Cutaneous Side Effects Associated With Targeted Therapy
Quick Facts
- Skin rash is a common side effect associated with targeted therapy, affecting more than 50% of patients receiving epidermal growth factor receptor (EGFR) inhibitors
- Several studies have demonstrated a positive correlation between rash and tumor response and/or survival
- Paronychia, hair alterations, and ocular changes can occur with HER1/EGFR inhibitors; however, symptoms are typically delayed, occurring within 4 to 8 weeks after initiation of treatment
- Nurses should visually examine affected areas and grade the severity to determine appropriate interventions for managing the side effects; early and prompt intervention for management of rash may help keep patients on therapy longer
Background
Skin rash associated with HER1/EGFR therapy is generally considered mild to moderate in nature,1,2 affecting more than 50% of patients receiving treatment. The incidence of severe rash (grade 3) is reported in 16% to 18% of patients.2,3 The cutaneous eruptions appear primarily on the face, neck, and upper torso, as seen inFigure 1, and the face is often the first area affected by the rash.4
The rash is characterized by interfollicular and follicular-based erythematous papules and pustules and is usually seen during the first 2 weeks of therapy.1,2
The follicular skin lesions are without the microcomedones and comedones characteristic of acne, indicating that this rash in not acne vulgaris.1,2,5
- The rash tends to wax and wane during therapy, with “flare-ups” occasionally noted following infusions.3,6
- Rash symptoms typically resolve without scarring within 1 to 2 months of stopping treatment.3
- Several studies have demonstrated a positive correlation between rash and tumor response and/or survival with cetuximab and erlotinib; findings are less consistent with gefitinib (Figure 2).1-3
FIGURE 1
FIGURE 2
Pathophysiology
The pathophysiology is not completely understood, but interference with the proliferation, differentiation, migration, and attachment of keratinocytes is believed to occur with EGFRI therapy, resulting in recruitment of inflammatory cells and injury to the cutaneous tissues.7,8 Since EGFR is highly expressed in the epidermal keratinocytes, sebaceous glands, and epithelium of the hair follicle, inhibition of these receptors can produce characteristic dermatologic effects.9
Grading and Management of EGFR-Associated Rash
Limitations with the National Cancer Institute Common Toxicity Criteria scales10 had prompted consensus panels of experts to revise grading of EGFR rash, as the third version was subject to variable interpretation and called for involvement of body surface area in calculating grades of rash.11,12 Recommendations for simplifying the approach to grading, for ease of patient care and more accuracy, now exist. This simplified approach (as illustrated below) calls for 3 categories: mild, moderate, and severe (Figure 3). The mild reaction is considered to be a generalized localized papulopustular reaction with minimal symptoms; the moderate reaction is a generalized papulopustular rash that is pruritic or tender, but minimally affects the activities of daily living (or ADLs); and the severe reaction is a generalized papulopustular rash with severe pruritus or tenderness that affects ADLs significantly and may possibly be infected.11 It is worth noting, however, that the NCI Common Terminology Criteria for Adverse Events Version 4 (NCI-CTC v.4) was released in May of 2009 and has a more specific descriptive grading scale for the EGFR rash and associated nail toxicities. The revised grading scales are available in Table 2 (Assessment Tools).
FIGURE 3
Photographs courtesy of Pamela Viale, RN,MS, CS, ANP, AOCNP, member of Advisory Panel.
There are no established evidence-based guidelines on the treatment of rash symptoms associated with HER1/EGFR inhibitors, and many of the interventions are based on anecdotal reports or the experience of our dermatologist colleagues.1,2,6 Many of these strategies were primarily based on the effectiveness noted with anti-acne strategies. However, the consensus panel did develop treatment recommendations for rash based on their expert opinion.
These recommendations are that patients should use emollients for the dry skin or xerosis that accompanies EGFR therapies, and sunscreen should be used early on, as inhibition of the EGFRs lessens their protective nature, allowing sun exposure to worsen rash symptoms. Sunscreen products should have a high sun protection factor (SPF). Mild rash may not require intervention; if needed, clindamycin gel and/or topical hydrocortisone may be adequate. Moderate rash may require the previous treatments, or consideration of pimecrolimus 1%, plus a tetracycline analogue agent, such as oral doxycycline 100 mg twice daily or minocycline 100 mg twice daily. Severe rash requires dose interruption of the EGFR agent, tetracycline analogue treatment, plus application of hydrocortisone cream, clindamycin gel, or pimecrolimus, plus an oral steroid dose pack.11 Each tier of care requires careful assessment of patient response to strategies for treatment of rash. Dermatologic consultation is advisable in uncontrolled or severe cases.
Limited evidence exists in the form of randomized, controlled trials for management of EGFR-associated rash; however, several studies were reported in the last 2 years regarding rash treatment. The results of selected studies are listed in Table 1.
Table 1. Clinical Trials on Treatment of Chemotherapy-Associated Rash
Study Author Study Design Study Results Recommendations
Kozloff et al. 200713
|
Pilot, randomized, prospective single-center observational study of 20 patients (8 reported) on cetuximab or other EGFR inhibitor therapy receiving Regenecare for cutaneous toxicity. Regenecare containscollagen / lidocaine / aloe.
|
Of 11 patients meeting criteria, 8 completed evaluation after 4 weeks of Regenecare application for cutaneous toxicity. The study data indicated that Regenecare was effective in reducing itching and pain associated with rash; relief occurred within 15 to 30 minutes.
|
100% of patients would recommend product to others.
|
Alexandrescu et al. 200714
|
Pilot study of 11 patients (10 assessable) on EGFR MAbs and TKI oral agents receiving colloidal oatmeal lotion for dermatologic toxicity.
|
Of 10 assessable patients, 6 had complete response, and 4 partial responses (100% response rate) with no associated toxicities. Colloidal oatmeal lotion demonstrates multiple anti-inflammatory properties on arachidonic acid and TNF-alpha pathways.
|
Treatment with colloidal oatmeal lotion is efficient in controlling EGFR rash with no associated toxicities and 100% response rate, allowing continuation of therapy.
|
Ocvirk et al. 200815
|
Pilot trial of 30 patients on cetuximab plus chemotherapy with rash treated with topical crème containing urea and 0.1% vitamin K1 (Reconval K1) started after the first cutaneous toxicity noted.
|
Of the 30 patients, 6 had grade 3 rash, 18 grade 2, and 6 grade 1. Crème was used twice daily. All patients had reduction in cutaneous toxicity, with median time to improvement 8 days, and 18 days to down-stage rash 1 grade. No toxicity noted with therapy.
|
Further studies are needed to evaluate the impact on the response rate of cetuximab and quality of life.
|
Scope et al. 200716
|
Randomized, double-blinded trial of prophylactic oral minocycline and topical tazarotene for cetuximab dermatological toxicity; 48 patients were randomized to either minocycline or placebo, with tazarotene on either left or right side of the face.
|
Total facial lesion counts were significantly lower in patients receiving minocycline at weeks 1 through 4. At week 4, 20% of patients reported moderate to severe itch vs placebo (50%). No benefits to tazarotene application and treatment was associated with significant irritation.
|
Prophylaxis with oral minocycline may be useful in decreasing the severity of acneiform rash during first month of treatment; topical tazarotene is not recommended.
|
Jatoi et al. 200817
|
Placebo-controlled, double-blinded trial enrolled patients starting therapy with an EGFR inhibitor agent. A total of 61 evaluable patients were enrolled; patients were randomly assigned to either tetracycline 500 mg orally twice a day for 28 days or placebo.
|
The incidence of rash was found to be comparable across treatment arms: 70% in tetracycline group vs 76% in placebo group. Tetracycline appeared to have lessened the rash severity; by week 4, grade 2 rash was present in 17% of tetracycline patients vs 55% of placebo patients. Symptoms were improved in tetracycline group.
|
Tetracycline was not found to prevent EGFR inhibitor rash and cannot be clinically recommended for this purpose; however, diminished rash severity and improved quality of life in tetracycline patients suggest further study warranted.
|
Lacouture et al. 200818
|
Prospective trial of 95 patients on panitumumab receiving either preemptive or reactive treatment with doxycycline for EGFR rash.
|
Only 29% of patients in preemptive group experienced serious skin reactions vs 62% in the reactive group; effectiveness of chemo/EGFR therapy was not affected by preemptive therapy.
|
Preemptive therapy for skin reactions appears to significantly reduce the rate of skin reactions associated with treatment with panitumumab without affecting effectiveness of therapy.
|
Scope et al. 200919
|
Prospective randomized trial of topical pimecrolimus for cetuximab-associated acnelike eruption; 24 patients received twice-daily pimecrolimus for 5 weeks.
|
Treatment sides had greater decrease in lesion counts vs observation sides of face at week 2 and 5 (P< .001 andP= .02, respectively); however, no significant differences in patients’ symptoms and review of facial photographs for severity.
|
Pimecrolimus application did not translate into clinically meaningful benefit for patients with cetuximab-associated facial rash.
|
Therefore, based on the information gleaned from the above trials, clinicians should consider preemptive therapy with a tetracycline analogue agent. The action of the tetracycline analogue agents is primarily anti-inflammatory.20 Figure 4 represents a patient on EGFR inhibitor agents who was successfully treated with a tetracycline analogue agent. Topical anti-acne therapies were not considered helpful and should be avoided. Regenecare gel may be helpful in reducing symptoms, although larger trials are necessary to confirm usefulness of this treatment. Colloidal oatmeal lotion may be useful in reducing inflammation associated with the rash, although additional studies are needed to confirm the role of this therapy.
FIGURE 4
Other Cutaneous Toxicities
There are other cutaneous toxicities associated with HER1/EGFR-targeted therapy. These include nail bed toxicity (paronychia), hair alterations, xerosis, telangiectasia, nasal mucositis, and ocular irritation (Figures 5-8).1,2,5
FIGURES 5-8
Paronychia2,5,21
- Described as painful inflammation of tissue around fingernails and toenails; more commonly seen in the big toe and thumbs, and observed in 12% to 16% of patients (Figure 5)
- Often delayed, developing after 4 to 8 weeks of treatment
- Symptoms may be improved by wearing shoes that are not too tight; avoid friction; hot soaks and cushioning provide comfort; Epsom salt soaks help promote drainage; topical antiseptic or antibiotic ointments may help
Hair Alterations2,5
- Hair changes may occur 2 to 3 months after initiation of therapy, with hair thinning and developing dry, brittle, or curly texture
- Trichomegaly can occur, although rare (increased hair growth of the eyelashes and eyebrows (Figure 6)
- Waxing or electrolysis may be recommended
Xerosis and Related Changes, Skin Fissures2,5
- Xerosis, (abnormally dry skin) is a common side effect of HER1/EGFR-targeted therapy
- Painful fissures may develop on the fingers and toes, in nail folds, and over interphalangeal joints (Figure 7)
- Hydration of the skin with use of bath oil or shower oil may alleviate symptoms. Gels and soap may exacerbate dryness and should be avoided; dryness can be alleviated with emollient creams
- Liquid BandAid may help protect fissures
Telangiectasia5
- Defined as chronic dilation of groups of capillaries leading to elevated dark red blotches on the skin (Figure 8)
- May be seen in early onset of rash symptoms, appearing on the face, nose, chest, back, and limbs around a follicular pustule
- Tend to fade over time, leaving some hyperpigmentation
- Consider dermatology consult for possible laser therapy
Nasal Mucositis
- Sores and irritation may develop inside the nostrils, which may become uncomfortable
- Bactroban Nasal can be applied to help prevent secondary infection1
Ocular Irritation21
- Manifests as dry eyes, progressing to erythematous lids and crusting in the eyelash follicles; looks like blepharitis or conjunctivitis
- Rare, but if it occurs, it is usually within the first the first 4 weeks of therapy
- Treatment may consist of ophthalmic antibiotic ointment, warm soaks, natural tears
Role of the Oncology Nurse
Oncology nurses caring for patients on EGFR-inhibitor therapy need to become competent in treatment of these common dermatologic toxicities. Because rash indicates a probable response to therapy, it is incumbent on the oncology nurse to implement care strategies for these toxicities, helping patients to maintain therapy for longer periods. Education of the patient regarding the characteristics and time course of the rash and associated toxicities is crucial.4 Care strategies should be instituted early and be based on current expert recommendations and clinical trial results for treatment of EGFR inhibitor rash.22 Although steroids were originally not recommended in product package inserts, short-term oral steroids or steroid creams have shown clinical use in reducing inflammation associated with EGFR inhibitor therapy.
When necessary, dosage reductions are important; however, this option is not considered optimal, as the goal of therapy is to keep responding patients on therapy.4EGFR inhibitor therapy is an integral part of cancer treatment today, and management of the dermatologic toxicities associated with this therapy is crucial as EGFR inhibitor therapy expands into additional indications.
Assessment Tools
The different scales and rash descriptions make it difficult to compare the severity of the rash.10 The scale in Table 2 is commonly used to grade adverse events associated with skin and toxicity.
Table 2. The National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.010
Adverse Event _ ---------------------------------------------Grade--------------------------------------------------------
Rash
|
1
|
2
|
3
|
4
|
5
|
Acneiform
|
Papules and/or pustules covering < 10% BSA, which may or may not be associated with symptoms of pruritus or tenderness
|
Papules and/or pustules covering 10%-30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; associated with psychosocial impact; limiting instrumental ADL
|
Papules and/or pustules covering > 30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; limiting self-care ADL; associated with local superinfection with oral antibiotics indicated
|
Papules and/or pustules covering any % BSA, which may or may not be associated with symptoms of pruritus or tenderness and are associated with extensive superinfection, with IV antibiotics indicated; life-threatening consequences
|
Death
|
Defined as a disorder characterized by an eruption of papules and pustules, typically appearing in face, scalp, upper chest, and back.
|
Maculo-papular
|
Macules/papules covering < 10% BSA with or without symptoms (eg, pruritus, burning, tightness)
|
Macules/papules covering 10%-30% BSA with or without symptoms (eg, pruritus, burning, tightness); limiting instrumental ADL
|
Macules/papules covering >30% BSA with or without symptoms (eg, pruritus, burning, tightness); limiting self-care ADL
|
–
|
–
|
Defined as a disorder characterized by the presence of macules (flat) and papules (elevated). Also known as morbilliform rash; one the most common cutaneous adverse events, frequently affecting the upper trunk, spreading centripetally, and associated with pruritus.
|
Nails
|
1
|
2
|
3
|
4
|
5
|
Discoloration
|
Asymptomatic; clinical or diagnostic observations only; intervention not indicated
|
–
|
–
|
–
|
–
|
Defined as a disorder characterized by a change in the color of the nail plate.
|
Loss
|
Asymptomatic separation of the nail bed from the nail plate or nail loss
|
Symptomatic separation of the nail bed from the nail palte or nail loss; limiting instrumental ADL
|
–
|
–
|
–
|
Defined as a disorder characterized by loss of all or a portion of the nail.
|
Ridging
|
Asymptomatic; clinical or diagnostic observations only; intervention not indicated
|
–
|
–
|
–
|
–
|
Defined as a disorder characterized by loss of all or a portion of the nail.
|
ADL = activities of daily living; BSA = body surface area.
References
- Perez-Soler R, Delord J, Halpern A, et al. HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the management forum. Oncologist. 2005;10:345-356.
- Dick S, Crawford G. Managing cutaneous side effects of epidermal growth factor receptor (HER1/EGFR) inhibitors. Community Oncol. 2005;2:492-496.
- Sipples R. Common side effects of anti-EGFR therapy: acneiform rash. Semin Oncol Nurs. 2006;22:28-34.
- Oishi K. Clinical approaches to minimize rash associated with EGFR inhibitors. Oncol Nurs Forum. 2008;35;103-111.
- Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor inhibitors. Ann Oncol. 2005;16:1425-1433.
- Fish-Steagall A, Searcy P, Sipples R. Clinical experience with anti-EGFR therapy. Semin Oncol Nurs. 2006;22(1 suppl 1):10-19.
- Lacouture M, Basti S, Patel J, Benson A. The SERIES Clinic: an interdisciplinary approach to the management of toxicities of EGFR inhibitors. J Support Oncol. 2006;4:236-238.
- Eaby B, Culkin A, Lacouture M. An interdisciplinary consensus on managing skin reactions associated with human epidermal growth factor receptor inhibitors.Clin J Oncol Nurs. 2007;12:283-290.
- Galimont-Collen AFS, Vos LE, Lavrijsen APM, et al. Classification and management of skin, hair, nail and mucosal side-effects of epidermal growth factor receptor (EGFR) inhibitors. Eur J Cancer. 2007;43:845-851.
- National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2009-09-15_QuickReference_8.5x11.pdf pages 73-74. Accessed January 27, 2010.
- Lynch TJ Jr, Kim ES, Eaby B, et al. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management.Oncololgist. 2007;12:610-621.
- Agero ALC, Dusza SW, Benvenuto-Andrade C, et al. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol. 2006;55:657-670.
- Kozloff MF, Gowlande PA, Vlamakis J, et al. Evaluation of Regenecare™ Topical Gel in the treatment of skin rash associated with cetuximab (Erbitux®), Tarceva® and other EGFR inhibitor-treated cancer patients. Ingalls Health System. http://www.mpmmedicalinc.com/pdf/Regenecare_Study_Ingalls_April07.pdf. Accessed January 27, 2010.
- Alexandrescu DT, Vaillant JG, Dasanu CA. Effect of treatment with a colloidal oatmeal lotion on the acneform eruption induced by epidermal growth factor receptor and multiple tyrosine-kinase inhibitors. Clin Exp Dermatol. 2007;32:71-74.
- Ocvirk J, Rebersek M. Managing cutaneous side effects with K1 vitamin crème reduces cutaneous toxicities induced by cetuximab. J Clin Oncol. 2008;26(suppl). Abstract 20750 can be accessed here.
- Scope A, Agero AL, Dusza SW, et al. Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol. 2007;25:5390-5396.
- Jatoi A, Rowland K, Sloan JA, et al. Tetracycline to prevent epidermal growth factor receptor inhibitor-induced skin rashes: results of a placebo-controlled trial from the North Central Cancer Treatment Group (N03CB), Cancer. 2008;113: 847-853.
- Lacouture ME, Mitchell EP, Shearer H, et al. Impact of pre-emptive skin toxicity (ST) treatment (tx) on paniutumumab (pomab)-related skin toxicities and quality of life (QoL) in patients (pts) with metastatic colorectal cancer (mCRC): results from STEPP. Presentation at: American Society of Clinical Oncology Gastrointestinal Cancers Symposium 2009. Abstract 291. http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=63&abstractID=10396. Accessed January 27, 2010.
- Scope A, Lieb JA, Dusza SW, et al. A prospective randomized trial of topical pimecrolimus for cetuximab-associated acnelike eruption. J Am Acad Dermatol. 2009;[Epub ahead of print].
- Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical implications. J Am Acad Dermatol. 2006;54:258-265.
- Morse L, Calarese P. EGFR-targeted therapy and related skin toxicity. Semin Oncol Nurs. 2006;22:152-162.
- Viale PH. Management of EGFRI associated toxicities: rash, pruritus, xerosis. Oncol Nurse. 2008;1:10-11.
Key Definitions
blepharitis—inflammation of the eyelid
comedones—bumpy skin, commonly known as blackheads
HER1/EGFR therapy—human epidermal growth factor receptor or HER family include HER1/EGFR. Agents that target HER1/EGFR are 2 types: tyrosine-kinase inhibitors (TKIs) and monoclonal antibodies (MAb). When activated, EGFR leads to cell proliferation, inhibits cells death, enhances angiogenesis, and triggers metastasis. Rash is the common side effect of HER1/EGFR inhibitors
interfollicular—between follicles
microcomedones—follicular casts
|