1. SERIES Clinic, Department of Dermatology and Robert H Lurie Comprehensive Cancer
Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
2. Vancouver Centre, BC Cancer Agency, Vancouver, BC, Canada
The epidermal growth factor receptor (EGFR) is often overexpressed or dysregulated in solid tumors. Targeting the EGFR-mediated signaling pathway has become routine practice in the treatment of lung, pancreatic, head and neck, and colon carcinomas. Available agents with selected activity towards the EGFR include low molecular weight tyrosine kinase inhibitors, e.g., erlotinib (Tarceva®, Genentech BioOncology/ OSI Pharmaceuticals/ F. Hoffmann-La Roche) and monoclonal antibodies, such as cetuximab (Erbitux®, Bristol-Myers Squibb/ ImClone Systems/ Merck) and panitumumab (Vectibix®, Amgen). Their use is anticipated to increase for treating other solid tumors that are dependent on this pathway for growth and proliferation. Health Canada and the US FDA have approved erlotinib for the treatment of advanced non-small cell lung carcinoma (NSCLC). It has also been approved in the US for use against pancreatic cancer in combination with gemcitabine (Gemzar®, Eli Lilly). Cetuximab and most recently panitumumab (Vectibix™, Amgen/ Abgenix) were approved by the US FDA for metastatic colorectal carcinoma. Cetuximab is also approved in the US for head and neck squamous cell carcinoma. The safety profile for this class of drugs is unique, with virtually no hematological toxicity, but frequent cutaneous and gastrointestinal side-effects. Although there is a dearth of randomized trials addressing treatment of the dermatological side-effects, some basic principles of management have been agreed upon and can likely improve patient compliance and decrease inappropriate dose reduction, which may negatively influence the antitumor effect.
Anticancer agents, epidermal growth factor receptor, EGFR inhibitor, monoclonal antibodies, tyrosine kinase inhibitors, cutaneous reactions
The human epidermal growth factor receptor (HER1/EGFR) is a transmembrane glycoprotein of the tyrosine kinase growth factor family that is expressed in many normal human tissues. It is finely regulated to control cell growth and proliferation. In many cancers, this growth factor is dysregulated and overexpressed, and this overexpression is common in many solid tumors, such as colorectal (65-75%), head and neck (90%), and lung (60%-90%) carcinomas. It correlates with increased metastasis, reduced survival, and a poor prognosis.1
Overexpression can result in uncontrolled cell growth, proliferation, angiogenesis and metastases. This growth factor can be successfully blocked by antibodies against the extracellular domain of the receptor, or small molecule inhibitors directed against the intracellular tyrosine kinase domain. Whereas a blockade of the receptor in tumors leads to beneficial effects, in skin and appendages this leads to undesirable reactions, including a papulopustular eruption, hair growth disorders, periungual and nail plate abnormailities, xerosis, and pruritus.
Tyrosine Kinase Inhibitors
Tyrosine kinase inhibitors are small molecules given orally that target the EGFR receptor. By blocking the intracellular ATP binding site, phosphorylation cannot be completed, thereby inhibiting the signaling cascade that activates growth and proliferation factors.
In 2004, erlotinib received US FDA approval for patients with advanced NSCLC who have failed at least one prior chemotherapy regimen. This was based on the results of a pivotal phase III trial (BR.21), in which erlotinib prolonged median survival by 42.5% over best supportive care (6.7 months vs. 4.7 months; P <0.001) in patients after one or two prior chemotherapy regimens.2
The side-effects reported in this trial included diarrhea (50%) and rash (75%). Typically, the rash developed about 7–10 days after the start of treatment, affecting the skin above the waist, and resolving spontaneously without treatment. In most patients, the rash was mild (grade 1 or 2); only 8% of patients had grade 3 rashes, and <1% had a grade 4 rash.2 For grade 3 and 4 rashes, the protocol recommended stopping the drug for 7–10 days, then resume at 30% dose reduction. Importantly, subsequent analysis suggested a positive correlation of the rash to response and survival.2
Monoclonal antibodies against the epidermal growth factor are given intravenously. By this action, the epidermal growth factor produces a similar end result as tyrosine kinase inhibitors. In 2004, the FDA approved cetuximab as a combination treatment with irinotecan (Camptosar®, Pfizer) for the treatment of patients with metastatic colorectal cancer. This was based on a randomized study that showed the combination of cetuximab and irinotecan had a response rate of 22.9 % and delayed tumor growth by 4.1 months.3 Rash was observed in 87% of these individuals.
Panitumumab, a fully humanized monoclonal antibody, is also approved for this same indication with a similar benefit in progression-free survival.4 Cetuximab has also shown an improvement in survival when given with radiation to patients with head and neck cancer.5 Like the tyrosine kinase inhibitors, a correlation of response and survival to those who experienced the highest grade of rash has been shown.2
Pathophysiology of Skin Toxicities
EGFR is expressed in the basal layer of the epidermis. Its roles include stimulation of epidermal growth, inhibition of differentiation, and acceleration of wound healing. Effects of EGFR inhibition include impaired growth and migration of keratinocytes, and inflammatory chemokine expression by these cells. These effects lead to inflammatory cell recruitment and subsequent cutaneous injury, which accounts for the majority of symptoms, including tenderness, papulopustules, and periungual inflammation.6 Histologic specimens reveal a mixed inflammatory infiltrate surrounding the upper areas of the dermis, follicular rupture, and epithelial acantholysis. Direct immunofluorescent studies show a nonspecific pattern of staining. Inhibition of mitogen activated protein kinase (MEK) by pharmacological methods, a downstream effector in the EGFR pathway, also leads to papulopustules, suggesting a mechanism-based effect.7 Similar inflammatory events may also account for the periungual inflammation and onycholysis, whereas abnormalities in keratinocyte differentiation i.e., premature expression of keratin 1 and STAT 3, may explain the impaired stratum corneum leading to xerosis and pruritus.7
Description of Dermatological Toxicities
The effects of EGFR inhibitors on epidermal-derived tissue includes a papulopustular eruption, dry skin, pruritus, ocular and nail changes.6 Common terms used to describe the rash are acneiform skin reaction, acneiform rash, acneiform follicular rash, acne-like rash, maculopapular skin rash, and monomorphic pustular lesions. However, the term papulopusular reaction is a more accurate description. The rash may be triggered by sun exposure,8 and develops in the following phases: sensory disturbance, erythema, and edema (week 1); papulopustular eruption (week 2); crusting (week 4); and, if the rash is treated successfully, a background of erythema and dry skin can be seen in areas previously affected by the papulopustular eruption (weeks 4–6).7 Other events such as pruritus, erythema, and paronychial inflammation associated with the lateral nail folds of the toes and fingers can occur. Paronychia may occur after a longer period of treatment.
|Reversible EGFR/ HER1||TKI||NSCLC and in combination with gemcitabine for pancreatic cancer||Genentech Inc/
OSI Pharmaceuticals Inc/
F. Hoffmann-La Roche
|Cetuximab (Erbitux®)||EGFR/ HER1||mAb chimeric IgG1||CRC and SCCHN with radiation||Bristol-Myers Squibb/
ImClone Systems Inc/ Merck
|Gefitinib (Iressa®)||Reversible EGFR/ HER1||TKI||NSCLC May 2003, now with restricted availability.1||AstraZeneca|
|Panitumumab (Vectibix®)||EGFR/ HER1||mAb humanized IgG2||Metastatic CRC||Amgen/Abgenix|
|Table 1: FDA approved tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs). NSCLC = non-small cell lung cancer; SCCHN = squamous cell carcinoma of the head and neck; CRC = colorectal carcinoma; IgG1 = gamma G Immunoglobulin; EGFR = epidermal growth factor receptor; HER1= human epidermal growth factor receptor type 1.|
Treatment of Rash
In the randomized trials where the primary endpoint was survival and response, rash treatment was often vague and not well documented. As well, there is difficulty in interpreting these trials because the rash was graded according to the National Cancer Institute (NCI) criteria (NCI CTC criteria version 2.0 and 3.0) and may not accurately reflect the clinical situation.9 A more accurate grading system is urgently needed, and this is one of the major tasks of the Skin Toxicity Study Group of the Multinational Association of Supportive Care in Cancer (www.mascc.org).
The specific treatment algorithms for rashes caused by EGFR inhibitors vary widely throughout different centers that use these agents in their clinics. Nonetheless, some basic principles may apply. In the following section, management recommendations from the dermatology-based SERIES (Skin and Eye Reactions to Inhibitors of EGFR and kinaseS) clinic10 (Figure 1, see page 5) will be presented along with those utilized in the BC Cancer Agency Oncology Department (Table 2). Both of these regimens are currently being investigated in clinical trials.
Patients need to be educated on the importance of taking oral TKIs on an empty stomach. Furthermore, patients should be instructed to use an alcohol-free emollient cream applied twice daily, preferably to their entire body. Physicians should also recommend that patients use a broad spectrum sunscreen, since sun exposure may aggravate their rash.8
Mild reactions (NCI-CTC grade 1) are generally localized with no associated physical symptoms. Treatment options include topical low-medium potency corticosteroids or calcineurin inhibitors (TCIs) (i.e., pimecrolimus [Elidel®, Novartis]; and tacrolimus [Protopic®, Astellas Pharma]), all of which are able to inhibit inflammation. TCIs do not cause the side-effects attributed to corticosteroids, such as skin atrophy, acne/rosacea-like reactions, and dyspigmentation. However, their use is hampered by the development of pruritus and burning in a subset of patients. Other options include the addition of clindamycin 1% gel to hydrocortisone 1% (B. M., unpublished data), and the use of oral semisynthetic tetracyclines (i.e., doxycycline or minocycline). The EGFR inhibitor should be continued while the rash is being treated.
Moderate reactions (NCI-CTC grade 2) are more disseminated and can include symptoms such as tenderness or pruritus. The recommended treatment is hydrocortisone 1% or 2.5% cream +/- clindamycin 1% gel, as well as a 4-week course of an oral tetracycline antibiotic, such as doxycycline 100mg or minocycline 100mg twice daily.
Severe reactions (NCI-CTC grade 3) are generalized with major symptoms affecting activities of daily living and are intolerable to the patient. In addition to the above measures, a short course of oral corticosteroids may be administered (i.e., methylprednisolone [Medrol® dose pack, Pfizer]). Although histological findings suggest that the papulopustular reaction has an inflammatory component, the use of topical/ oral corticosteroids is based on empirical data. Alternatively, a temporary 7–10 day discontinuation of the drug involved is recommended with subsequent reintroduction at a lower dose according to the product monograph. Treatment with both a steroid cream and oral tetracycline as per moderate rash is encouraged during the interruption period. Oral isotretinoin (Accutane®, Roche) may be considered for patients who do not respond to the above measures. Therapy with low dose (10-20mg daily) oral isotretinoin must be employed with caution, as it may exacerbate xerosis and paronychia, all of which may be present with EGFR inhibitor use. Thus, oral isotretinoin should only be considered when other antitoxicity interventions have failed and a positive antitumor response is documented, making it imperative to maintain the patient on antiEGFR therapy.
Figure 1: SERIES Management algorithm for papulopustular reactions to EGFR inhibitors (from Lacouture et al., J Supportive Oncol,10 reprinted with permission). Severity of papulopustular reaction is graded based on clinical findings and symptoms (mild/moderate, severe). Abbreviations: EGFR=epidermal growth factor receptor inhibitor; SERIES=Skin and Eye Reactions to Inhibitors of EGFR and kinaseS; STCN= semisynthetic tetracyclines (doxycycline); topicals (steroids or calcineurin inhibitors); dose mod=EGFR inhibitor dose reduction or interruption; isotretinoin=low doses (10-20mg a day) isotretinoin.
Rashes on the Scalp
The rash may be successfully treated with the basic principles above, but often patients can develop lesions and plaques on the scalp. Scalp lesions can be treated with topical clindamycin 2% plus triamcinolone acetonide 0.1% in equal parts of propylene glycol and water until resolution.
Severity of Rash
|Mild||Topical clindamycin 2%, with hydrocortisone 1% in lotion base applied twice-daily.|
|Moderate||Topical clindamycin 2%, with hydrocortisone 1% in lotion base applied twice-daily AND oral minocycline 100mg twice-daily for a minimum of 4 weeks and continuing thereafter as required, until resolution of the rash by one severity grade. Scalp lesions will be treated with a topical lotion clindamycin 2%, triamcinolone acetonide 0.1% in equal parts of propylene glycol and water.|
|Severe||Stop erlotinib therapy for 1 week and restart at 100mg once-daily. Treatment of rash with topical clindamycin 2%, with hydrocortisone 1% in lotion base applied twice-daily AND oral minocycline 100mg twice-daily for a minimum of 4 weeks and continuing thereafter as required. Scalp lesions will be treated with a topical lotion clindamycin 2%, triamcinolone acetonide 0.1% in equal parts of propylene glycol and water until resolution.|
|Table 2: BCCA EGFR Inhibitors: Rash protocol. Note: Erlotinib dose re-escalation is optional based on discretion of physician and improvement of rash by one grade.|
Management of Dermatological Toxicities Other Than Rash
Due to the lower frequency and visibility of additional toxicities when compared to rash, management recommendations and uncontrolled reports are limited. Nail changes are usually mild, but like the rash, may be severe and symptomatic. Oral doxycycline may be effective along with topical corticosteroids,11 but in resistant cases, intralesional corticosteroid injections or removal of the nail plate may be beneficial.12 Dry skin in the trunk and extremities is very common. Fragrance free creams and ointments are preferred over lotions, which may contain alcohol. For scaling and hyperkeratosis, ammonium lactate and urea containing preparations are also useful, but they should be used with care because of greater skin sensitivity. Eyelash growth can be seen when epidermal growth factors are given for a prolonged period of time. Cutting the eyelashes intermittently to a shorter length can add to patient comfort.
Currently, the EGFR pathway is targeted for cancer treatment using oral tyrosine kinase inhibitors or intravenous monoclonal antibodies. These agents have become standard treatment in both lung and colorectal carcinomas and their usage will only gain in frequency as they move into the treatment of other solid tumors and other indications like adjuvant therapy following curative resection. The side-effects shared by this class of drugs primarily affect the skin and appendages. Rash management is a key factor in patient tolerance and compliance. Severe rash and dose reductions can be avoided with proactive/early intervention and proper education directed to both patient and physician.
- Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19(3):183-232 (1995 Jul).
- Shepherd FA, Rodriques Pereira JR, Ciuleanu T, et al. Erlotinib in previoulsy treated non-small-cell lung cancer. N Engl J Med 353(2):123-32 (2005 Jul).
- Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus ironotecan in ironotecan-refractory metastatic colorectal cancer. N Engl J Med 351(4):337–45 (2004 Jul).
- Wainberg Z, Hecht JR. Panitumumab in colon cancer: a review and summary of ongoing trials. Expert Opin Biol Ther 6(11):1229-35 (2006 Nov).
- Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354(6):567-78 (2006 Feb).
- Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nature Rev Cancer 6(10):803-12 (2006 Oct).
- Lacouture ME, Lai SE. The PRIDE (Papulopustules and/or paronychia, Regulatory abnormalities of hair growth, Itching, Dryness due to EGFR inhibitors) syndrome. Br J Dermatol 155(4):852-4 (2006 Oct).
- Perez-Soler R, Delord JP, Halpern A, et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes form the HER1/EGFR inhibitor rash management forum. Oncologist 10(5):345-56 (2005 May).
- Luu M, Lai SE, Patel J, Guitart J, Lacouture ME. Photosensitive rash due to the epidermal growth factor receptor inhibitor erlotinib. Photodermatol Photoimmunol Photomed 23(1):42-5 (2007 Feb).
- Lacouture ME, Basti S, Patel J, Benson A 3rd. The SERIES Clinic: an interdisciplinary approach to the management of toxicities to EGFR inhibitors. J Support Oncol 4(5):236-8 (2006 May).
- Shu KY, Kindler HL, Medenica M, Lacouture M. Doxycycline for the treatment of paronychia induced by the epidermal growth factor receptor inhibitor cetuximab. Br J Dermatol 154(1):191-2 (2006 Jan).
- Fox LP. Nail toxicity associated with epidermal growth factor receptor inhibitor therapy. J Am Acad Dermatol 56(3):460-5 (2007 Mar).