Pathology and Management of Dermatologic Toxicities Associated With Anti-EGFR Therapy

As inhibitors of the epidermal growth factor receptor (EGFR) become an increasingly common therapeutic option in cancer, appropriate management of their associated toxicities emerges as a critical part of treatment. Cutaneous manifestations, probably linked to the function of the EGFR in epithelial development, are the most common adverse reactions to EGFR inhibition. The key manifestations are follicular eruptions, nail disorders, xerosis, and desquamation. Growing attention continues to be devoted to the analysis of these events, particularly given their potential role as markers of responsiveness to treatment. However, to date, there are few evidence-based guidelines for the appropriate management of these dermatologic events. Multidisciplinary collaboration between oncologists and dermatologists will be required to improve our understanding and optimize the characterization of these skin toxicities, and to design effective management approaches.

Increasing attention is currently being directed toward the chemotherapeutic selective inhibition of the epidermal growth factor receptor (EGFR) in colon, head and neck, pancreatic, and non-small-cell lung cancers. As the use of EGFR inhibitors is becoming more widespread, growing amounts of data are being collected regarding their efficacy and adverse effects.

The earliest reports of toxicities from EGFR inhibitors in the oncologic literature noted cutaneous toxicities as one of the most consistent side effects of EGFR blockade.[1,2] Cutaneous reactions to EGFR inhibitors include a characteristic follicular eruption, toxicity of the nails and distal digits, generalized xerosis, desquamation, pruritus without rash, hyperpigmentation, erythema, oral and nasal mucosal aphthae, skin hyperpigmentation, vaginal dryness and pruritus, blepharitis, ingrown eyelashes, trichomegaly, mild ocular irritation, alopecia, fine, brittle, and curlier hair, and a seborrheic dermatitis-like facial eruption (for major categories of dermatologic events, see Table 1).[4-9] Data now suggest that the follicular eruption is the most clinically significant of the cutaneous toxicities, as it is a potential marker of response to therapy. The remainder of this article will further characterize the cutaneous toxicities associated with EGFR inhibition, discuss the criteria for grading cutaneous toxicities, and make treatment recommendations.

Grading Cutaneous Toxicities

The symptoms used to evaluate cutaneous toxicities of EGFR inhibitors are outlined according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC), which establishes a scale of 1 to 5 to grade the severity of these events (Table 1). Most academic centers use version 3. Cutaneous reactions to EGFR inhibitors are usually mild to moderate (grades 1/2). One important point is that in the multitude of clinical trials of EGFR inhibitors, “rash” has been defined rather broadly. It is therefore difficult to differentiate based on the reports alone whether rash was defined as one entity or a combination of “acneiform,” “follicular,” “pustular,” “vesicobullous,” “maculopapular,” “xerotic,” or “desquamative” rash. Therefore, future trials must include a more precise description of the cutaneous toxicity noted with each medication. Some authors have also suggested the subdivision of grade 2 eruptions into whether the rash interferes with activities of daily living and if intervention is indicated.[10]

Follicular Eruption

A follicular eruption on the face and trunk, experienced by 55% to 100% of patients in some studies (see Table 2), is the most significant cutaneous toxicity noted with EGFR inhibitors. Follicular papules and pustules on the scalp, face, chest, and back with sparing of the palms, soles, and mucous membranes usually appear within 7 to 10 days after initiation of therapy, but the window for onset can range from > 7 days to 42 days after initial drug administration.[2,4,5,16,32]

The follicular papules and pustules are located primarily in an acneiform distribution, hence the initial description of an “acneiform” eruption. However, the follicular eruption is probably not related in etiology or pathogenesis to acne vulgaris. The eruption is independent of an individual or family history of acne. In addition, histologic features of the follicular eruption typically include either superficial perifollicular lymphocytic inflammation surrounding hyperkeratotic and ectatic follicular infundibula or a frank suppurative folliculitis[5,8,16]-findings that are more consistent with folliculitis than acne vulgaris.[10] When looked for by potassium hydroxide test, Gram stain, culture, or biopsy, an infectious etiology is rarely found. At the outset of lesions, cultures for Candida or bacteria are invariably negative; however, in some persistent lesions, Staphylococcus aureus can be isolated, implying superinfection rather than an etiologic role in pathogenesis.

The severity of the follicular eruption appears to be a dose-dependent class phenomenon. More importantly, the follicular eruption has repeatedly been found to be the most significant predictor of response to therapy and prolonged survival.[4,11,21,45,46] Clinical trials of cetuximab (Erbitux) in combination with chemotherapy in patients with colorectal cancer (two studies), squamous cell carcinoma of the head and neck (one study), or pancreatic cancer (one study) showed that development of a follicular rash was significantly correlated with response to treatment.[45] In addition, studies of erlotinib in non-small-cell lung cancer, head and neck cancer, and ovarian cancer have shown that rash was associated with objective response and stable disease with prolonged survival.[46]

In one study of erlotinib in non-small-cell lung cancer, the median survival of patients without rash was 1.5 months, compared with 8.5 and 19.6 months for patients with a maximum grade 1 rash and grade 2 or 3 rash, respectively.[4] In this same study, the median time to the first occurrence of rash, regardless of severity, was 10 days, with a range of 2 to 44 days. When rash, regardless of severity, was further evaluated as a time-dependent variable in a multivariate analysis, it continued to be a significant predictor of survival.

In an analysis of three studies investigating cetuximab in different tumor types (colorectal, head and neck, and pancreatic), patients who experienced rash survived significantly longer than those who did not; patients with the most severe rash achieved the longest survival times. The most pronounced differences were observed in pancreatic cancer, where median survival was 2.3 months in patients with no rash and reached 13.9 months in those with grade 3 events (P = .0007).[47] Thus, presence of a follicular eruption during therapy with EGFR inhibitors is a fortuitous finding that might actually represent a surrogate marker for tumor damage. This premise requires confirmation in future studies.

While the follicular eruption is usually well-tolerated and does not require cessation of therapy,[4,32,45] in a few cases EGFR inhibitor therapy was held or discontinued due to the severity of the eruption.[1,16] Patients may experience waxing and waning of the eruption despite continuation of therapy.[2,9] The severity of cutaneous symptoms may be of particular concern when anti-EGFR agents are combined with radiotherapy (a treatment modality itself associated with skin manifestations, particularly within the radiation field of the patient). Importantly, results from large studies indicate that patients receiving combined modality therapy experience dermatologic toxicities, but there does not seem to be substantial exacerbation of severe events overall or within the radiation fields.[12,26]

In addition, although not commonly reported, this author has seen dramatic scarring, erythema, and postinflammatory hyperpigmentation following a particularly severe follicular eruption due to (successful) EGFR inhibitor therapy for pancreatic cancer. Furthermore, as mentioned previously, severity of the follicular eruption correlates with response to therapy, thereby implying that patients with the worst cutaneous reactions might be the ones with the best response to EGFR inhibitor therapy. Therefore, dermatologists and oncologists should take a multidisciplinary approach to maximize patient tolerance of EGFR inhibitors.

Etiology of Cutaneous Toxicities

Attempting to understand the etiology of the EGFR inhibitor-induced follicular eruption is the first step in determining the appropriate therapy. The EGFR is normally expressed in epidermal keratinocytes, sebaceous and eccrine glands, and hair follicle epithelium, with the most intense expression occurring where keratinocytes are proliferating and undifferentiated (ie, in the basal layer of the epidermis and in the outer root sheath of hair follicles).[5,19,32] Activation of the EGFR normally inhibits basal keratinocyte differentiation, while promoting terminal differentiation of suprabasal epidermal keratinocytes. In addition, the EGFR is thought to play a role in promoting keratinocyte survival.[32] Likewise, EGF plays a critical role in the differentiation of sebocytes and keratinocytes in the human pilosebaceous infundibulum[5] and functions to slow growth and differentiation of cell types within the hair follicle.[6]

Epidermal growth factor might have a role in the development and maintenance of hair follicles. In transgenic mice expressing an EGFR-dominant negative mutation in the basal layer of the epidermis and follicular outer root sheath, hair follicles fail to enter the catagen stage, resulting in a severe inflammatory follicular necrosis and alopecia. Also, addition of EGF or TGF-alpha to cultured human pilo-sebaceous infundibulae causes infundibular keratinocyte disorganization similar to that seen in acne, suggesting that regulation of EGFR activity is integral to follicular keratinization.[16]

Drug-induced blockade of the EGF receptor is thought to alter suprabasal keratinocyte maturation in a way that may be responsible for both the follicular eruption (through alteration of maturation of the outer root sheath keratinocytes) and desquamation (through alteration of maturation of the interfollicular epidermal keratinocytes).[32] To better understand the pharmacodynamic properties of the EGFR, Albanell et al[32] evaluated 104 skin biopsies from 65 patients receiving escalating doses of gefitinib (Iressa) and compared these biopsies to those of normal skin taken from the same patients prior to gefitinib therapy. These investigators demonstrated that EGFR activation was abolished in the skin samples of patients treated with gefitinib, strengthening the argument that EGFR blockade in some way contributes to the follicular eruption.

One hypothesis regarding the pathogenesis of follicular eruption suggests that EGFR inhibitors interfere with the signal pathway of the EGFR in epidermis and skin adnexal epithelium through a direct effect on keratinocyte expression of the negative growth regulator p27Kip1.[5] Another hypothesis is that the drug affects follicular growth and differentiation in such a way as to lead to hyperkeratosis, follicular plugging, and subsequent obstruction of the follicular ostium.[5,6] Another hypothesis is that the perifollicular inflammatory infiltrate is a secondary reaction either to alteration of follicular growth and differentiation or to the presence of an antibody on the surface of follicular epithelial cells that reacts with the drug, elicits an inflammatory reaction, and leads to follicular rupture. Furthermore, the EGFR is known to be expressed on sweat duct epithelium, and neutrophils have been found around sweat duct epithelium in some biopsies.[5]

Management of Anti-EGFR-Related Follicular Eruption

Because the etiology of the EGFR inhibitor-induced follicular eruption is still unknown, management to date has been largely empiric. Most studies report anecdotal evidence with topical and/or systemic antibiotics, topical retinoids, and topical and/or systemic corticosteroids. The remainder of this section will discuss several treatment options (see Table 3). The information contained herein is based on anecdotal reports. We need additional information in the way of controlled trials to optimize tolerance to EGFR inhibitor-induced cutaneous eruptions. Furthermore, a multidisciplinary approach, with collaboration between oncologists and dermatologists and referrals to dermatologists for complicated cases, cannot be overemphasized.

Topical agents most often used in the treatment of acne vulgaris such as benzoyl peroxide, topical retinoids, and topical antibiotics have been used for the treatment of the follicular eruption with less than impressive results. Benzoyl peroxide is minimally helpful in the management of follicular eruption and tends to promote dryness and irritation. Tretinoin cream, used in the treatment of acne vulgaris for its ability to regulate keratinocyte differentiation, was reported as slowing the formation of lesions in several patients, although it increased dryness.[8] Topical antibiotics such as clindamycin and erythromycin were also tried based on their use in the treatment of acne vulgaris, but had modest results and can also be irritating.[6] Taken together, agents typically used in the topical therapy of acne vulgaris appear to have little effect on the follicular eruption due to EGFR inhibition and might worsen symptoms by increasing irritation and xerosis.

As there is both clinical and histologic evidence of a marked inflammatory component to the follicular eruption, topical anti-inflammatory agents might play a role in treatment. Topical corticosteroids of mid-to-high potency are worth considering as treatment options, although anecdotal observations do not suggest they are effective, particularly in severe cases.[10] The sequelae of long-term mid-to-high potency corticosteroid use to sensitive areas such as the face and intertriginous areas are well known. However, the potential benefits of a finite therapeutic trial with a topical agent that augments tolerance to the EGFR inhibitors in patients undergoing therapy for life-threatening malignancies appear to outweigh the risks of corticosteroid-induced atrophy, pigmentary changes, and/or rosacea.

Also worth investigation and consideration are the newer topical immunomodulators (tacrolimus [Protopic] ointment and pimecrolimus [Elidel] cream) that exert anti-inflammatory effects without inducing atrophy or pigmentary changes. Of note, in the first several days of application, topical immunomodulators often induce pruritus or a “stinging” sensation, symptoms that usually abate after several days of therapy. Patients should be informed about this expected reaction to avoid unnecessary discontinuation of these agents.

Systemic antibiotics with known anti-inflammatory effects are also worth consideration for the treatment of follicular eruption. Several studies reported treatment (usually empiric) of the follicular eruption with tetracycline or similar agents (minocycline),[2] all of which have a long history of use in dermatology not only for the treatment of acne vulgaris, but also for the treatment of other inflammatory dermatoses such as sarcoidosis and bullous pemphigoid.[48,49] Again, there are minimal data regarding efficacy of systemic antibiotic therapy, but further investigation is warranted.

The follicular eruption is thought to be sterile, at least initially, as investigations for infectious etiologies rarely yield positive findings in the early stages of the eruption.[5,16,24] It is worth noting that the follicular eruption often has a pustular component and may take on a “honey-crusted” appearance similar to that seen in impetigo during the evolution of the eruption. Therefore, secondary infection of the follicular eruption may be more common than initially thought and should be ruled out. Culture of pustules or persistently crusted lesions for bacteria, viruses (HSV), and yeast is recommended. Empiric therapy with topical mupirocin or systemic antibiotics for suspected S aureus infection may be considered. One group advocates intranasal mupirocin applied daily to each nostril as a preventative measure to decrease the likelihood of superinfection.[10]

Dose adjustments for cutaneous eruptions due to the EGFR inhibitors are not currently the standard of care, but may be considered for severe cases unresponsive to the aforementioned therapies (Table 4).

Paronychia and Ingrown Nails

Clinically, EGFR inhibitor-induced toxicity of the nails and surrounding skin occurs after several weeks to months of therapy and presents as xerosis and desquamation of the distal digits, an acute paronychia, or pyogenic granuloma-like inflammation.[9] Marked pain, tenderness, and fissuring of the distal tufts of the digits is often present. The great toes and thumbs are most commonly affected.[5] The paronychia is clinically similar to that seen in reaction to antiretroviral therapy and systemic retinoid therapy.[6] Although cultures taken from areas of paronychial inflammation are occasionally positive for S aureus, positive cultures likely represent secondary infection as initial cultures for Candida and bacteria are usually negative at the onset of the paronychia, and lesions often persist despite antibiotic therapy.

Nail toxicity is graded similarly to other cutaneous toxicities according to the NCI-CTC. It is important to note, however, that the clinical features described in this grading scale do not reflect those typically seen in response to the EGFR inhibitors. Thus, modification of this scale to reflect the toxicities noted is imperative if we are to accurately characterize and determine the significance of the nail and periungual toxicities seen with EGFR inhibition. Based on a review of the literature (Fox, manuscript submitted), it appears that most patients who develop a paronychia at some time also experience the drug-induced follicular eruption. However, there are not enough data to determine if the reverse is true (ie, if all patients who develop a follicular eruption also have paronychia). Whether the nail disorder represents a surrogate marker of response to therapy and/or survival is an interesting proposition that warrants further evaluation through rigorous observation, data collection, and close collaboration between oncologists and dermatologists.

The etiology of the paronychia and nail disorder associated with the EGFR inhibitors is unknown, but several hypotheses exist. As mentioned previously, altered terminal keratinocyte maturation in suprabasal keratinocytes as a result of EGFR inhibition may be responsible for both the follicular eruption and desquamation noted clinically.[7] A very similar paronychia with exuberant inflammation and granulation tissue formation occurs in patients on either systemic retinoid or antiretroviral therapy.[32,52] Patients undergoing treatment with EGFR inhibitors histologically demonstrate a markedly thinned and compact stratum corneum with loss of the normal basket-weave pattern-changes that might account for the clinical picture of xerosis and desquamation.[21,45] Similarly, thinning of the epidermis is a well-accepted consequence of retinoid therapy.[53] Furthermore, as retinoids, antiretrovirals, and EFGR inhibitors all have the side effects of paronychia, xerosis, and desquamation, the mechanisms underlying the paronychia might be related to the xerotic or desquamative dermatitis of the distal fingers and lateral nail folds.[5,52,54]

Paronychial lesions tend to persist during EGFR inhibitor therapy,[53] but are usually well tolerated and can be managed with local care including petrolatum emolliation, soaks, and cushioning of the affected areas.[11] In mild to moderate cases, the paronychia can be treated with disinfectants, topical antibiotics, and mid-to-high potency topical corticosteroids. If bacterial superinfection is suspected, cultures should be obtained and therapy with appropriate systemic antibiotics should be initiated. Severe cases warrant dermatologic referral where intralesional corticosteroids or surgical treatments (electrodessication,[53] cryosurgery,[32] surgical debridement, nail plate avulsion,[45] or matricectomy[32]) might be instituted. Although rare, extremely severe cases can interfere with patients’ daily activities and may require temporary discontinuation of the medication.[21]

Important to the management of the paronychia is anticipatory guidance when the patient begins therapy with an EGFR inhibitor. Patients should implement preventative measures such as avoidance of irritants (including frequent water immersion or harsh chemicals) and frequent petrolatum emolliation upon initiation of EGFR inhibitor therapy.

Other Cutaneous Reactions

Other cutaneous reactions due to EGFR inhibitors include xerosis, desquamation, pruritus without rash, erythema, oral and nasal mucosal aphthae, skin hyperpigmentation, a seborrheic dermatitis-like facial eruption, flushing, vaginal dryness and pruritus, blepharitis, ingrown eyelashes, trichomegaly, mild ocular irritation, alopecia, and fine, brittle, curlier hair.[4-9,11] These cutaneous reactions can usually be managed with conservative therapy and do not usually require dose modification or cessation of therapy.

Conclusion

The relationship between the follicular eruption and the nail and periungual changes due to EGFR inhibition is unclear, but the follicular eruption, in particular, appears to be a valuable clinical indicator of a positive response to therapy. Meticulous data collection and controlled treatment trials are required if we are to better characterize the etiology and pathophysiology of the eruption and maximize patients’ tolerability to therapy with EGFR inhibitors.

Disclosures:

The author has received honoraria and grant support from Bristol-Myers Squibb.

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