, suppurative folliculitis with rupture of the epithelial lining [36,37].

The stratum corneum is compact and eosinophilic, and its normal, basket-weave appearance is lost [22,38]. Epidermal atrophy, keratinocyte dysmaturation, and dyskeratosis may be seen [39]. Other reported alterations include intraepidermal acantholysis, vacuolar degeneration of the basal cell layer, prominent keratin plugs, and lichenoid changes [22,28]. The sebaceous glands are hypoplastic, with poorly differentiated sebocytes and keratinocytes [27]. The histologic alterations of the pilosebaceous units without an inflammatory infiltrate can also be seen in uninvolved skin [27].

CLINICAL MANIFESTATIONS

Clinical features and skin areas involved — The primary lesion of the EGFR/MEK inhibitor-induced acneiform eruption is a folliculocentric, erythematous papule or pustule. Areas rich in sebaceous glands (eg, the scalp, face (picture 1), and particularly the nose, cheeks, nasolabial folds, and perioral region) are most commonly affected. The upper trunk and, especially, the "V" region of the neck and chest (picture 2) are also involved [28,40]. Less frequently, the eruption may extend to the lower trunk (picture 3), buttocks, and extremities. The palmoplantar surfaces are characteristically spared [41].

Pruritus, irritation, burning sensation, and skin pain are frequent associated symptoms [42].

Timing of rash development — The onset of the eruption typically occurs within the first two weeks of therapy, but it can occur up to two months after starting the treatment [43,44].

The acneiform eruption generally evolves through four distinct phases [45]:

●Week 1 – Sensory disturbance (dysesthesia) accompanied by erythema and edema.

●Weeks 1 to 3 – Development of erythematous papules and pustules.

●Weeks 3 to 4 – Formation of crusts from purulent material and necrotic keratinocytes/debris.

●Weeks 4 and later – Persistent erythema with scattered telangiectasias and skin dryness. Late-phase presentations may have purpura and punched-out ulcers, which favor the buttocks and legs [46].

Clinical course — The clinical course is characterized by waxing and waning of lesions. Partial or even complete resolution may be seen despite continued EGFR inhibitor therapy [43,47,48]. Following the discontinuation of the offending agent, resolution typically occurs in four weeks [48,49].

RELATIONSHIP BETWEEN RASH AND SURVIVAL — Several studies have noted an association between acneiform eruption and increased overall response rate or survival [36,50-57]. This suggests that the skin eruption may be a surrogate marker for efficacy of EGFR inhibitor therapy and that acneiform eruption is not a contraindication to continued EGFR inhibitor therapy. However, the strategy for dose escalation based upon the rash grade ("dosing to rash") requires further study before it can be routinely recommended.

●In a meta-analysis of 24 trials (3312 patients) of erlotinib or gefitinib for non-small cell lung cancer, patients who developed a rash had a lower risk of death (hazard ratio [HR] 0.30, 95% CI 0.21-0.43) and disease progression (HR 0.50, 95% CI 0.41-0.61) than patients without a rash [58].

●In another meta-analysis of 14 trials with 1106 patients with advanced biliary cancer treated with EGFR inhibitors, higher grades of acneiform rash were associated with longer overall and progression-free survival (HR 0.47, 95% CI 0.31-0.71, and HR 0.51, 95% CI 0.36-0.72, respectively) compared with lower grades or no rash [59].

Similarly, patients with metastatic colorectal cancer with wild-type KRAS who developed moderate or severe rash when treated with panitumumab or cetuximab had a significantly prolonged overall survival, progression-free survival, and overall response rate [60]. In addition, in a small, randomized trial, dose escalation of EGFR inhibitors in patients with grade ≤1 rash was associated with an increased response rate to treatment [61].

COMPLICATIONS AND SEQUELAE — Acneiform eruption is rarely life threatening [4]. However, it affects cosmetically sensitive areas, causes pain and pruritus, and may impair the patient's quality of life and adherence to cancer therapies.

Secondary infection — Although the initial pustules are sterile, secondary infection of the affected skin may occur [28]. A retrospective analysis of 221 patients treated with cetuximab, panitumumab, erlotinib, or lapatinib found that 38 percent of patients developed infections from bacteria, dermatophytes, or viruses [62]. S. aureus was isolated from approximately 60 percent of infected lesions. Staphylococcal bacteremia has been reported in patients with severe skin toxicity induced by erlotinib [63,64]. A 2014 meta-analysis of 26 randomized trials (14,066 patients) reported an increased risk for severe infections in patients treated with anti-EGFR monoclonal antibodies (relative risk 1.34, 95% CI 1.10-1.62) [65].

Cutaneous sequelae — Long-term, cutaneous sequelae of EGFR inhibitor-induced acneiform rash include postinflammatory hyperpigmentation, telangiectasias, and erythema [66,67]:

●Postinflammatory hyperpigmentation − Postinflammatory hyperpigmentation is typically a late adverse event, manifesting after several months of treatment. It occurs most often in patients with darkly pigmented skin (table 2) and can be exacerbated by excessive ultraviolet (UV) radiation exposure [67]. Topical hydroquinone 4% cream may be used in an attempt to reduce the hyperpigmentation [66].

●Telangiectasias and erythema – Dilated, superficial capillaries and erythema may be observed in areas previously affected by the acneiform eruption one to two months after treatment. The initiating event in the development of telangiectasias could be the loss of structural support secondary to connective tissue destruction or the proliferation of endothelial cells in areas of keratinocyte necrosis that are present in follicular pustules [17]. Pulsed dye laser therapy may be used to reduce the redness [68].

Impact on patients' quality of life — Symptoms such as pain, pruritus, burning, and irritation are observed in approximately 60 percent of patients with EGFR inhibitor-induced acneiform eruption and can negatively affect the quality of life [49,69]. A retrospective study examined the data from 67 patients who had completed the Skindex-16 (a self-reported, dermatology-specific, quality-of-life questionnaire) at the time of their initial visit for skin reaction to EGFR inhibitors [42]. A positive correlation was found between rash severity and median scores for symptoms, emotions, and function, with the highest score reported for the emotions domain.

DIAGNOSIS — The diagnosis of acneiform eruption in patients receiving EGFR inhibitor therapy is usually straightforward and clinical, based upon the morphology and distribution of the rash (eg, erythematous, follicular papules and pustules in areas rich in sebaceous glands) (picture 3).

A skin biopsy is not routinely performed in clinical practice and is generally not needed for the diagnosis. However, if the clinical presentation is atypical or the eruption does not respond to treatment, a skin biopsy may be performed for accurate diagnosis.

If viral or bacterial superinfection is suspected based on the morphology of lesions (eg, yellow crusts or discharge, no response to treatment, painful skin lesions, peripheral erythema) or worsening of the initial eruption, cultures of exudates should be obtained. A potassium hydroxide (KOH) preparation may be useful to exclude Pityrosporum folliculitis or tinea barbae. (See 'Differential diagnosis' below.)

GRADING OF SEVERITY — Although not always performed in clinical practice, grading the severity of the acneiform eruption is important in guiding the approach to management (algorithm 1). In clinical trials and in some oncology practices, the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) is the most commonly employed scale to assess the severity of cutaneous adverse reactions to cancer treatment (table 1) [70,71]. However, the CTCAE scale, which is based upon the body surface area involvement and symptoms, may not capture specific features of the acneiform rash (eg, involvement of cosmetically sensitive areas, subacute/chronic course) and does not incorporate the patient's perception of severity [72,73].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of EGFR inhibitor-induced acneiform eruption includes acneiform eruptions induced by other drugs and other uncommon, papulopustular eruptions:

●Drug-induced acne – Drug-induced acne typically presents with a monomorphous, inflammatory, papular eruption involving the trunk (picture 4). Medications associated with drug-induced acne are listed in the table (table 3) [74]. Other anticancer agents that may also be associated with an acneiform eruption include [75-78]:

•Inhibitors of mammalian target of rapamycin (mTOR), such as sirolimus, tacrolimus, everolimus, temsirolimus

•Multikinase inhibitors, such as sunitinib, sorafenib, axitinib, pazopanib, regorafenib, and cabozantinib (see "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy")

●Pityrosporum folliculitis – Pityrosporum folliculitis is a skin infection caused by yeasts of the genus Malassezia and characterized by a monomorphous eruption of papules and pustules on the upper trunk or arms (picture 5A-B). Characteristic budding yeasts are detected on histologic examination of a skin biopsy after treatment with potassium hydroxide (KOH). (See "Invasive Malassezia infections", section on 'Diagnosis'.)

●Tinea barbae – Tinea (sycosis) barbae is a skin infection caused by dermatophytes of the genus Trichophyton, occurring predominantly in males. The superficial type presents with papules and pustules in the beard and mustache area (picture 6A-B). A KOH preparation shows the segmented hyphae and arthrospores characteristic of dermatophyte infections (picture 7). (See "Dermatophyte (tinea) infections".)

●Eosinophilic folliculitis – Eosinophilic folliculitis is a pruritic eruption most commonly occurring in patients with HIV and presenting with recurrent crops of follicular papules and pustules predominantly involving the head, neck, and upper trunk (picture 8A-B). Peripheral eosinophilia is often present. Histology reveals infiltration of eosinophils into hair follicles and perifollicular areas (picture 9A-B). (See "HIV-associated eosinophilic folliculitis".)

PREVENTION

General measures — Before initiating treatment with EGFR inhibitors, patients should be educated about adopting general skin care measures, which include [7]:

●Avoiding frequent washing with hot water (hand washing, shower, baths).

●Avoiding antibacterial or perfumed soaps and detergents.

●Avoiding the use of skin irritants, such as over-the-counter antiacne medications, solvents, or disinfectants.

●Avoiding excessive sun exposure.

●Regularly using a broad-spectrum ultraviolet A/ultraviolet B (UVA/UVB) sunscreen with a sun protection factor (SPF) ≥15 with inorganic ingredients (zinc oxide, titanium dioxide). Sunscreens should be applied to exposed areas of the body every two hours when outside.

●Using thick, alcohol-free moisturizers (creams or ointments) twice daily.

Preemptive therapy — We suggest prophylactic oral antibiotics in conjunction with topical corticosteroids for patients initiating treatment with EGFR inhibitors. Treatment is started on the same day as EGFR inhibitor therapy and continued for six weeks. We typically use doxycycline 100 mg twice a day, minocycline 100 mg daily, or oxytetracycline 500 mg twice daily for six weeks [7]. Alternative antibiotics include cephalosporins (eg, cefadroxil 500 mg twice daily) or trimethoprim-sulfamethoxazole (160 mg/800 mg twice daily).

A low-potency topical corticosteroid (eg, hydrocortisone 2.5%, alclometasone 0.05% cream (table 4)) is applied twice daily to the face and chest.

The efficacy of oral tetracyclines for the prevention of the acneiform eruption has been evaluated in several randomized and nonrandomized studies and in two meta-analyses [79-81]:

●In a 2012 meta-analysis of four randomized trials including 351 patients [82-85], patients who initiated prophylactic treatment with a tetracycline on the same day as or the day before initiating EGFR inhibitor therapy had a decreased incidence of moderate to severe (grade ≥2 (table 1)) folliculitis (combined odds ratio [OR] 0.19, 95% CI 0.12-0.31) [79]. However, the benefit was lost after discontinuation of treatment. The incidence of mild (grade 1 (table 1)) folliculitis was not changed by prophylactic tetracyclines. The data were insufficient to determine the optimal treatment regimen and duration.

●A subsequent 2016 meta-analysis including nine randomized trials and four observational studies (1073 patients) confirmed the benefit of preemptive antibiotic therapy for the prevention of the acneiform eruption [80]. In this meta-analysis, prophylactic treatment with doxycycline or minocycline reduced the risk of developing a skin rash of any grade by approximately 50 percent (OR 0.54, 95% CI 0.40-0.73) and reduced the risk of grade 2 or 3 rash by approximately 70 percent (OR 0.36, 95% CI 0.22-0.60). The results were similar when the analysis was restricted to randomized trials.

There are a few studies evaluating the efficacy of topical treatments alone or in conjunction with oral antibiotics for the prevention of acneiform eruption:

●Tazarotene – In a randomized trial of 48 patients initiating cetuximab therapy with or without prophylactic minocycline, tazarotene 0.05% cream applied to one side of the face was not effective in preventing the acneiform eruption when used as a single agent and provided little benefit beyond that seen with minocycline alone when used in combination with oral minocycline [82]. In addition, tazarotene was associated with significant skin irritation.

●Topical vitamin K1 – In a randomized trial including 126 colon cancer patients initiating cetuximab therapy, vitamin K1 cream given in combination with oral doxycycline was not effective in preventing the acneiform eruption compared with doxycycline and vehicle [86]. Grade 2 to 4 acneiform rash (defined according to the Common Terminology Criteria for Adverse Events [CTCAE] v.4.02) occurred in 73 percent of patients in the vitamin K1 group and 64 percent of those in the vehicle group.

●Topical dapsone 5% gel – In a small, randomized, split-face/chest study of 11 patients, dapsone 5% gel applied twice daily was associated with a nonstatistically significant reduction in lesion count compared with a moisturizer [87]. All patients were also treated with minocycline 100 mg daily.

●Topical doxycycline – In a small, phase II trial, 24 patients with metastatic colorectal cancer applied topical doxycycline 4% foam twice daily on one side of the face and vehicle foam on the other side before the initiation of EGFR inhibitor therapy [88]. Grade 2 or 3 rash occurred less frequently on the sides treated with topical doxycycline compared with the sides treated with vehicle. Topical treatment was well tolerated, with mild, local reaction reported in five patients.

●Topical erythromycin 2% ointment – In a randomized trial, 88 patients with colorectal cancer receiving panitumumab were treated with either doxycycline 100 mg twice daily or erythromycin ointment 2% followed by doxycycline in case of insufficient activity [89]. More patients treated with prophylactic erythromycin 2% ointment developed moderate or severe skin toxicity, as measured with the WoMo (Wollenberg and Moosmann) score [90], at an earlier time compared with those treated with doxycycline.

●Topical chloramphenicol – A single-center, randomized trial investigated the efficacy of chloramphenicol 3%/prednisolone 0.05% ointment and chloramphenicol 3% ointment alone versus placebo (aqua cream) in preventing the acneiform eruption from EGFR inhibitors [91]. At 14 and 30 days, there was no difference among groups in the primary endpoint (proportion of patients developing grade ≥3 rash). However, at 30 days, fewer patients in the chloramphenicol groups than in the placebo group had >10 papulopustular lesions (6, 16, and 43 percent, respectively).

MANAGEMENT

General principles — The management of the acneiform eruption should be individualized for each patient, based upon the type, severity, and location of the lesions. In most cases, acneiform eruption is not a contraindication to continued EGFR inhibitor therapy. In intolerable or severe cases, dose modification or interruption of a potentially life-prolonging therapy may be necessary [92]. However, clinicians should take into consideration the patient's willingness to continue treatment despite a severe cutaneous reaction [93].

Management in consultation with a dermatologist is suggested in the following situations:

●The skin reaction does not improve within two weeks of treatment.

●The eruption is severe (grade 3 to 4 (table 1)).

●The eruption has an atypical appearance or distribution. (See 'Clinical manifestations' above.)

Randomized trials have shown benefit with topical corticosteroids, topical and systemic antibiotics, and oral isotretinoin [45,94]. Prophylactic therapy is recommended for all patients (algorithm 1). Grading the severity of rash is discussed above. (See 'Grading of severity' above.)

Treatment of pruritus — Oral H1 antihistamines, including sedating (eg, diphenhydramine, hydroxyzine, doxepin) or nonsedating (eg, cetirizine, fexofenadine, loratadine) agents, may be beneficial for patients with pruritus [49,95]. In a clinical trial, aprepitant (a neurokinin 1 [NK1] receptor antagonist) was effective in reducing pruritus intensity by >80 percent in 41 of 45 patients treated with EGFR inhibitors and tyrosine kinase inhibitors (TKIs) [96]. Pruritus did not recur in 87 percent of patients during the 90-day study period. However, aprepitant should be used with caution in patients receiving erlotinib, since aprepitant-induced inhibition of the liver cytochrome P450 3A4 may increase the trough levels of erlotinib [97].

Gamma-aminobutyric acid (GABA) agonists, such as gabapentin and pregabalin, may be tried if oral antihistamines are ineffective. Evidence of benefit in patients with acneiform eruption secondary to EGFR inhibitors is limited [98], but they are used to treat other forms of chronic pruritus. (See "Pruritus: Therapies for localized pruritus".)

Patients with grade 1 rash — For patients with grade 1 rash (table 1), we suggest topical corticosteroids and topical antibiotics (algorithm 1). We typically use low-potency topical corticosteroids (groups 6 and 7 (table 4)) plus clindamycin 1% or dapsone 5% gel twice a day for at least four weeks.

We generally reassess patients after four weeks of treatment. If the acneiform eruption has not improved or has worsened, patients are treated in the same way as those with grade 2 rash.

Patients with grade 2 rash — For patients with grade 2 rash (table 1), we suggest topical corticosteroids and oral tetracycline antibiotics (algorithm 1). We use low-potency topical corticosteroids (group 6 (table 4)) twice a day on the face and neck and fluocinonide 0.05% cream twice a day on the chest and back for at least four weeks and either doxycycline 100 mg or minocycline 100 mg twice per day for four to six weeks.

If a patient with grade 2 rash is already on an oral tetracycline, an alternative antibiotic, such as a first-generation oral cephalosporin (eg, cephalexin 500 mg twice per day, cefadroxil 500 mg twice per day) or trimethoprim-sulfamethoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice per day), can be given for four weeks. For pediatric patients under age 8, we recommend a first-generation oral cephalosporin or amoxicillin 500 mg twice daily instead of an oral tetracycline [99].

If viral or bacterial superinfection is suspected based on the morphology of lesions (eg, yellow crusts or discharge, no response to antibiotics, painful skin lesions, peripheral erythema), degree of suppurative exudate, or worsening of the initial eruption, cultures of exudates should be obtained to determine appropriate antimicrobial therapy.

We generally reassess patients after two weeks of treatment. If no improvement or worsening is noted after two weeks of treatment, patients are treated in the same way as those with grade ≥3 rash.

Patients with grade ≥3 rash — In patients with grade ≥3 rash, intolerable grade 2 rash, or rash that interferes with self-care activities of daily living or impairs the quality of life (table 1), dose modification as per prescribing information or interruption is warranted (algorithm 1).

Decisions regarding interruption or even discontinuation of EGFR inhibitor therapy must involve the patient, the patient's oncologist, and the patient's dermatologist. The potential risks and benefits and the patient's values and preferences must be considered. Treatment may be reinitiated after toxicity has resolved to baseline or grade ≤1, according to the instructions provided in the prescribing information for the particular agent [45,94].

In addition to interruption or discontinuation of EGFR inhibitor therapy, we suggest treatment with oral antibiotics plus a short course of systemic corticosteroids:

●Oral doxycycline 100 mg or minocycline 100 mg is given twice a day for at least four weeks. First-generation oral cephalosporins (eg, cephalexin 500 mg twice per day, cefadroxil 500 mg twice per day) or trimethoprim-sulfamethoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg/twice per day) given for four weeks can be used as alternatives when patients do not benefit from tetracycline antibiotics or have a culture-proven infection with organisms resistant to tetracycline antibiotics.

●Oral prednisone 0.5 mg/kg up to a maximum of 40 mg per day is given for seven days.

Improvement should be noted within two weeks. If a viral or bacterial superinfection is suspected, cultures of exudates should be obtained prior to the initiation of the antibiotic treatment to determine appropriate antimicrobial therapy.

Oral corticosteroids for the treatment of severe acneiform eruption have not been evaluated in randomized trials, and their use is based upon their anti-inflammatory properties and clinical experience.

Refractory grade ≥3 rash — For patients with grade ≥3 rash that does not improve in two weeks with dose modification or interruption and the regimen of oral antibiotics plus systemic corticosteroids described above, low-dose isotretinoin (20 to 30 mg per day) or acitretin (10 to 25 mg a day) may be tried [100].

Oral tetracyclines are discontinued before initiating oral isotretinoin. Improvement is generally evident within four weeks [101]. Therapy is continued for at least two months after patients resume EGFR inhibitor at regular dose.

The evidence for efficacy of oral isotretinoin for severe acneiform eruption is limited to single case reports and small case series [101-105]. Indirect evidence of efficacy is derived from studies of the treatment of acne vulgaris. (See "Acne vulgaris: Management of moderate to severe acne in adolescents and adults", section on 'Oral isotretinoin'.)

In a retrospective chart review, nine patients treated with EGFR or MEK inhibitors with or without immunotherapy who developed an acneiform eruption were treated with acitretin or isotretinoin [106]. Improvement was evident within one month, and the rash remained stable at grade 1 or less without a need for dose modification of cancer therapy. Improvement of pruritus and pain was also noted following initiation of oral retinoids.

Isotretinoin may aggravate some EGFR inhibitor adverse effects, such as skin dryness, cheilitis, or photosensitivity. Skin dryness and cheilitis can be alleviated by the application of alcohol-free emollients multiple times per day. Patients with increased photosensitivity should adopt sun protection measures, which include limiting the exposure to the sun, wearing protective clothing, and regular use of sunscreens with a sun protection factor (SPF) ≥30. (See "Oral isotretinoin therapy for acne vulgaris", section on 'Mucocutaneous'.)

EXPERIMENTAL TREATMENTS

Topical recombinant epidermal growth factor — Two small studies have evaluated the efficacy of an ointment containing recombinant epidermal growth factor (EGF) [107,108]:

●In an open-label study, 46 patients with grade ≥2 erlotinib-related skin effects (ERSE) were treated twice daily with an EGF ointment containing 1 part per million (ppm) of nepidermin [108]. At eight weeks, the overall response rate was 78 percent, with 31 patients (67 percent) having grade 2, 3, or 4 ERSE downgraded to grade ≤1 and 5 patients (11 percent) having grade 3 or 4 ERSE downgraded to grade 2 and lasting for at least two weeks.

●In a randomized trial, 80 patients with grade ≥2 ERSE received EGF ointment at a concentration of 1 ppm, 20 ppm, or placebo twice daily [107]. Response was defined as reduction of ERSE from grade ≥2 to grade ≤1 or grade ≥3 ERSE downgrading to grade 2 and lasting for at least two weeks. The response rate was 61.5 percent (95% CI 40.6-79.8 percent) in the 1 ppm group, 77.8 percent (95% CI 57.7-91.4 percent) in the 20 ppm group, and 44.4 percent (95% CI 25.5-64.7 percent) in the placebo group. Adverse events related to EGF treatment occurred in three patients (skin fissure, pyogenic granuloma, and periungual overgrowth).

Topical BRAF inhibitors — Based on the observation that the incidence of acneiform eruption is lower in patients treated with EGFR inhibitors in combination with BRAF inhibitors, a four-week, phase I trial investigated the efficacy of a topical BRAF inhibitor in 10 patients treated with cetuximab or panitumumab for metastatic colorectal cancer who developed grade 1 or 2 rash [109]. Six patients with grade 2 rash improved to grade 1, two patients remained stable, and two worsened.

Topical polydatin — A pilot study evaluated the efficacy of topical polydatin, a natural precursor of resveratrol, as adjunctive therapy to oral minocycline 100 mg/day for the treatment and prevention of acneiform eruption [110]. In 20 patients with acneiform eruption, polydatin 1.5% cream applied twice daily resulted in a decrease of the eruption's grade according to the Common Terminology Criteria for Adverse Events (CTCAE) compared with baseline. Prophylactic treatment with polydatin 0.8% cream twice daily prevented the development of acneiform eruption through 24 weeks in all 20 patients who were symptom free at baseline. However, the benefit of topical polydatin for acneiform eruption should be confirmed in a randomized trial.

SUMMARY AND RECOMMENDATIONS

●Incidence − The acneiform (papulopustular) eruption is the prototypical cutaneous adverse reaction to treatment with epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase kinase (MEK) inhibitors. It occurs in over 80 percent of patients and may be more frequent in older patients and in patients with lightly pigmented skin (phototypes I to III (table 2)). (See 'Introduction' above and 'Epidemiology' above.)

●Clinical presentation − The eruption develops mainly in areas rich in sebaceous glands (eg, scalp, face, upper trunk) within the first two weeks of therapy (picture 3). Erythematous papules and pustules evolve to crusted lesions and eventually resolve, leaving persistent erythema, telangiectasias, and skin dryness. (See 'Clinical manifestations' above.)

●Diagnosis − The diagnosis of acneiform eruption in patients receiving EGFR inhibitor therapy is usually straightforward, based upon the morphology and distribution of the skin lesions (eg, erythematous and follicular papules or pustules in areas rich in sebaceous glands with sparing of palmoplantar surfaces) (picture 3). The severity is graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (table 1). (See 'Diagnosis' above.)

●Prevention − We suggest a prophylactic oral tetracycline in conjunction with topical corticosteroids for patients initiating treatment with EGFR inhibitors (Grade 2A). Treatment is started on the same day as EGFR inhibitor therapy:

•We typically use doxycycline 100 mg twice a day or minocycline 100 mg daily for six to eight weeks.

•Low-potency corticosteroids (table 4), such as hydrocortisone 2.5% or alclometasone 0.05% cream, are applied twice a day. (See 'Prevention' above.)

●Treatment (algorithm 1):

•Grade 1 rash − For patients with grade 1 rash (table 1) who have not initiated prophylactic therapy, we suggest topical corticosteroids with or without topical antibiotics (Grade 2C). We use low-potency topical corticosteroids (group 6 (table 4)) twice a day for four weeks and clindamycin 1% gel twice a day for four weeks. (See 'Patients with grade 1 rash' above.)

•Grade 2 rash − For patients with grade 2 rash (table 1) who are not taking prophylactic tetracycline, we suggest topical corticosteroids and oral tetracycline antibiotics (algorithm 1) (Grade 2C). We use low-potency topical corticosteroids (group 6 (table 4)) twice a day for four weeks and either doxycycline 100 mg or minocycline 100 mg orally twice a day for four weeks. First-generation oral cephalosporins (eg, cephalexin, cefadroxil) or trimethoprim-sulfamethoxazole can be used as alternative antibiotics for patients who are taking prophylactic tetracyclines or do not benefit from tetracyclines as well as for pediatric patients under age 8. (See 'Patients with grade 2 rash' above.)

•Grade ≥3 rash − For patients with grade ≥3 rash who are not taking a prophylactic tetracycline, we suggest treatment with an oral tetracycline plus a short course of systemic corticosteroids in addition to EGFR or MEK inhibitor dose modification or interruption (Grade 2C). We use either doxycycline 100 mg or minocycline 100 mg orally twice a day for at least four weeks and prednisone 0.5 mg/kg orally once per day for seven days.

A first-generation oral cephalosporin (eg, cephalexin, cefadroxil) or trimethoprim-sulfamethoxazole can be used as alternative antibiotics for patients who are taking a prophylactic tetracycline or do not benefit from tetracyclines. Tetracyclines should be discontinued. (See 'Patients with grade ≥3 rash' above.)

•Refractory grade ≥3 rash − Low-dose isotretinoin (20 to 30 mg per day) or acitretin (10 to 25 mg a day) may be tried for patients with grade ≥3 rash that does not improve within two weeks with dose modification or interruption and the regimen of oral antibiotics plus systemic corticosteroids. Oral tetracyclines are discontinued before initiating oral isotretinoin. (See 'Refractory grade ≥3 rash' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Yevgeniy Balagula, MD, and Mario E Lacouture, MD, who contributed to earlier versions of this topic review.