Zárraga CA; Vega Memije ME; Rodríguez Cid JR

Review Article

Austin J Dermatolog. 2017; 4(3): 1078.

Dermatologic Adverse Effects Secondary to EGFR Inhibitors Use as Oncological Treatment: Pathophysiology, Clinical Manifestations and Treatment

Zárraga CA¹*, Vega Memije ME¹ and Rodríguez Cid JR²

¹Department of Dermatology, General Hospital, Mexico City

²Department of Oncology, National Institute of Respiratory Diseases, Mexico City

*Corresponding author: Castañeda Zárraga A, Department of Dermatology, Hospital General “Dr Manuel Gea González”, Calzada de Tlalpan 4800, Tlalpan, CP 14000, Mexico City

Received: June 15, 2017; Accepted: OOctober 17, 2017; Published: October 30, 2017

Abstract

Through the last few years the use of Epidermal Growth Factor Receptor Inhibitors (EGFR) has increased within the treatment of several oncological diseases. Though these drugs offer advantages regarding their systemic adverse events profile, they relate with the appearing of skin lesions among patients. Most frequent are: xerosis, acneiform dermatitis, pruritus, paronychia, and hair alterations. These adverse effects are due to these drugs mechanism of action, and their incidence is a sign of their efficacy.

Regardless the frequency of dermatologic lesions, and the impact these may have on oncological treatment duration, there is still a lack of an established standard treatment or prophylaxis. So far, the treatment is based on antimicrobial agents such as tetracycline and minocycline, topical steroids, anthistaminics, and skin care general measures. This paper reviews dermatologic adverse events of EGFR inhibitors, more common clinical manifestations and different treatments suggested to date.

Keywords: Epidermal Growth Factor Receptor Inhibitors (EGFR); Dermatologic adverse effects; Chemotherapy toxicity

Introduction

Most human epithelial cancers display a marked increase of growing factors, and a particularly high activity of EGFR receptors. When the phenomenon was understood, EGFR became the most important receptor to investigate for researchers, and main therapeutic target for oncological treatment in patients portraying the aforementioned activation [1].

Currently there are two EGFR inhibitor classes for oncological use: monoclonal antibodies and tyrosine kinase inhibitors (TKIs) [1].

Anti EGFR treatments allow for a larger selectivity with better success rates portrayed as response rates, quality of life, progressionfree survival, and overall survival, and for lesser adverse events related to chemotherapy agents [2].

Most common side effects with EGFR treatment are those related to skin, since EGFR activation plays an important role for skin’s innate immunity, and its inhibition reduces the immunity’s integrity. This has been seen in phase II trials with this kind of drugs [3-6] (Table 2).

Although adverse side effects secondary to EGFR inhibition are seldom severe, they do have a high impact on the patient’s quality of life, including physical, financial, emotional, and social aspects [7]. A decrease in dose, and a lack of continuity in treatment have been reported in 60% and 32%, respectively, secondary to dermatological adverse effects caused by EGFR inhibitors, which have diminished therapeutic benefits [2]. Joshi et al observed that emotional impact and detriment in quality of life is greater in patients younger than 50 years old [8].

Pathophysiology

EGFR, also known as ErbB1 (HER1) is part of the tyrosine kinase family of Erb receptors, is a transmembrane protein consisting in an extracellular ligand, a transmembrane region, and an intracellular region located in epithelial origin cells. Inhibiting the signal mediated by EGFR can be achieved using monoclonal antibodies (cetuximab, panitumumab) that bind extracellular domain and prevent ligand binding, or using low molecular weight agents (erlotinib, gefitinib, afatinib) that block triphosphate adenosine binding to receptor’s intracellular portion [9] (Figure 1, Table 1).

Table 1: EGFR inhibitors and their approved use in oncological treatment.




  
    Drug 
    Approved uses 
  
  
    Erlotinib
    Non-small cells lung    cancer
      Pancreatic carcinoma
  
  
    Gefitinib
    Non-small cells lung    cance
  
  
    Afatinib
    Non-small cells lung    cancer
  
  
    Cetuximab
    Colon and rectal    cancer
      Squamous    cell carcinoma of the head and neck 
  
  
    Panitumumab
    Colon and rectal    cancer



Table 1: EGFR inhibitors and their approved use in oncological treatment.

Table 2: EGFR inhibitors approved by FDA (2015) and their most common adverse effects [6].




  
    Tyrosine    Kinase Inhibitors 
  
  
    Drugs 
    Adverse    Effects
  
  
    Erlotinib
    Acneiform dermatitis
      Diarrhea
      Asthenia
    Cough
      Dyspnea
      Anorexia
  
  
    Gefitinib
    Non-Specific    dermatitis
      Transaminase elevation
      Proteinuria
    Diarrhea
      Hepatotoxicity
      Interstitial lung    disease (ILD)
  
  
    Afatinib
    Diarrhea
      Acneiform dermatitis
      Stomatitis
      Paronychia
      Xerosis
      Anorexy
    Pruritus
      Vomit
      Dyspnoea
      Dysphagia
      Hipokalemia
  
  
    Monoclonal    Antibodies 
  
  
    Drugs 
    Adverse    Effects
  
  
    Cetuximab
    Nausea
      Anemia
      Vomit
      Neutropenia
      Unspecified    dermatitis
    Asthenia
      Diarrhea
      Anorexia
      Conjunctivitis
      Electrolyte disturbances
      (hypomagnesemia, hypokalemia, hypocalcemia)
  
  
    Panitumumab
    Acneiform dermatitis
      Pruritus
      Xerosis
    Paronychia
      Erythema
      Angioedema



Table 2: EGFR inhibitors approved by FDA (2015) and their most common
adverse effects [6].

Figure 1: EGFR, HER2, HER3, and/or Her4 receptors are activated, homodimers or heterodimers are constitute. This starts a phosphorylation chain ATP dependent of the intracellular domains EGFR specific of tyrosine kinase. This triggers 2 signaling pathways, the fist (left) activates the anti apoptotic cascade, and the second (right) activates RAS, RAF, MEK, MAPK and controls gene transcription from G1 to S and cellular proliferation.

    
    
    Figure 1:  EGFR, HER2, HER3, and/or Her4 receptors are activated,
homodimers or heterodimers are constitute. This starts a phosphorylation
chain ATP dependent of the intracellular domains EGFR specific of tyrosine
kinase. This triggers 2 signaling pathways, the fist (left) activates the anti
apoptotic cascade, and the second (right) activates RAS, RAF, MEK, MAPK
and controls gene transcription from G1 to S and cellular proliferation.

When EGFR is activated, different signaling pathways are produced, of which there are 3 main ones: 1) RAS / RAF /MEK / ERK pathway, with repercussion on cell proliferation, cell cycle progression and migration; 2) Via JAK/ STAT which also promotes cell proliferation, protects against apoptosis and promotes cell motility and 3) PI3K (phosphoinositol 3 kinase) / Akt which acts by inhibiting apoptosis [10].

EGFR is responsible for several skin essential functions throughout development, like epidermal proliferation, differentiation, migration, repairing and carcinogenesis, keeping keratinocytes in an active and proliferative state, in order to promote motility and apoptosis protection [9,11]. EGFR inhibition stimulates pro-inflammatory cytokines CCL2, CCL5 and interleukins. These are important because they are related to dermatitis onset [12].

EGFR participates in the differentiation and development of epidermal keratinocytes, stimulating their growth, inhibiting differentiation, protecting against UV radiation, inhibiting inflammation, and accelerating wounds repairing. It expresses at follicular and epidermal keratinocytes, at the epidermis basal layer, at hair follicle roots, at sebaceous epithelium, at eccrine epithelium, at dendritic cells and other connective tissues [9,12-14].

This process results in a debridement that causes the loss of hydration, and starts xerosis [15]. It is clear that dermatologic damage mechanism started with EGFR inhibition is related with the effects on proliferation and differentiation of keratinocytes promoting secondary inflammation [13].

The mechanism of the effects of EGFR is explained by the inhibition of EGFR that directly affect keratinocytes by inhibiting growth, promoting apoptosis, decreasing cell migration and stimulating inflammation [16]. Acneiform dermatitis is explained by follicular occlusion that occurs as a consequence of the lack of cellular differentiation of the epithelium and release of cytosines leading to inflammation [17], xerosis by the role that EGFR plays in maintaining the integrity of the epidermal barrier; skin fragility and thinning are related to the action of EGFR in the proliferation, differentiation and survival of keratinocytes [18]. Epidermal changes reflect the altered balance between proliferation and differentiation, which may be responsible for xerosis and desquamation observed in some patients treated with Gefitinib [19].

Cell cultures have shown that inhibiting EGFR increases apoptosis levels up to five times between days 4 and 12, which correlates with the clinical appearing of papulopustular skin lesions among patients treated with these drugs [14].

Clinical Manifestations

Different dermatologic adverse effects manifestations have been reported, such as acneiform dermatitis, xerosis, pruritus, hyperpigmentation, eczema, hair damage, paronychia, hand-foot reactions, and even vitiligo [20].

Acneiform dermatitis

The most common dermatologic adverse effect in patients treated with EGFR inhibition, occurring in up to 85% of patients, with a 10%- 20% of them showing severe forms. It has been reported that treatment with monoclonal antibodies and tyrosine kinases inhibitors causes these effects, being most prominent in the first group, particularly with the use of Panitumumab [15,21]. Dermatologic side effects promote treatment cessation in about a 32% of patients, and dose changing in up to 76% of patients [15].

Acneiform dermatitis is characterized by papulopustular lesions, generally accompanied by honey colored scabs and not visible black heads [22]. The most common location is on the face, scalp and upper chest (Figure 2). It has a face flow dissemination, and generally appears during the first month of treatment, and most commonly during first seven to ten days of treatment, though they may appear between days 7 and 42. It generally improves with time, but in only few cases disappears completely while EGFR inhibitors are used [2,23,24]. The lack of open black points distinguishes it from acne; secondary lesions to EGFR therapy are monomorphic, indicating they appeared in a common date [2].

Figure 2: Patient with lung adenocarcinoma treated with afatinib. It can be seen localized dermatosis on the face, predominantly on the cheeks, chin and nose with multiple pustules and papules.

    
    
    Figure 2:  Patient with lung adenocarcinoma treated with afatinib. It can be
seen localized dermatosis on the face, predominantly on the cheeks, chin and
nose with multiple pustules and papules.

Several risk factors have been identified for development of lesions: no smokers, white race, and male sex. Severe forms are more frequent as a consequence of using monoclonal antibodies, and they appear in 10%-17%, when comparing with tyrosine kinases inhibitors with only 5%-9% [15] (Table 3).

Table 3: Dermatologic adverse effects and adverse severe effects by drug group incidence.




  
    Overall dermatologic adverse    effects Incidence: 
  
  
    a) Monoclonal antibodies
      1) Cetuximab
      2) Panitumumab
    a) 80% - 100%
      1) 88 - 90%
      2) 100%
  
  
    b) Tyrosine kinase inhibitors 
    b) 43%-54% 
  
  
    Severe dermatologic    adverse effects (Grades 3 & 4) 
  
  
    a)    Monoclonal antibodies: 10%-17%
    10%-17%
  
  
    b) Tyrosine kinase inhibitors 
    5%-9%



Table 3: Dermatologic adverse effects and adverse severe effects by drug group
incidence.

It has not been seen a relationship between severity and a seborrhea, rosacea or acne background, or dermatologic adverse effects; and when used with RT, the effects are dose dependent [23, 25-28].

Xerosis, pruritus and digital fissures

Xerosis is often observed since the first two months of treatment. At third month, up to a 50% of patients portray it, and at 6 months up to 100% of patients have some degree of xerosis. Skin dryness is usually accompanied by pruritus, which is generalized and present day and night, and it is exacerbated by heat exposition [21]. Elder patients that have received previous therapy with cytotoxic agents and have or have had atopy, usually portray more xerosis [13].

Digital fissures are usually painful, and may impair handy skills [21]. Incidence rate is about 18% in general, and severe forms are about a 3%. Usually they affect finger tips, but they may be seen between fingers, and are related to xerosis [24].

Paronychia

Its characteristic features are painful, edematous and frequently purulent inflammation at the cuticle that can be seen in hands and feet nails, being more common at first fingers. Traumatism is considered an exacerbating factor [15]. It is present in a 12%-58% of cases [24].

It usually appears after six months. It may affect several nails at once, and can be accompanied by onycholysis and lingual pustules (Figure 3). Pain and discomfort frequently require a dose adjustment of oncological treatment [2,21, 23].

Figure 3: Patient with lung adenocarcinoma treated with afatinib. Paronychia at third and fourth singers, as well as nails hyperpigmentation.

    
    
    Figure 3:  Patient with lung adenocarcinoma treated with afatinib. Paronychia
at third and fourth singers, as well as nails hyperpigmentation.

Hair alterations

Hair manifestations are observed in a 4%-23% of patients, usually appearing after 2-3 months after beginning treatment with EGFR inhibitors. Changes include trichomegaly, facial hair growth, and dry, brittle and fragile hair, as well as no scarring alopecia [21].

Other

Telangiectasia has been observed, usually on the face, behind pinnae, at thorax and extremities, as well as post-inflammatory hyperpigmentation at the areas where acneiform dermatitis and eczema developed, which gets worse with UV radiation [9,29]. Palmoplantar erythrodysesthaesia has been reported as specially related to tyrosine kinase inhibition [30].

Histopathology

At initial stages, inflammatory infiltrate was observed with CD68+ macrophages, CD1+ intraepidermal Lagerhans cells recruitment, and T CD8+ lymphocytes, which usually are not seen in healthy skin. Augmented CD4+ and CD8+ lymphocytes, neutrophil elastase + and mast cells [31].

Similar changes were found at Busam et al trial, where patients were treated with cetuximab therapy, and serial biopsies taken. They began with normal skin and, in subsequent biopsies the first changes seen were T lymphocytes infiltrates, surrounding follicular infundibulum; after a week of treatment, surface perifollicular hyperkeratosis, suppurative folliculitis and focal intraepidermal acantholysis with neutrophils infiltrates involving the terminal portion of the sudoriparous duct. At immunohistochemistry, it was observed that after 8 days of treatment there was 3 to 4 times increment of p27 Kip1 at dermal keratinocytes [26].

Treatment

Side effects importance for treatment resides in the impact of lesions on the patients, since they are cosmetically unpleasant and painful, which jeopardizes both dosing changes and possible treatment continuation. That is the reason for orienting patients about possible adverse effects before the beginning of treatment and starting prophylactic measures to avoid them. Treatment is based in the type of lesions, as well as their severity and extension [13]. Fortunately, dermatologic lesions treatment does not influence patient’s survival [21].

General measures

Treatment begins with skin care general measures and an adequate solar protection. Patients must be oriented to avoid cleaning products that may promote skin dryness. Emollients use may be used in order to avoid xerosis and fissures, but emollients must not be used on the face and trunk, since these can worsen acneiform dermatitis [32].

Acneiform dermatitis

Treatment is based on oral antimicrobials. Low potency steroids (1% hydrocortisone. Level of evidence 2A) may help diminishing pruritus, although potent steroids may aggravate the situation [21]. Topical retinoids and isotretinoin are commonly used, whereas their efficacy has not been proved, as it happens with other topic drugs (metronidazole, clindamycin, benzoyl peroxide, salicylic acid) [13,21].

Segaert et al, proposed as the basis of treatment drugs as metronidazole topical treatment that can be used at 2% cream, applied twice a day. Oral drugs are reserved (Table 4) for clinical cases with a poor response to topical treatment or according to the extent of injuries [32].

Download PDF

Citation: Zárraga CA, Vega Memije ME and Rodríguez Cid JR. Dermatologic Adverse Effects Secondary to EGFR Inhibitors Use as Oncological Treatment: Pathophysiology, Clinical Manifestations and Treatment. Austin J Dermatolog. 2017; 4(3): 1078.

Instruction for Authors

Submit Your Article

Drug	Approved uses
Erlotinib	Non-small cells lung cancer Pancreatic carcinoma
Gefitinib	Non-small cells lung cance
Afatinib	Non-small cells lung cancer
Cetuximab	Colon and rectal cancer Squamous cell carcinoma of the head and neck
Panitumumab	Colon and rectal cancer

Tyrosine Kinase Inhibitors
Drugs	Adverse Effects
Erlotinib	Acneiform dermatitis Diarrhea Asthenia	Cough Dyspnea Anorexia
Gefitinib	Non-Specific dermatitis Transaminase elevation Proteinuria	Diarrhea Hepatotoxicity Interstitial lung disease (ILD)
Afatinib	Diarrhea Acneiform dermatitis Stomatitis Paronychia Xerosis Anorexy	Pruritus Vomit Dyspnoea Dysphagia Hipokalemia
Monoclonal Antibodies
Drugs	Adverse Effects
Cetuximab	Nausea Anemia Vomit Neutropenia Unspecified dermatitis	Asthenia Diarrhea Anorexia Conjunctivitis Electrolyte disturbances (hypomagnesemia, hypokalemia, hypocalcemia)
Panitumumab	Acneiform dermatitis Pruritus Xerosis	Paronychia Erythema Angioedema

Overall dermatologic adverse effects Incidence:
a) Monoclonal antibodies 1) Cetuximab 2) Panitumumab	a) 80% - 100% 1) 88 - 90% 2) 100%
b) Tyrosine kinase inhibitors	b) 43%-54%
Severe dermatologic adverse effects (Grades 3 & 4)
a) Monoclonal antibodies: 10%-17%	10%-17%
b) Tyrosine kinase inhibitors	5%-9%

Drugs	Dose
Minocycline	100mg/day
Doxycycline	100mg/day
Lymecycline	300mg/day