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Asia-Pacific Journal of Clinical Oncology 2014; 10(Suppl. 1): 11–17
doi: 10.1111/ajco.12160
ORIGINAL ARTICLE
Anticipating and managing the cutaneous side effects of epidermal growth factor receptor inhibitors Rod SINCLAIR Epworth Hospital and the University of Melbourne, Melbourne, Victoria, Australia
Abstract Aims: Epidermal growth factor receptor inhibitor (EGFRi) therapy for tumor suppression produces significant cutaneous toxicity that may necessitate dose reduction or treatment cessation. This manuscript aims to describe the skin toxicity associated with these agents and equip oncologists with the tools to best manage these patients. Methods: A literature review of skin toxicity associated with EGFRi was conducted by a clinical dermatologist experienced in the management of these patients and a management strategy developed for EGFRi skin toxicity Results: The sequence of development of EGFRi cutaneous toxicity is predictable. Many skin side effects can be ameliorated by prophylactic therapy. Management of established skin toxicity is complex and needs to be continued throughout the period of EGFRi drug treatment. Conclusion: Early referral to a dermatologist experienced in the management of these patients is recommended. Key words: cetuximab, drug-induced rash, EGF receptor inhibitor, guideline, MASCC.
BACKGROUND Epidermal growth factor receptor (EGFR) stimulation activates the tyrosine kinase pathway, an important mechanism in communicating signals within a cell (signal transduction) and in regulating cellular activity, such as cell division. Protein kinase mutations may cause unregulated growth of the cell, which is a necessary step for the development of cancer. Chemotherapies that specifically target EGFR expression or the protein kinase pathway are becoming established treatments for certain epithelial cancers. Kinase inhibitors, small molecules and monoclonal antibodies that inhibit EGFR include:
Correspondence: Professor/Director of Dermatology Rod Sinclair MD FACD, Epworth Hospital and the University of Melbourne, Melbourne, 89 Bridge Road, Richmond, Melbourne, Vic. 3121, Australia. Email: [email protected] Conflict of interest: The author has spoken at educational meetings and received honoraria from Merck Serono. Accepted for publication 22 October 2013.
© 2014 Wiley Publishing Asia Pty Ltd
• cetuximab (a chimeric or recombinant monoclonal antibody) • gefitinib • erlotinib • panitumumab • lapatinib Some agents such as cetuximab have complex mechanisms of action that include inhibition of EGFR signaling, down-regulation of EGFR expression (internalization into the cell), as well as direct inhibition of tumor growth through antibody-dependent cellular cytotoxicity.
DRUG – INDUCED SKIN TOXICITY The most common toxicity associated with EGFR inhibitors (EGFRi) and kinase inhibitors is skin rash. Activation of EGFR plays a role in the innate immune response in the human skin, and inhibition reduces skin integrity. Skin toxicity has four distinct cutaneous manifestations. In order of appearance, these are: • folliculitis • xerosis, generalized pruritus and distal fissuring
12
• paronychia • hair changes. There is a direct correlation between severity of rash with EGFR-targeted agents and response to therapy and patient survival across tumor types.1–3 Fortunately, treatment of the rash does not influence response to treatment or patient survival, and the availability of other, more reliable indicators of therapeutic response to EGFRi therapy removes an impediment to the treatment of the skin.3
FOLLICULITIS Acne-like papules and pustules that are centered on hair follicles occur on the face, scalp and upper trunk, usually within the first month of therapy. The absence of open comedos (blackheads) distinguishes this condition from teenage acne. In contrast to teenage acne where individual lesions appear at varying intervals and are in different phases of development, the individual lesions in EGFRi folliculitis are monomorphic, indicating a common start date. This is also seen with other druginduced acne-like reactions. EGFRi folliculitis is probably the most debilitating cutaneous manifestation of EGFRi therapy and commonly necessitates dose reduction or cessation of treatment. Folliculitis occurs to some degree in 85% of patients, of whom 10–20% develop this condition severely (grades 3–4 toxicity). Folliculitis has been reported with all EGFR blockers and is most common with panitumumab. The usual onset is 7–10 days after starting treatment; it begins on
R Sinclair
the central face before involving the upper torso. The folliculitis becomes increasingly severe and refractory to conventional treatments. It may respond initially to treatment and then relapse when treatment is reduced or suspended. Relapses are notoriously more difficult to manage and the treatments should not be prematurely discontinued. In the absence of side effects, it is reasonable to maintain the folliculitis treatments for the duration of EGFRi chemotherapy. Different morphologies of the lesions are shown in Figure 1, while toxicity grading is displayed in Figure 2.4 Subjectively, some patients with grade 3 toxicity have minimal distress while others with grade 1 or 2 folliculitis may be very distressed. In clinical practice, folliculitis frequently leads to EGFRi dose modifications. A survey of 110 oncology practices revealed that 60% of patients required dose reduction and 75% dose interruption as a result of rash alone. Drug discontinuations were reported by up to 32% of oncologists, even though a significant proportion of patients (73%) only had grades 1 and 2 toxicity.6 EGFRi therapy is relatively new and the underlying mechanism of EGFRi skin toxicity is poorly understood. Dermatologists may not be familiar with these agents or their unique skin toxicities. Skin biopsy reveals suppurative folliculitis, and neutrophils and the occasional eosinophil, keratin plugging in follicular ostia, and necrosis of sweat glands may be seen in severe cases; however, histology is unlikely to alter management and is rarely performed. Traditional acne treatments such as oral antibiotics (doxycycline, minocycline, erythromycin), topical
Figure 1 Various morphologies in papulopustular folliculitis lesions. Left, macular erythema of the scalp; center, papules or blind bumps; right, more pustular-type lesions, with evidence of pustules becoming confluent. From Scope et al. with permission.7
© 2014 Wiley Publishing Asia Pty Ltd
Asia-Pac J Clin Oncol 2014; 10(Suppl. 1): 11–17
13
EGFRi cutaneous side effects
(a)
(b)
(c)
(d)
Figure 2 Acneiform eruption. (a) Papular lesions on the chest (grade 1); (b) V-shaped papulopustular eruption on the back (grade 2); (c) closeup of follicular pustules (grade 3); and (d) confluent pustules on the nose (grade 4).5 From Segaert et al.4 with permission.
retinoids and isotretinoin are commonly helpful with EGFRi folliculitis. Retinoid use requires care so as not to aggravate the dryness of the skin. Low-potency corticosteroid, such as 1% hydrocortisone, may alleviate the itch that sometimes accompanies folliculitis; however, stronger steroids should be avoided as they may aggravate the acneform eruption. In view of the high incidence of skin eruptions, significant morbidity and the frequent need for dose reduction or drug holidays which interfere with oncological treatment, prophylactic dermatological therapy has been investigated. As all of the proposed dermatological treatments are relatively safe and well tolerated, and as established folliculitis may become refractory to treatment, this prophylaxitic treatment is increasing.
Asia-Pac J Clin Oncol 2014; 10(Suppl. 1): 11–17
A randomized double-blind trial by Scope et al.7 of prophylactic minocycline found that 100 mg/day decreased the severity of cetuximab-associated acneiform rash, with a greater than 50% reduction in lesion counts compared with placebo in the first 2–4 weeks of an 8-week trial. In contrast, prophylactic treatment with topical retinoid tazaratene was no better than placebo. This is not surprising as topical retinoids are most useful in comedonal acne and the comedones are not a feature of EGFRi-induced folliculitis. The oral retinoid isotretinoin is the most effective agent for papulo-pustular acne and is also effective in EGFRi folliculitis. In Australia, oral retinoids for acne must be prescribed by a dermatologist. Early referral to a dermatologist will facilitate prophylactic isotretinoin treatment.
© 2014 Wiley Publishing Asia Pty Ltd
14
R Sinclair
XEROSIS, PRURITIS AND DIGITAL FISSURES Dry skin or xerosis usually begins between the first and second months of therapy. By 3 months, 50% of patients are affected, and by 6 months 100% of those who receive EGFR-targeted therapy will have some degree of xerosis.8–10 This may manifest as dry skin, asteotitic dermatitis or in severe cases, with skin splitting or fissuring. Xerosis can be managed with moisturizers, soap avoidance and other general measures to reduce exposure to skin irritants that can damage skin barrier function and add to the EGFRi-induced skin dryness. Hygroscopic moisturizers such as urea cream are particularly useful, as is colloidal oatmeal. Petrolatum-based moisturizers are also widely used and may be preferred by some patients. Xerosis is commonly complicated by pruritus. This is usually generalized and presents day and night and interrupts sleep. It is exacerbated by warmth. There is often no primary rash; however, there may be numerous linear excoriations on the skin secondary to scratching. Calamine lotion can alleviate the symptoms of itch but often exacerbates the xerosis. Oily calamine or 1% menthol in aqueous cream is preferable. Systemic agents for pruritus, such as antihistamines, γ-aminobutyric acid agonists, such as gabapentin and pregabalin, and doxepin, which is an antidepressant, may be useful in some cases. Phototherapy with narrowband UVB spectrum light may be required and this is facilitated by referral to a dermatologist. Distal fissures of the skin fingertips is usually painful and can be a significant impediment to manual activities,
Figure 3
such as typing, gardening or even doing up buttons. A number of agents can be used to alleviate fissuring, including 20% urea cream, liquid DuoDerm or flexible collodion. The risk of fissuring of the toes and heels is reduced by wearing socks.
PARONYCHIA Paronychia or painful swelling of the nail folds may occur on the fingers and toes. It usually does not occur until after 6 months of therapy as a late manifestation of EGFRi skin toxicity.5,7,11 This paronychia is indistinguishable from the druginduced paronychia seen with Roaccutane (isotretinoin). It affects toenails and fingernails (Fig. 3) and may resemble an ingrown toenail, except that it affects multiple nails simultaneously, and onycholysis (detachment of the nail from the nail bed) and subungual pustules, which may also occur in EGFRi nail toxicity, are not seen in ingrowing nails. Pain and discomfort frequently necessitate dose modification. Prophylactic measures include daily application of mild corticosteroid cream to the nail folds and antiseptic soaks. Saline (1 tsp of salt in a glass of water) or bleach (1 tbsp of White King in a liter of water) soaks are well tolerated and practical. Instructions from a podiatrist on nail care, nail trimming and hangnails are also recommended. In the skin toxicity evaluation protocol with panitumumab (STEPP) study,11 prophylactic oral antibiotic therapy, together with moisturizers, sunscreen and topical corticosteroids, was shown to decrease the incidence of grade 3 paronychia. According to the Multinational Association of Supportive Care in Cancer
Paronychia of the toenails and fingernails.
© 2014 Wiley Publishing Asia Pty Ltd
Asia-Pac J Clin Oncol 2014; 10(Suppl. 1): 11–17
15
EGFRi cutaneous side effects
Table 1
Paronychia management recommendations12
Preventive Topical
Recommended
Not recommended
Dilute beach baths Avoid irritants Daily moisturizer and topical corticosteroid Recommended
Not recommended
Topical
Corticosteroids Calcineurin inhibitors
Antifungals Antibiotics
Systemic
Tetracyclines Antimicrobials: reserved for culture-proven infection Biotin for brittle nails
Empiric antibiotics, employed without culturing lesional skin Antifungals
Treatment
Other
†
Silver nitrate chemical cauterization weekly Electrodessication
Level of evidence
Recommendation grades
†
II
A
Recommended final concentration of ∼0.005%‡
Level of evidence II†
Recommendation grades A
Comments
IV‡/II†
D/A
III†
B
IV†
D
Comments
Recommended usage of ultrapotent topical steroids as first-line therapy given cost and availability of these agents
Reserved for pyogenic granulomata; consensus of experts
EGFR inhibitor study. ‡Non-EGFR inhibitor cancer treatment study. EGFR, epidermal growth factor receptor.
(MASCC) guidelines (Table 112), the recommendation for prevention of paronychia is to avoid irritants and use diluted bleach baths. For patients with established paronychia, highpotency topical corticosteroids are recommended. If infection is suspected, swabs should be performed. Oral antimicrobials should only be administered when the culture confirms an infection. Exuberant granulation tissue at the lateral nail folds can be treated with silver nitrate chemical cautery, potent topical corticosteroid cream applied daily or nail avulsion under local anesthesia. Dose interruptions are not recommended for paronychia, as the slow growth of the nail suggests that interruption would need to be prolonged for the paronychia to improve. Interventions aimed at minimizing infection or inflammation are the preferred approach.
HAIR MANIFESTATIONS EGFRi treatment often produces alterations in hair growth. These hair side effects usually begin after 2–3 months of treatment, vary in severity and remain unpredictable. Changes include: trichomegaly or long curly
Asia-Pac J Clin Oncol 2014; 10(Suppl. 1): 11–17
eyelashes; increased facial hair; and scalp hair that is dry, brittle and becomes fine and curly, as well as the development of frontal alopecia.
LIMITATIONS OF CURRENT MANAGEMENT RECOMMENDATIONS Current management recommendations produced by MASCC are outlined in Table 2.12 For the prevention of acneiform rash, the recommendations include topical treatment with hydrocortisone 1% cream, moisturizer and sunscreen twice daily, as well as systemic therapy with minocycline 100 mg/day or doxycycline 100 mg twice daily. Doxycycline is preferred in patients with renal impairment, and minocycline is preferred in areas that have a high UV index because it is less photosensitizing than doxycycline. As there is no evidence of phototoxicity associated with the use of EGFRi, sunscreen is likely to be superfluous, as is hydrocortisone in the absence of itch. Minocycline doses of 50 mg daily are likely to be sufficient, as is doxycycline 50 mg daily. Higher doses of doxycycline are phototoxic.
© 2014 Wiley Publishing Asia Pty Ltd
16
Table 2
R Sinclair
Acneiform rash management recommendations12
Preventive Topical
Recommended
Not recommended
Level of evidence
Recommendation grades
†
II
C
II†
A
Hydrocortisone 1% cream with moisturizer, sunscreen twice daily Minocycline 100 mg/day Doxycycline 100 mg BID
Pimecrolimus 1% cream Tazarotene 0.05% cream Sunscreen as single agent Tetracycline 500 mg BID
Treatment
Recommended
Not recommended
Topical
Alclometasone 0.05% cream Fluocinonide 0.05% cream BID Clindamycin 1% Doxycycline 100 mg BID Minocycline 100 mg/day Isotretinoin at low doses (20–30 mg/day)
Level of evidence IV†
Recommendation grades C
Acitretin
IV†
C
Systemic
Systemic
†
Comments
Doxycycline is preferred in patients with renal impairment; minocycline is less photosensitizing Comments
Photosensitizing agents
EGFR inhibitor study. EGFR, epidermal growth factor receptor.
GUIDE TO EGFRi SKIN CARE EGFRi-induced skin rashes are common, often severe and difficult to treat. Many dermatologists have little or no experience in the direct management of EGFRi skin rash, but are expert in the principals of treatment of all skin diseases and will over time further optimize the treatment of this patient group. Oncologists should refer their patients early to promote good skin care and to allow specific prophylactic measures to be commenced before the onset of rash. Aggressive dermatological care is relatively benign when compared with standard oncological treatments. As many of these conditions recur with dose reduction or cessation, maintenance treatment is usually required for the duration of the EGFRi treatment course.
PRINCIPALS OF DERMATOLOGICAL CARE • Go early. • Go hard. • Go long.
© 2014 Wiley Publishing Asia Pty Ltd
REFERENCES 1 Vincenzi B, Santini D, Rabitti C et al. Cetuximab and irinotecan as third-line therapy in advanced colorectal cancer patients: a single centre phase II trial. Br J Cancer 2006; 94: 792–7. 2 Saltz LB, Meropi NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004; 22: 1201–8. 3 Hecht JR, Patniak A, Berlin J et al. Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer 2007; 110: 980–8. 4 Segaert S, Chiritescu G, Lemmens L, Dumon K, Van Cutsem E, Tejpar S. Skin toxicities in targeted therapies. Eur J Cancer 2009; 45 (Suppl 1): 295–308. 5 Van Cutsem E. Challenges in the use of epidermal growth factor receptor inhibitors in colorectal cancer. Oncologist 2006; 11: 1010–17. 6 Boone SL, Rademaker A, Liu D, Pfeiffer C, Mauro DJ, Lacouture ME. Impact and management of skin toxicity associated with anti-epidermal growth factor receptor therapy: survey results. Oncology 2007; 72: 152–9. 7 Scope A, Agero AL, Dusza SW et al. Randomized doubleblind trial of prophylactic oral minocycline and topical
Asia-Pac J Clin Oncol 2014; 10(Suppl. 1): 11–17
EGFRi cutaneous side effects
tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol 2007; 25: 5390–6. 8 Lacouture ME, Lai SE. The PRIDE (Papulopustules and/or paronychia, Regulatory abnormalities of hair growth, Itching, and Dryness due to Epidermal growth factor receptor inhibitors) syndrome. Br J Dermatol 2006; 155: 852–4. 9 Mitchell EP, Perez-Soler R, Van Cutsem E, Lacouture ME. Clinical presentation and pathophysiology of EGFRI dermatologic toxicities. Oncology (Williston Park) 2007; 21 (11 Suppl 5): 4–9. 10 Osio A, Mateus C, Soria JC et al. Cutaneous side-effects in patients on long-term treatment with epidermal growth
Asia-Pac J Clin Oncol 2014; 10(Suppl. 1): 11–17
17
factor receptor inhibitors. Br J Dermatol 2009; 161: 515– 21. 11 Lacouture ME, Mitchell EP, Piperdi B et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol 2010; 28: 1351–7. 12 Lacouture ME, Anadkat MJ, Bensadoun RJ et al. Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer 2011; 19: 1079–95.
© 2014 Wiley Publishing Asia Pty Ltd
Asia-Pacific Journal of Clinical Oncology 2014; 10(Suppl. 1): 11–17
doi: 10.1111/ajco.12160
ORIGINAL ARTICLE
Anticipating and managing the cutaneous side effects of epidermal growth factor receptor inhibitors Rod SINCLAIR Epworth Hospital and the University of Melbourne, Melbourne, Victoria, Australia
Abstract Aims: Epidermal growth factor receptor inhibitor (EGFRi) therapy for tumor suppression produces significant cutaneous toxicity that may necessitate dose reduction or treatment cessation. This manuscript aims to describe the skin toxicity associated with these agents and equip oncologists with the tools to best manage these patients. Methods: A literature review of skin toxicity associated with EGFRi was conducted by a clinical dermatologist experienced in the management of these patients and a management strategy developed for EGFRi skin toxicity Results: The sequence of development of EGFRi cutaneous toxicity is predictable. Many skin side effects can be ameliorated by prophylactic therapy. Management of established skin toxicity is complex and needs to be continued throughout the period of EGFRi drug treatment. Conclusion: Early referral to a dermatologist experienced in the management of these patients is recommended. Key words: cetuximab, drug-induced rash, EGF receptor inhibitor, guideline, MASCC.
BACKGROUND Epidermal growth factor receptor (EGFR) stimulation activates the tyrosine kinase pathway, an important mechanism in communicating signals within a cell (signal transduction) and in regulating cellular activity, such as cell division. Protein kinase mutations may cause unregulated growth of the cell, which is a necessary step for the development of cancer. Chemotherapies that specifically target EGFR expression or the protein kinase pathway are becoming established treatments for certain epithelial cancers. Kinase inhibitors, small molecules and monoclonal antibodies that inhibit EGFR include:
Correspondence: Professor/Director of Dermatology Rod Sinclair MD FACD, Epworth Hospital and the University of Melbourne, Melbourne, 89 Bridge Road, Richmond, Melbourne, Vic. 3121, Australia. Email: [email protected] Conflict of interest: The author has spoken at educational meetings and received honoraria from Merck Serono. Accepted for publication 22 October 2013.
© 2014 Wiley Publishing Asia Pty Ltd
• cetuximab (a chimeric or recombinant monoclonal antibody) • gefitinib • erlotinib • panitumumab • lapatinib Some agents such as cetuximab have complex mechanisms of action that include inhibition of EGFR signaling, down-regulation of EGFR expression (internalization into the cell), as well as direct inhibition of tumor growth through antibody-dependent cellular cytotoxicity.
DRUG – INDUCED SKIN TOXICITY The most common toxicity associated with EGFR inhibitors (EGFRi) and kinase inhibitors is skin rash. Activation of EGFR plays a role in the innate immune response in the human skin, and inhibition reduces skin integrity. Skin toxicity has four distinct cutaneous manifestations. In order of appearance, these are: • folliculitis • xerosis, generalized pruritus and distal fissuring
12
• paronychia • hair changes. There is a direct correlation between severity of rash with EGFR-targeted agents and response to therapy and patient survival across tumor types.1–3 Fortunately, treatment of the rash does not influence response to treatment or patient survival, and the availability of other, more reliable indicators of therapeutic response to EGFRi therapy removes an impediment to the treatment of the skin.3
FOLLICULITIS Acne-like papules and pustules that are centered on hair follicles occur on the face, scalp and upper trunk, usually within the first month of therapy. The absence of open comedos (blackheads) distinguishes this condition from teenage acne. In contrast to teenage acne where individual lesions appear at varying intervals and are in different phases of development, the individual lesions in EGFRi folliculitis are monomorphic, indicating a common start date. This is also seen with other druginduced acne-like reactions. EGFRi folliculitis is probably the most debilitating cutaneous manifestation of EGFRi therapy and commonly necessitates dose reduction or cessation of treatment. Folliculitis occurs to some degree in 85% of patients, of whom 10–20% develop this condition severely (grades 3–4 toxicity). Folliculitis has been reported with all EGFR blockers and is most common with panitumumab. The usual onset is 7–10 days after starting treatment; it begins on
R Sinclair
the central face before involving the upper torso. The folliculitis becomes increasingly severe and refractory to conventional treatments. It may respond initially to treatment and then relapse when treatment is reduced or suspended. Relapses are notoriously more difficult to manage and the treatments should not be prematurely discontinued. In the absence of side effects, it is reasonable to maintain the folliculitis treatments for the duration of EGFRi chemotherapy. Different morphologies of the lesions are shown in Figure 1, while toxicity grading is displayed in Figure 2.4 Subjectively, some patients with grade 3 toxicity have minimal distress while others with grade 1 or 2 folliculitis may be very distressed. In clinical practice, folliculitis frequently leads to EGFRi dose modifications. A survey of 110 oncology practices revealed that 60% of patients required dose reduction and 75% dose interruption as a result of rash alone. Drug discontinuations were reported by up to 32% of oncologists, even though a significant proportion of patients (73%) only had grades 1 and 2 toxicity.6 EGFRi therapy is relatively new and the underlying mechanism of EGFRi skin toxicity is poorly understood. Dermatologists may not be familiar with these agents or their unique skin toxicities. Skin biopsy reveals suppurative folliculitis, and neutrophils and the occasional eosinophil, keratin plugging in follicular ostia, and necrosis of sweat glands may be seen in severe cases; however, histology is unlikely to alter management and is rarely performed. Traditional acne treatments such as oral antibiotics (doxycycline, minocycline, erythromycin), topical
Figure 1 Various morphologies in papulopustular folliculitis lesions. Left, macular erythema of the scalp; center, papules or blind bumps; right, more pustular-type lesions, with evidence of pustules becoming confluent. From Scope et al. with permission.7
© 2014 Wiley Publishing Asia Pty Ltd
Asia-Pac J Clin Oncol 2014; 10(Suppl. 1): 11–17
13
EGFRi cutaneous side effects
(a)
(b)
(c)
(d)
Figure 2 Acneiform eruption. (a) Papular lesions on the chest (grade 1); (b) V-shaped papulopustular eruption on the back (grade 2); (c) closeup of follicular pustules (grade 3); and (d) confluent pustules on the nose (grade 4).5 From Segaert et al.4 with permission.
retinoids and isotretinoin are commonly helpful with EGFRi folliculitis. Retinoid use requires care so as not to aggravate the dryness of the skin. Low-potency corticosteroid, such as 1% hydrocortisone, may alleviate the itch that sometimes accompanies folliculitis; however, stronger steroids should be avoided as they may aggravate the acneform eruption. In view of the high incidence of skin eruptions, significant morbidity and the frequent need for dose reduction or drug holidays which interfere with oncological treatment, prophylactic dermatological therapy has been investigated. As all of the proposed dermatological treatments are relatively safe and well tolerated, and as established folliculitis may become refractory to treatment, this prophylaxitic treatment is increasing.
Asia-Pac J Clin Oncol 2014; 10(Suppl. 1): 11–17
A randomized double-blind trial by Scope et al.7 of prophylactic minocycline found that 100 mg/day decreased the severity of cetuximab-associated acneiform rash, with a greater than 50% reduction in lesion counts compared with placebo in the first 2–4 weeks of an 8-week trial. In contrast, prophylactic treatment with topical retinoid tazaratene was no better than placebo. This is not surprising as topical retinoids are most useful in comedonal acne and the comedones are not a feature of EGFRi-induced folliculitis. The oral retinoid isotretinoin is the most effective agent for papulo-pustular acne and is also effective in EGFRi folliculitis. In Australia, oral retinoids for acne must be prescribed by a dermatologist. Early referral to a dermatologist will facilitate prophylactic isotretinoin treatment.
© 2014 Wiley Publishing Asia Pty Ltd
14
R Sinclair
XEROSIS, PRURITIS AND DIGITAL FISSURES Dry skin or xerosis usually begins between the first and second months of therapy. By 3 months, 50% of patients are affected, and by 6 months 100% of those who receive EGFR-targeted therapy will have some degree of xerosis.8–10 This may manifest as dry skin, asteotitic dermatitis or in severe cases, with skin splitting or fissuring. Xerosis can be managed with moisturizers, soap avoidance and other general measures to reduce exposure to skin irritants that can damage skin barrier function and add to the EGFRi-induced skin dryness. Hygroscopic moisturizers such as urea cream are particularly useful, as is colloidal oatmeal. Petrolatum-based moisturizers are also widely used and may be preferred by some patients. Xerosis is commonly complicated by pruritus. This is usually generalized and presents day and night and interrupts sleep. It is exacerbated by warmth. There is often no primary rash; however, there may be numerous linear excoriations on the skin secondary to scratching. Calamine lotion can alleviate the symptoms of itch but often exacerbates the xerosis. Oily calamine or 1% menthol in aqueous cream is preferable. Systemic agents for pruritus, such as antihistamines, γ-aminobutyric acid agonists, such as gabapentin and pregabalin, and doxepin, which is an antidepressant, may be useful in some cases. Phototherapy with narrowband UVB spectrum light may be required and this is facilitated by referral to a dermatologist. Distal fissures of the skin fingertips is usually painful and can be a significant impediment to manual activities,
Figure 3
such as typing, gardening or even doing up buttons. A number of agents can be used to alleviate fissuring, including 20% urea cream, liquid DuoDerm or flexible collodion. The risk of fissuring of the toes and heels is reduced by wearing socks.
PARONYCHIA Paronychia or painful swelling of the nail folds may occur on the fingers and toes. It usually does not occur until after 6 months of therapy as a late manifestation of EGFRi skin toxicity.5,7,11 This paronychia is indistinguishable from the druginduced paronychia seen with Roaccutane (isotretinoin). It affects toenails and fingernails (Fig. 3) and may resemble an ingrown toenail, except that it affects multiple nails simultaneously, and onycholysis (detachment of the nail from the nail bed) and subungual pustules, which may also occur in EGFRi nail toxicity, are not seen in ingrowing nails. Pain and discomfort frequently necessitate dose modification. Prophylactic measures include daily application of mild corticosteroid cream to the nail folds and antiseptic soaks. Saline (1 tsp of salt in a glass of water) or bleach (1 tbsp of White King in a liter of water) soaks are well tolerated and practical. Instructions from a podiatrist on nail care, nail trimming and hangnails are also recommended. In the skin toxicity evaluation protocol with panitumumab (STEPP) study,11 prophylactic oral antibiotic therapy, together with moisturizers, sunscreen and topical corticosteroids, was shown to decrease the incidence of grade 3 paronychia. According to the Multinational Association of Supportive Care in Cancer
Paronychia of the toenails and fingernails.
© 2014 Wiley Publishing Asia Pty Ltd
Asia-Pac J Clin Oncol 2014; 10(Suppl. 1): 11–17
15
EGFRi cutaneous side effects
Table 1
Paronychia management recommendations12
Preventive Topical
Recommended
Not recommended
Dilute beach baths Avoid irritants Daily moisturizer and topical corticosteroid Recommended
Not recommended
Topical
Corticosteroids Calcineurin inhibitors
Antifungals Antibiotics
Systemic
Tetracyclines Antimicrobials: reserved for culture-proven infection Biotin for brittle nails
Empiric antibiotics, employed without culturing lesional skin Antifungals
Treatment
Other
†
Silver nitrate chemical cauterization weekly Electrodessication
Level of evidence
Recommendation grades
†
II
A
Recommended final concentration of ∼0.005%‡
Level of evidence II†
Recommendation grades A
Comments
IV‡/II†
D/A
III†
B
IV†
D
Comments
Recommended usage of ultrapotent topical steroids as first-line therapy given cost and availability of these agents
Reserved for pyogenic granulomata; consensus of experts
EGFR inhibitor study. ‡Non-EGFR inhibitor cancer treatment study. EGFR, epidermal growth factor receptor.
(MASCC) guidelines (Table 112), the recommendation for prevention of paronychia is to avoid irritants and use diluted bleach baths. For patients with established paronychia, highpotency topical corticosteroids are recommended. If infection is suspected, swabs should be performed. Oral antimicrobials should only be administered when the culture confirms an infection. Exuberant granulation tissue at the lateral nail folds can be treated with silver nitrate chemical cautery, potent topical corticosteroid cream applied daily or nail avulsion under local anesthesia. Dose interruptions are not recommended for paronychia, as the slow growth of the nail suggests that interruption would need to be prolonged for the paronychia to improve. Interventions aimed at minimizing infection or inflammation are the preferred approach.
HAIR MANIFESTATIONS EGFRi treatment often produces alterations in hair growth. These hair side effects usually begin after 2–3 months of treatment, vary in severity and remain unpredictable. Changes include: trichomegaly or long curly
Asia-Pac J Clin Oncol 2014; 10(Suppl. 1): 11–17
eyelashes; increased facial hair; and scalp hair that is dry, brittle and becomes fine and curly, as well as the development of frontal alopecia.
LIMITATIONS OF CURRENT MANAGEMENT RECOMMENDATIONS Current management recommendations produced by MASCC are outlined in Table 2.12 For the prevention of acneiform rash, the recommendations include topical treatment with hydrocortisone 1% cream, moisturizer and sunscreen twice daily, as well as systemic therapy with minocycline 100 mg/day or doxycycline 100 mg twice daily. Doxycycline is preferred in patients with renal impairment, and minocycline is preferred in areas that have a high UV index because it is less photosensitizing than doxycycline. As there is no evidence of phototoxicity associated with the use of EGFRi, sunscreen is likely to be superfluous, as is hydrocortisone in the absence of itch. Minocycline doses of 50 mg daily are likely to be sufficient, as is doxycycline 50 mg daily. Higher doses of doxycycline are phototoxic.
© 2014 Wiley Publishing Asia Pty Ltd
16
Table 2
R Sinclair
Acneiform rash management recommendations12
Preventive Topical
Recommended
Not recommended
Level of evidence
Recommendation grades
†
II
C
II†
A
Hydrocortisone 1% cream with moisturizer, sunscreen twice daily Minocycline 100 mg/day Doxycycline 100 mg BID
Pimecrolimus 1% cream Tazarotene 0.05% cream Sunscreen as single agent Tetracycline 500 mg BID
Treatment
Recommended
Not recommended
Topical
Alclometasone 0.05% cream Fluocinonide 0.05% cream BID Clindamycin 1% Doxycycline 100 mg BID Minocycline 100 mg/day Isotretinoin at low doses (20–30 mg/day)
Level of evidence IV†
Recommendation grades C
Acitretin
IV†
C
Systemic
Systemic
†
Comments
Doxycycline is preferred in patients with renal impairment; minocycline is less photosensitizing Comments
Photosensitizing agents
EGFR inhibitor study. EGFR, epidermal growth factor receptor.
GUIDE TO EGFRi SKIN CARE EGFRi-induced skin rashes are common, often severe and difficult to treat. Many dermatologists have little or no experience in the direct management of EGFRi skin rash, but are expert in the principals of treatment of all skin diseases and will over time further optimize the treatment of this patient group. Oncologists should refer their patients early to promote good skin care and to allow specific prophylactic measures to be commenced before the onset of rash. Aggressive dermatological care is relatively benign when compared with standard oncological treatments. As many of these conditions recur with dose reduction or cessation, maintenance treatment is usually required for the duration of the EGFRi treatment course.
PRINCIPALS OF DERMATOLOGICAL CARE • Go early. • Go hard. • Go long.
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REFERENCES 1 Vincenzi B, Santini D, Rabitti C et al. Cetuximab and irinotecan as third-line therapy in advanced colorectal cancer patients: a single centre phase II trial. Br J Cancer 2006; 94: 792–7. 2 Saltz LB, Meropi NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004; 22: 1201–8. 3 Hecht JR, Patniak A, Berlin J et al. Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer 2007; 110: 980–8. 4 Segaert S, Chiritescu G, Lemmens L, Dumon K, Van Cutsem E, Tejpar S. Skin toxicities in targeted therapies. Eur J Cancer 2009; 45 (Suppl 1): 295–308. 5 Van Cutsem E. Challenges in the use of epidermal growth factor receptor inhibitors in colorectal cancer. Oncologist 2006; 11: 1010–17. 6 Boone SL, Rademaker A, Liu D, Pfeiffer C, Mauro DJ, Lacouture ME. Impact and management of skin toxicity associated with anti-epidermal growth factor receptor therapy: survey results. Oncology 2007; 72: 152–9. 7 Scope A, Agero AL, Dusza SW et al. Randomized doubleblind trial of prophylactic oral minocycline and topical
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EGFRi cutaneous side effects
tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol 2007; 25: 5390–6. 8 Lacouture ME, Lai SE. The PRIDE (Papulopustules and/or paronychia, Regulatory abnormalities of hair growth, Itching, and Dryness due to Epidermal growth factor receptor inhibitors) syndrome. Br J Dermatol 2006; 155: 852–4. 9 Mitchell EP, Perez-Soler R, Van Cutsem E, Lacouture ME. Clinical presentation and pathophysiology of EGFRI dermatologic toxicities. Oncology (Williston Park) 2007; 21 (11 Suppl 5): 4–9. 10 Osio A, Mateus C, Soria JC et al. Cutaneous side-effects in patients on long-term treatment with epidermal growth
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factor receptor inhibitors. Br J Dermatol 2009; 161: 515– 21. 11 Lacouture ME, Mitchell EP, Piperdi B et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol 2010; 28: 1351–7. 12 Lacouture ME, Anadkat MJ, Bensadoun RJ et al. Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer 2011; 19: 1079–95.
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