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Non-Rash Skin Toxicities Associated with Novel Targeted Therapies
Non-Rash Skin Toxicities Associated with Novel Targeted Therapies Mario E. Lacouture,1 Scott A. Boerner,2 Patricia M. LoRusso2 Abstract Many novel targeted agents have emerged against a variety of malignancies. Although papulopustular rash is the most commonly observed side effect associated with many of these agents, several non-rash skin toxicities have been identified that frequently result in the delay or discontinuation of anticancer therapy. These toxicities include skin hyperpigmentation, xerosis, pruritus, hair growth and color abnormalities, periungual and nail alterations, and hand-foot skin reaction. It is important to recognize these toxicities, so that they can be diagnosed early and treatment or dose modification can be initiated, if necessary. This review discusses several non-rash dermatologic toxicities observed with targeted therapeutic agents and guidelines for their diagnosis and treatment. Clinical Lung Cancer, Vol. 8, Suppl. 1, S36-S42, 2006
Key words: Cutaneous toxicity, Dermatologic toxicity, Kinase inhibitors, Novel agents
Introduction
tologic toxicities in > 30% of treated patients.5 In addition, agents designed to inhibit targets further downstream in the signal transduction pathway, such as MEKK inhibitors ARRY142886 (AZD6244) and PD 0325901, have also reported skin toxicities as a frequent and often significant occurrence.6,7 A papulopustular reaction can affect nearly all patients treated with EGFR-targeted agents (eg, occurring in 75%-95% of patients treated with erlotinib, cetuximab, and panitumumab) and are the most visible of the adverse events associated with them.8-10 This subject is reviewed elsewhere.11 Although typically not life threatening, dermatologic toxicities, especially rashes, are frequently the primary cause of erlotinib discontinuation by patients early on in treatment. Although not as prevalent as rashes, other dermatologic toxicities of these targeted agents can actually be more debilitating. Other than the papulopustular reaction, patients treated with these agents report multiple degrees of hyperpigmentation, xerosis, pruritus, hair growth and color abnormalities, periungual and nail alterations, and hand-foot skin reactions. The etiology of these dermatologic manifestations appears to be multifactorial in nature and, because of the lack of consistent evaluation, not completely understood at this point. We present here a review of the non-rash dermatologic events observed with the use of some of the novel targeted therapies currently under development.
A fast growing area of cancer therapy involves novel treatments that target specific pathways critical to the growth and development of tumors. There are several major classes of targeted therapies, including tyrosine kinase (TK) receptor inhibitors, angiogenesis inhibitors, and proteasome inhibitors. Several types of agents lead to dermatologic toxicities as a consequence of their use, and skin toxicity is the primary side effect associated with many targeted agents, especially those that target the epidermal growth factor receptor (EGFR) signal transduction pathway (Table 1). The EGFR is upregulated in several malignancies, and it is also important for normal skin development and function.1-3 Epidermal growth factor receptor inhibitors, including monoclonal antibodies such as cetuximab and panitumumab and small molecule TK inhibitors (TKIs) such as gefitinib and erlotinib, induce varying degrees of skin toxicities.4 The multitargeted TKIs sunitinib and sorafenib, which act as tumor and angiogenesis inhibitors, cause derma1Department
of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 2Department of Internal Medicine, Barbara Ann Karmanos Cancer Institute/Wayne State University, Detroit, MI Submitted: Nov 29, 2006; Revised: Dec 13, 2006; Accepted: Dec 13, 2006 Address for correspondence: Patricia M. LoRusso, DO, Department of Internal Medicine, Barbara Ann Karmanos Cancer Institute/Wayne State University, Hudson-Webber Cancer Research Center, 4100 John R, Detroit, MI 48201 Fax: 313-576-9719; e-mail: [email protected]
Hyperpigmentation Hyperpigmentation, in which patches of skin become darker in color than the normal surrounding skin, has been reported with the use of imatinib and EGFR inhibitors.12,13 Inhibi-
Dr. Lacouture has served as a paid consultant for or been on the Advisory Board of Agmen and ImClone and is also a member of the Speaker's Bureau for ImClone. Dr. Boerner has no relevant relationships to disclose. Dr. LoRusso has received research support from the Exelexis, Ziopharm, Pfizer, Bristol-Myers Squibb, and Amgen. She has also served as a paid consultant for or been on the Advisory Board of Genentech BioOncology and AstraZeneca and is a member of the Speaker’s Bureau for sanofi-aventis, AstraZeneca, Novartis, Pfizer, and Abraxis.
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Table 1
Examples of Novel Targeted Agents and Their Corresponding Non-Rash Skin Toxicities
Agent Erlotinib Cetuximab Gefitinib Panitumumab
Specificity
Figure 1 Hyperpigmentation
Dermatologic Side Effects
Reversible EGFR/HER1 EGFR/HER1/Erb1 Reversible EGFR/HER1
Pruritus, xerosis, hair and nail changes (paronychia, trichomegaly, dark facial hair growth, scalp alopecia)
EGFR/HER1
Sorafenib
VEGFR-1, -2, -3; PDGFR, c-Kit, RET, Raf
Facial erythema, pruritus, xerosis, hair and nail changes (alopecia, subungual splinter hemorrhages), HFSR, desquamation
Sunitinib
VEGFR-1, 2 PDGFRs, c-Kit, FLT3
Hair depigmentation, periorbital edema, subungual splinter hemorrhages, HFSR
Imatinib
PDGFR, c-Kit
Hair repigmentation, periorbital edema, pruritus, blistering
Abbreviations: FLT3 = FMS-like TK 3; RET = neurotrophic factor receptor
tor-induced hyperpigmentation is postinflammatory in nature and is typically observed after a papulopustular eruption (Figure 1) or also other causes of skin inflammation such as eczema or an inflamed sebaceous cyst.12,14 The condition appears to gradually progress as kinase inhibitor treatment continues. The mechanism by which hyperpigmentation is induced is unknown, but it has been proposed that inhibitor-induced functional alterations or postinflammatory process in melanocytes results in increased pigment transfer to basal keratinocytes or dermal macrophages.12 No treatment is currently known, but sun exposure has been reported to aggravate the condition, and wearing broad spectrum sunscreen is strongly advised.14
Telangiectasias Dilated superficial blood vessels resulting in red areas on the skin (telangiectasias) have been reported in patients treated with EGFR inhibitors, predominantly as a late manifestation of papulopustular reaction.11,14 Scattered patches of telangiectasia can appear on the face, on and behind the ears, on the chest, back, and limbs, usually in the vicinity of a follicular pustule.14 The development of telangiectasia could be related to the loss of structural support because of connective tissue destruction or endothelial cell sprouts that extend toward the larger numbers of necrotic keratinocytes that are present in follicular pustules.11,15 No treatment for telangiectasia has been proven consistently effective. However, pulsed-dye lasers, cosmetic makeup, and self-tanning lotion can be used to cover up telangiectasias and might provide some relief to patients who are self-conscious about their appearance. The condition typically fades over time, sometimes leaving hyperpigmentation.14
Xerosis and Pruritus Xerosis (dry skin) is very common in patients given TKIs, including those that target the EGFR.14,16-20 It typically manifests with dry, scaly, itchy skin especially of the limbs and of skin areas that were affected by papulopustular rash.21
Photo shows hyperpigmented macules, a consequence of inflammation, in this case to a papulopustular reaction to the EGFR inhibitor erlotinib. Pustules are also observed in this photo.
It occurs in approximately 7%-35% of patients treated, with pruritus (itching sensation) also occurring in approximately 8%-35% of patients.11 Clinically, it is similar to the xerosis observed with retinoid use.22 Dry skin tends to appear after 2-3 months of therapy initiation and is persistent, often lasting for several months. Xerosis presents in the fingertips, toes, and heels and commonly results in pulpitis with painful fissures (Figure 2).23,24 Secondary infection with Staphylococcus aureus can occur, along with acute oozing dermatitis and yellow crusting.14 Xerosis can be accentuated by the age of the patient, previous therapy with cytotoxic agents, and history of atopic eczema, and can develop into chronic asteatotic eczema.21 The role of EGFR in maintaining the epidermal permeability barrier is consistent with the association of xerosis with EGFR inhibitor treatment.25 Xerosis has been reproduced in EGFR knockout mice.3 Dry skin has been attributed to abnormal keratinocyte differentiation, leading to a disturbed stratum corneum and interference of sebaceous gland function, which results in the epidermis losing the capability to retain water.26 Flaking can result from abnormal shedding and the accumulation of nucleated corneocytes in areas of visible parakeratosis.11 The appearance of xerosis is typically delayed, when compared with the earlier presentation of papulopustules in patients who have been treated with EGFR inhibitors. This delay might be caused by the 2 weeks that postmitotic epidermal cells require to reach the stratum corneum.11,27 Thin, tightly adherent skin develops, analogous to that observed in patients afflicted with the rare disease restrictive dermopathy, in which EGFR and transforming growth factor–_ are absent in the skin.28 Pruritus occurs as a consequence of loss of moisture in the skin and is a predominant symptom in other conditions that are characterized by an abnormal permeability barrier, such as atopic dermatitis.11 Treatment of xerosis includes frequent application of emollients that contain ammonium lactate or 5%-10% urea, which
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Non-Rash Skin Toxicities Associated with Novel Targeted Therapies Figure 2 Xerosis and Hyperkeratosis in the Heel of a Patient Receiving the EGFR Inhibitor Erlotinib23,24
substantially improve skin dryness.29 General hydrating measures are very important in treatment. Alcoholic lotions or gels should be discontinued when dryness appears. Patients should be encouraged to switch to moisturizing creams that contain oils (ie, creams or ointments) and should be cautioned to avoid use of occlusive topical agents because they have been associated with increased folliculitis. If xerosis is combined with dermatitis, a short-term course (1-2 weeks) of topical steroids is recommended. Oral antihistamines should be used to control severe pruritus.30 Fissures can be treated with propylene glycol (50%) under plastic occlusion, salicylic acid 10% ointment, colloid dressing, flurandrenolide tape, and liquid cyanoacrylate glue.
Hair Growth and Color Abnormalities During prolonged treatment with EGFR inhibitors, hair changes have been observed. Epidermal growth factor receptor is normally expressed in the epidermis, the sweat gland apparatus, and hair follicle epithelium.23,31,32 Expression is highest in the basal layer of the epidermis and in the outer root sheath of hair follicles, where the keratinocytes are proliferating and undifferentiated.31 There is an inverse correlation between EGFR expression and keratinocyte differentiation, and there is evidence that the stratification and maturation of keratinocytes is repressed by EGFR.33 Animal models have established that EGFR signaling plays a key role in the normal differentiation and development of hair follicles and skin.31 Epidermal growth factor has pleiotropic effects on keratinocytes, and administration of epidermal growth factor to newborn mice delays hair follicle development, decreases the rate of growth, and reduces the hair diameter.34 Mice harboring a targeted disruption of the EGFR allele exhibit a disorganized hair follicle phenotype,
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Figure 3 Hypertrichosis of the Eyelashes Occurring After 3 Months of Erlotinib Therapy30
with long, curly whiskers and alopecia at other sites.23,35 Thus, EGFR seems to play a central role in numerous aspects of keratinocyte biology, and it is important for autocrine regulation of the growth of the epidermis, cell cycle progression, cell differentiation, cell movement, and cellular survival.36 Histopathologic aspects of skin biopsy results obtained from patients before and after administration with the EGFR inhibitor gefitinib have been compared.31 Changes were noted in the stratum corneum, which appeared markedly thinner and more compact after treatment, and in hair follicles, where prominent keratin plugs and microorganisms were found in dilated infundibula. These changes might be the consequence of altered terminal keratinocyte differentiation (maturation) in suprabasal keratinocytes as a result of EGFR blockade.31,37 It has been suggested that upregulation of the cyclin-dependent kinase inhibitor p27Kip1, a negative growth regulator, might be the mechanism by which gefitinib can affect follicular and epidermal homeostasis.31 Similar upregulation of p27Kip1 has been reported with the use of cetuximab.23 Modifications to the hair observed in patients treated with EGFR inhibitors include an inflammatory, non-scarring alopecia on the scalp, distorted hair growth, and trichomegaly of the eyebrows and eyelashes and hypertrichosis in the face. Hair on the scalp often grows more slowly and adopts a finer, more brittle and curly aspect after prolonged treatment, and mild, non-scarring (reversible) hair loss can be seen on the scalp, arms, or legs.11,14,21 Fewer shavings of the beard might be noted in men, whereas hypertrichosis with small vellus hairs might develop on a woman’s face and lip.14 This observed frontal alopecia and growth of facial hair are androgen-like in appearance and suggest that modification of androgen signaling might occur after treatment with EGFR inhibitors.29 No efficient treatment is currently available for alopecia, although if there is evidence of inflammation (ie, tenderness, erythema, papulopustules), antiinflammatory topical or oral agents (ie, corticosteroids or oral tetracycline antibiotics) might be of benefit. Undesirable facial hair can be treated with wax depilation or laser, which offers good cosmetic results for several months.
Mario E. Lacouture et al Figure 4 Paronychia to the Anti-EGFR Monoclonal Antibody Cetuximab17,49,50
Figure 5 Splinter Hemorrhages in a Patient Receiving Sunitinib for Renal Cell Carcinoma
Trichomegaly of the eyelashes is defined by increased length, thickness, stiffness, curling, and pigmentation of existing hair shafts (Figure 3).30 Trichomegaly has been found in association with congenital, paraneoplastic, or advanced HIV disease or dermatomyositis, and to be induced by medications (eg, interferon-_2b).38-41 Several cases of EGFR inhibitor–induced trichomegaly have been reported.30,37,42,43 Often, the trichomegaly results in visual discomfort to the patient, which is alleviated by cutting the eyelashes. Therefore, recommended treatment for trichomegaly involves regular trimming.29 If an eyelash grows on the inferior edge of the eyelid (trichiasis), it can result in corneal abrasion or scarring and will require removal through electrolysis or other methods. Importantly, abnormalities in tear film formation and meibomian gland inflammation can coexist, requiring an ophthalmologic consultation.8 In addition to modifications of hair growth, changes to hair coloration have also been observed with the use of targeted inhibitors. Sunitinib, a low molecular weight receptor TKI, has been found to have direct antitumor and antiangiogenic activity via targeting of the vascular endothelial growth factor (VEGF), platelet-derived growth factor, c-Kit, FMS-like TK 3, colony-stimulating factor–1R, and the neurotrophic factor receptor.44 Patients in phase I studies of sunitinib exhibited bands of depigmentation and pigmentation in their scalp hair that corresponded, respectively, to periods of treatment and dosing rest periods.45 Pigment of the hair shaft is formed by the follicular melanocytes. Stem cell factor (SCF) and its TK receptor c-Kit are critically important for the maintenance of hair follicle melanocytes.46 The period of active hair growth of the hair follicle (anagen) is the most significant for hair pigmentation, and during early anagen, SCF/c-Kit signaling is vitally important for melanocyte proliferation/differentiation and proper pigment production. Regeneration of the hair pigmentation unit requires c-Kit, and without SCF/c-Kit signaling during anagen, melanocytes are absent or unable to pass melanin to the growing ke-
ratinocytes, resulting in a follicle partially or completely devoid of color. The changes in hair pigmentation observed with the use of sunitinib raise the possibility that hair color can serve as a dose-dependent, dynamic, biologic readout for c-Kit inhibition, and perhaps, as a surrogate marker of drug activity.45
Periungual and Nail Alterations There have been several reports of EGFR inhibitor–induced periungual inflammation (also known as paronychia).14,23,29,47,48 Paronychia affects the area around the fingernail or toenail and occurs in 12%-16% of patients, typically after 4-8 weeks of treatment with EGFR inhibitors (Figure 4).17,49,50 It is another typical side effect of EGFR inhibitors that has been observed with any of the inhibitors currently in use.23,51 It is characterized by crusted lesions, with inflammation of the nail fold usually appearing as the first sign and eventually progressing into painful lateral nail-fold pyogenic granuloma-like lesions.14,23,29 The nails tend to grow slower, become brittle, and sometimes crack.24 Paronychia can affect any fingernail or toenail, and the reason why some fingers are affected when others are not is unknown.29 The condition might be severe enough to impair the ability to perform simple manual work or prevent the patient from wearing any shoes other than sandals. The pathogenesis of paronychia in patients treated with EGRF inhibitors is unknown. Histologic examination shows granulation tissue with prominent capillaries and a diffuse inflammatory infiltrate that consists of plasma cells, lymphocytes, and some neutrophils within an edematous stroma.12,52 Although occasional cultures have been positive for Staphylococcus aureus, there has been no report of infection with Candida albicans.29,52 Paronychia is clinically similar to the lesions that can arise with the use of antiretroviral drugs and retinoids.53 As with retinoids, skin fragility with retention and penetration of nail-plate fragments or desquamation into the periungual tissues might lead to a foreign-body reaction. Further findings include a brittle, slower-growing nail plate that might result from EGFR inhibition in the nail matrix.
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Non-Rash Skin Toxicities Associated with Novel Targeted Therapies Figure 6 Hand-Foot Skin Reaction to the Multitargeted Antitumor and Antiangiogenic Agent Sorafenib29
Figure 7 Cyst-Like Lesion Observed in a Patient Receiving Sorafenib; Histology Showed Abundant Neutrophils
Paronychia can resolve spontaneously and always disappears within a few days of discontinuation of EGFR-inhibitor treatment.29 Topical corticosteroids and oral synthetic tetracyclines, such as minocycline and doxycycline, have shown success in the management of paronychia, in addition to destructive measures such as electrodesiccation or partial nail-plate excision.4,47 Advanced lesions that appear with excessive granulation tissue in the nail sulci should be treated with silver nitrate, antiseptic soaks, and cushioning.29 Patients should be encouraged to refrain from putting pressure on their nails, biting them, and cutting them too short, as well as wearing shoes that fit too tightly during treatment. Alterations in the hair and nails that develop in patients treated with EGFR inhibitors are reported less frequently than the papulopustular rash.11 Whether this is because of fewer incidences of these cases or underreporting remains to be determined.
Hand-foot skin reaction typically develops after 2-4 weeks of treatment with these agents, and the condition seems to be dose dependent and disappears after treatment discontinuation, although tachyphylaxis is seen in some patients in whom full doses can be restored after dose reduction.16,29 Histology shows a decreased or absent granular layer, with some areas of parakeratosis in the stratum corneum.29 Epidermal cells are edematous in the stratum spinosum. Many mitoses are seen in the basal layers and also above the basal and suprabasal layers, suggesting altered differentiation. Apoptotic keratinocytes are also observed, and deep bullous lesions are present. A nonspecific dermal inflammatory infiltrate is usually evident. The pathogenesis of HFSR is not well understood, but the dose dependence in most cases suggests a direct toxic effect of the agent. Sunitinib and sorafenib inhibit VEGFR and FMS-like TK 3, but neither of these receptors is known to be expressed on keratinocytes.29,55 Hand-foot syndrome (HFS) is a condition marked by pain, swelling, numbness, tingling, or redness of the hands or feet. It is often reported as a complication of various traditional chemotherapies, including 5-fluorouracil,56 capecitabine,57 liposomal doxorubicin,58 and docetaxel.59 Although HFSR can sometimes clinically resemble HFS, most patients with the reaction induced by kinase inhibitors seem to have more localized and hyperkeratotic lesions that are distinct from classic HFS.29 Histologic examination of HFSR shows epidermal changes that suggest maturation modifications unlike those seen with HFS, in which cell death seems to play a major role.29,55 Hand-foot syndrome had not been previously described with biologic agents or small molecule TKIs until 3 cases were recently reported in patients treated with the EGFR inhibitor gefitinib.55 However, each of these patients had been previously treated with liposomal doxorubicin, and it was proposed that the observed HFS could be a “recall reaction” as a result of previous exposure to liposomal doxorubicin. Recall dermatitis of the HFS type was described in patients who received several chemotherapeutic agents after originally developing HFS be-
Subungual Splinter Hemorrhages Subungual splinter hemorrhages (Figure 5) are small areas of bleeding under the fingernails or, less commonly, the toenails.29 They take the shape of straight lines of red or reddish-black color that are similar to wood splinters in appearance. They appear in the epidermis of the nail bed and consist of a small area of blood that adheres to the undersurface of the nail plate.54 They vary in their pattern of appearance, color, location (distal or proximal), frequency, and might or might not be associated with pain.29 Subungual splinter hemorrhages have been observed in patients treated with the kinase inhibitors sunitinib and sorafenib, which target the VEGF receptor (VEGFR) and the platelet-derived growth factor receptor, both of which have been implicated in angiogenesis. It has been proposed that subungual splinter hemorrhages occur as a result of elective VEGFR blocking and might reflect the antiangiogenic effects of therapy with these agents.54 There is no particular care for splinter hemorrhages.
Hand-Foot Skin Reaction There have been reports of hand-foot skin reaction (HFSR) with the kinase inhibitors sunitinib and sorafenib (Figure 6).29
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Mario E. Lacouture et al cause of troxacitabine and liposomal doxorubicin.60 Physicians treating patients with targeted agents who have previously undergone chemotherapeutic therapy known to cause HFS should be aware of the possibility of such a recall reaction. For HFSR and HFS, patient education in the early phases of treatment is vital for minimizing discomfort and preventing complications. Patients should be instructed to avoid wearing tightfitting clothes and shoes as well as to avoid excessive sun exposure, hot baths and showers, and excessive rubbing of the soles of the feet and palms of the hands.61 Sandals or shock absorbers in shoes can be worn to relieve painful pressure points.29 Control of symptomatic pain can occur through the use of cold compresses or ice packs and frequent application of highly occlusive emollients.61 For thick, hyperkeratotic areas, keratolytics such as 40% urea or salicylic acid are beneficial in decreasing lesion thickness.
Abscesses and Neutrophil-Rich Lesions The multitargeted TKIs (sunitnib, sorafenib) have been associated with the development of tender, well-defined, subcutaneous nodules. The exact incidence is unknown, but they are probably infrequent. These lesions are reminiscent of abscesses, and they occur most commonly in the trunk, groin, and buttocks. Histologic examination reveals an abundant neutrophilic infiltrate with no microorganisms, suggesting a noninfectious origin (Figure 7).
Conclusion It has become increasingly clear that many novel targeted agents present themselves with unique toxicities relative to standard cytotoxic agents. Included among these toxicities, especially for agents targeting the signal transduction pathways, are dermatologic toxicities that can manifest as more than a rash. It is important to be aware of these untoward events, so that they can be diagnosed early and treatment or dose modification can be initiated, if necessary. It is also essential to educate the patient so that the patient knows when it is important to communicate toxicity development with the physician. Initiation of therapy to treat these toxicities early might delay treatment interruption or discontinuation, thus allowing for potentially greater success of the anticancer therapy.
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Hansen LA, Alexander N, Hogan ME, et al. Genetically null mice reveal a central role for epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development. Am J Pathol 1997; 150:1959-1975. Jost M, Kari C, Rodeck U. The EGF receptor - an essential regulator of multiple epidermal functions. Eur J Dermatol 2000; 10:505-510. Dueland S, Sauer T, Lund-Johansen F, et al. Epidermal growth factor receptor inhibition induces trichomegaly. Acta Oncol 2003; 42:345-346. Haritoglou C, Rudolph G, Kalpadakis P, et al. Congenital trichomegaly (OliverMcFarlane syndrome): a case report with 9 years’ follow up. Br J Ophthalmol 2003; 87:119-120. Tosti A, Pazzaglia M, Voudouris S, et al. Hypertrichosis of the eyelashes caused by bimatoprost. J Am Acad Dermatol 2004; 51:S149-S150.
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Non-Rash Skin Toxicities Associated with Novel Targeted Therapies 40. Sharma RC, Mahajan VK, Sharma NL, et al. Trichomegaly of the eyelashes in dermatomyositis. Dermatology 2002; 205:305. 41. Farina MC, Tarin N, Grilli R, et al. Acquired hypertrichosis lanuginosa: case report and review of the literature. J Surg Oncol 1998; 68:199-203. 42. Bouche O, Brixi-Benmansour H, Bertin A, et al. Trichomegaly of the eyelashes following treatment with cetuximab. Ann Oncol 2005; 16:1711-1712. 43. Pascual JC, Banuls J, Belinchon I, et al. Trichomegaly following treatment with gefitinib (ZD1839). Br J Dermatol 2004; 151:1111-1112. 44. Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003; 9:327-337. 45. Moss KG, Toner GC, Cherrington JM, et al. Hair depigmentation is a biological readout for pharmacological inhibition of KIT in mice and humans. J Pharmacol Exp Ther 2003; 307:476-480. 46. Botchkareva NV, Khlgatian M, Longley BJ, et al. SCF/c-kit signaling is required for cyclic regeneration of the hair pigmentation unit. Faseb J 2001; 15:645-658. 47. Shu KY, Kindler HL, Medenica M, et al. Doxycycline for the treatment of paronychia induced by the epidermal growth factor receptor inhibitor cetuximab. Br J Dermatol 2006; 154:191-192. 48. Monti M, Mancini LL, Ferrari B, et al. Complications of therapy and a diagnostic dilemma case. Case 2. Cutaneous toxicity induced by cetuximab. J Clin Oncol 2003; 21:4651-4653. 49. Tarceva [package insert]. Melville, NY: OSI Pharmaceuticals; 2005. 50. Erbitux [package insert]. New York, NY: ImClone Systems; 2006.
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51. Boucher KW, Davidson K, Mirakhur B, et al. Paronychia induced by cetuximab, an antiepidermal growth factor receptor antibody. J Am Acad Dermatol 2002; 47:632-633. 52. Dainichi T, Tanaka M, Tsuruta N, et al. Development of multiple paronychia and periungual granulation in patients treated with gefitinib, an inhibitor of epidermal growth factor receptor. Dermatology 2003; 207:324-325. 53. Baran R. Etretinate and the nails (study of 130 cases) possible mechanisms of some side-effects. Clin Exp Dermatol 1986; 11:148-152. 54. Robert C, Faivre S, Raymond E, et al. Subungual splinter hemorrhages: a clinical window to inhibition of vascular endothelial growth factor receptors? Ann Intern Med 2005; 143:313-314. 55. Razis E, Karina M, Karanastassi S, et al. Three case reports of hand-foot syndrome with gefitinib. Cancer Invest 2006; 24:514-516. 56. Comandone A, Bretti S, La Grotta G, et al. Palmar-plantar erythrodysestasia syndrome associated with 5-fluorouracil treatment. Anticancer Res 1993; 13:1781-1783. 57. Gressett SM, Stanford BL, Hardwicke F. Management of hand-foot syndrome induced by capecitabine. J Oncol Pharm Pract 2006; 12:131-141. 58. Ellerhorst JA, Bedikian A, Ring S, et al. Phase II trial of doxil for patients with metastatic melanoma refractory to frontline therapy. Oncol Rep 1999; 6:1097-1099. 59. Zimmerman GC, Keeling JH, Burris HA, et al. Acute cutaneous reactions to docetaxel, a new chemotherapeutic agent. Arch Dermatol 1995; 131:202-206. 60. Hui YF, Giles FJ, Cortes JE. Chemotherapy-induced palmar-plantar erythrodysesthesia syndrome--recall following different chemotherapy agents. Invest New Drugs 2002; 20:49-53. 61. Wilkes GM, Doyle D. Palmar-plantar erythrodysesthesia. Clin J Oncol Nurs 2005; 9:103-106.
Key words: Cutaneous toxicity, Dermatologic toxicity, Kinase inhibitors, Novel agents
Introduction
tologic toxicities in > 30% of treated patients.5 In addition, agents designed to inhibit targets further downstream in the signal transduction pathway, such as MEKK inhibitors ARRY142886 (AZD6244) and PD 0325901, have also reported skin toxicities as a frequent and often significant occurrence.6,7 A papulopustular reaction can affect nearly all patients treated with EGFR-targeted agents (eg, occurring in 75%-95% of patients treated with erlotinib, cetuximab, and panitumumab) and are the most visible of the adverse events associated with them.8-10 This subject is reviewed elsewhere.11 Although typically not life threatening, dermatologic toxicities, especially rashes, are frequently the primary cause of erlotinib discontinuation by patients early on in treatment. Although not as prevalent as rashes, other dermatologic toxicities of these targeted agents can actually be more debilitating. Other than the papulopustular reaction, patients treated with these agents report multiple degrees of hyperpigmentation, xerosis, pruritus, hair growth and color abnormalities, periungual and nail alterations, and hand-foot skin reactions. The etiology of these dermatologic manifestations appears to be multifactorial in nature and, because of the lack of consistent evaluation, not completely understood at this point. We present here a review of the non-rash dermatologic events observed with the use of some of the novel targeted therapies currently under development.
A fast growing area of cancer therapy involves novel treatments that target specific pathways critical to the growth and development of tumors. There are several major classes of targeted therapies, including tyrosine kinase (TK) receptor inhibitors, angiogenesis inhibitors, and proteasome inhibitors. Several types of agents lead to dermatologic toxicities as a consequence of their use, and skin toxicity is the primary side effect associated with many targeted agents, especially those that target the epidermal growth factor receptor (EGFR) signal transduction pathway (Table 1). The EGFR is upregulated in several malignancies, and it is also important for normal skin development and function.1-3 Epidermal growth factor receptor inhibitors, including monoclonal antibodies such as cetuximab and panitumumab and small molecule TK inhibitors (TKIs) such as gefitinib and erlotinib, induce varying degrees of skin toxicities.4 The multitargeted TKIs sunitinib and sorafenib, which act as tumor and angiogenesis inhibitors, cause derma1Department
of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 2Department of Internal Medicine, Barbara Ann Karmanos Cancer Institute/Wayne State University, Detroit, MI Submitted: Nov 29, 2006; Revised: Dec 13, 2006; Accepted: Dec 13, 2006 Address for correspondence: Patricia M. LoRusso, DO, Department of Internal Medicine, Barbara Ann Karmanos Cancer Institute/Wayne State University, Hudson-Webber Cancer Research Center, 4100 John R, Detroit, MI 48201 Fax: 313-576-9719; e-mail: [email protected]
Hyperpigmentation Hyperpigmentation, in which patches of skin become darker in color than the normal surrounding skin, has been reported with the use of imatinib and EGFR inhibitors.12,13 Inhibi-
Dr. Lacouture has served as a paid consultant for or been on the Advisory Board of Agmen and ImClone and is also a member of the Speaker's Bureau for ImClone. Dr. Boerner has no relevant relationships to disclose. Dr. LoRusso has received research support from the Exelexis, Ziopharm, Pfizer, Bristol-Myers Squibb, and Amgen. She has also served as a paid consultant for or been on the Advisory Board of Genentech BioOncology and AstraZeneca and is a member of the Speaker’s Bureau for sanofi-aventis, AstraZeneca, Novartis, Pfizer, and Abraxis.
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Table 1
Examples of Novel Targeted Agents and Their Corresponding Non-Rash Skin Toxicities
Agent Erlotinib Cetuximab Gefitinib Panitumumab
Specificity
Figure 1 Hyperpigmentation
Dermatologic Side Effects
Reversible EGFR/HER1 EGFR/HER1/Erb1 Reversible EGFR/HER1
Pruritus, xerosis, hair and nail changes (paronychia, trichomegaly, dark facial hair growth, scalp alopecia)
EGFR/HER1
Sorafenib
VEGFR-1, -2, -3; PDGFR, c-Kit, RET, Raf
Facial erythema, pruritus, xerosis, hair and nail changes (alopecia, subungual splinter hemorrhages), HFSR, desquamation
Sunitinib
VEGFR-1, 2 PDGFRs, c-Kit, FLT3
Hair depigmentation, periorbital edema, subungual splinter hemorrhages, HFSR
Imatinib
PDGFR, c-Kit
Hair repigmentation, periorbital edema, pruritus, blistering
Abbreviations: FLT3 = FMS-like TK 3; RET = neurotrophic factor receptor
tor-induced hyperpigmentation is postinflammatory in nature and is typically observed after a papulopustular eruption (Figure 1) or also other causes of skin inflammation such as eczema or an inflamed sebaceous cyst.12,14 The condition appears to gradually progress as kinase inhibitor treatment continues. The mechanism by which hyperpigmentation is induced is unknown, but it has been proposed that inhibitor-induced functional alterations or postinflammatory process in melanocytes results in increased pigment transfer to basal keratinocytes or dermal macrophages.12 No treatment is currently known, but sun exposure has been reported to aggravate the condition, and wearing broad spectrum sunscreen is strongly advised.14
Telangiectasias Dilated superficial blood vessels resulting in red areas on the skin (telangiectasias) have been reported in patients treated with EGFR inhibitors, predominantly as a late manifestation of papulopustular reaction.11,14 Scattered patches of telangiectasia can appear on the face, on and behind the ears, on the chest, back, and limbs, usually in the vicinity of a follicular pustule.14 The development of telangiectasia could be related to the loss of structural support because of connective tissue destruction or endothelial cell sprouts that extend toward the larger numbers of necrotic keratinocytes that are present in follicular pustules.11,15 No treatment for telangiectasia has been proven consistently effective. However, pulsed-dye lasers, cosmetic makeup, and self-tanning lotion can be used to cover up telangiectasias and might provide some relief to patients who are self-conscious about their appearance. The condition typically fades over time, sometimes leaving hyperpigmentation.14
Xerosis and Pruritus Xerosis (dry skin) is very common in patients given TKIs, including those that target the EGFR.14,16-20 It typically manifests with dry, scaly, itchy skin especially of the limbs and of skin areas that were affected by papulopustular rash.21
Photo shows hyperpigmented macules, a consequence of inflammation, in this case to a papulopustular reaction to the EGFR inhibitor erlotinib. Pustules are also observed in this photo.
It occurs in approximately 7%-35% of patients treated, with pruritus (itching sensation) also occurring in approximately 8%-35% of patients.11 Clinically, it is similar to the xerosis observed with retinoid use.22 Dry skin tends to appear after 2-3 months of therapy initiation and is persistent, often lasting for several months. Xerosis presents in the fingertips, toes, and heels and commonly results in pulpitis with painful fissures (Figure 2).23,24 Secondary infection with Staphylococcus aureus can occur, along with acute oozing dermatitis and yellow crusting.14 Xerosis can be accentuated by the age of the patient, previous therapy with cytotoxic agents, and history of atopic eczema, and can develop into chronic asteatotic eczema.21 The role of EGFR in maintaining the epidermal permeability barrier is consistent with the association of xerosis with EGFR inhibitor treatment.25 Xerosis has been reproduced in EGFR knockout mice.3 Dry skin has been attributed to abnormal keratinocyte differentiation, leading to a disturbed stratum corneum and interference of sebaceous gland function, which results in the epidermis losing the capability to retain water.26 Flaking can result from abnormal shedding and the accumulation of nucleated corneocytes in areas of visible parakeratosis.11 The appearance of xerosis is typically delayed, when compared with the earlier presentation of papulopustules in patients who have been treated with EGFR inhibitors. This delay might be caused by the 2 weeks that postmitotic epidermal cells require to reach the stratum corneum.11,27 Thin, tightly adherent skin develops, analogous to that observed in patients afflicted with the rare disease restrictive dermopathy, in which EGFR and transforming growth factor–_ are absent in the skin.28 Pruritus occurs as a consequence of loss of moisture in the skin and is a predominant symptom in other conditions that are characterized by an abnormal permeability barrier, such as atopic dermatitis.11 Treatment of xerosis includes frequent application of emollients that contain ammonium lactate or 5%-10% urea, which
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Non-Rash Skin Toxicities Associated with Novel Targeted Therapies Figure 2 Xerosis and Hyperkeratosis in the Heel of a Patient Receiving the EGFR Inhibitor Erlotinib23,24
substantially improve skin dryness.29 General hydrating measures are very important in treatment. Alcoholic lotions or gels should be discontinued when dryness appears. Patients should be encouraged to switch to moisturizing creams that contain oils (ie, creams or ointments) and should be cautioned to avoid use of occlusive topical agents because they have been associated with increased folliculitis. If xerosis is combined with dermatitis, a short-term course (1-2 weeks) of topical steroids is recommended. Oral antihistamines should be used to control severe pruritus.30 Fissures can be treated with propylene glycol (50%) under plastic occlusion, salicylic acid 10% ointment, colloid dressing, flurandrenolide tape, and liquid cyanoacrylate glue.
Hair Growth and Color Abnormalities During prolonged treatment with EGFR inhibitors, hair changes have been observed. Epidermal growth factor receptor is normally expressed in the epidermis, the sweat gland apparatus, and hair follicle epithelium.23,31,32 Expression is highest in the basal layer of the epidermis and in the outer root sheath of hair follicles, where the keratinocytes are proliferating and undifferentiated.31 There is an inverse correlation between EGFR expression and keratinocyte differentiation, and there is evidence that the stratification and maturation of keratinocytes is repressed by EGFR.33 Animal models have established that EGFR signaling plays a key role in the normal differentiation and development of hair follicles and skin.31 Epidermal growth factor has pleiotropic effects on keratinocytes, and administration of epidermal growth factor to newborn mice delays hair follicle development, decreases the rate of growth, and reduces the hair diameter.34 Mice harboring a targeted disruption of the EGFR allele exhibit a disorganized hair follicle phenotype,
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Figure 3 Hypertrichosis of the Eyelashes Occurring After 3 Months of Erlotinib Therapy30
with long, curly whiskers and alopecia at other sites.23,35 Thus, EGFR seems to play a central role in numerous aspects of keratinocyte biology, and it is important for autocrine regulation of the growth of the epidermis, cell cycle progression, cell differentiation, cell movement, and cellular survival.36 Histopathologic aspects of skin biopsy results obtained from patients before and after administration with the EGFR inhibitor gefitinib have been compared.31 Changes were noted in the stratum corneum, which appeared markedly thinner and more compact after treatment, and in hair follicles, where prominent keratin plugs and microorganisms were found in dilated infundibula. These changes might be the consequence of altered terminal keratinocyte differentiation (maturation) in suprabasal keratinocytes as a result of EGFR blockade.31,37 It has been suggested that upregulation of the cyclin-dependent kinase inhibitor p27Kip1, a negative growth regulator, might be the mechanism by which gefitinib can affect follicular and epidermal homeostasis.31 Similar upregulation of p27Kip1 has been reported with the use of cetuximab.23 Modifications to the hair observed in patients treated with EGFR inhibitors include an inflammatory, non-scarring alopecia on the scalp, distorted hair growth, and trichomegaly of the eyebrows and eyelashes and hypertrichosis in the face. Hair on the scalp often grows more slowly and adopts a finer, more brittle and curly aspect after prolonged treatment, and mild, non-scarring (reversible) hair loss can be seen on the scalp, arms, or legs.11,14,21 Fewer shavings of the beard might be noted in men, whereas hypertrichosis with small vellus hairs might develop on a woman’s face and lip.14 This observed frontal alopecia and growth of facial hair are androgen-like in appearance and suggest that modification of androgen signaling might occur after treatment with EGFR inhibitors.29 No efficient treatment is currently available for alopecia, although if there is evidence of inflammation (ie, tenderness, erythema, papulopustules), antiinflammatory topical or oral agents (ie, corticosteroids or oral tetracycline antibiotics) might be of benefit. Undesirable facial hair can be treated with wax depilation or laser, which offers good cosmetic results for several months.
Mario E. Lacouture et al Figure 4 Paronychia to the Anti-EGFR Monoclonal Antibody Cetuximab17,49,50
Figure 5 Splinter Hemorrhages in a Patient Receiving Sunitinib for Renal Cell Carcinoma
Trichomegaly of the eyelashes is defined by increased length, thickness, stiffness, curling, and pigmentation of existing hair shafts (Figure 3).30 Trichomegaly has been found in association with congenital, paraneoplastic, or advanced HIV disease or dermatomyositis, and to be induced by medications (eg, interferon-_2b).38-41 Several cases of EGFR inhibitor–induced trichomegaly have been reported.30,37,42,43 Often, the trichomegaly results in visual discomfort to the patient, which is alleviated by cutting the eyelashes. Therefore, recommended treatment for trichomegaly involves regular trimming.29 If an eyelash grows on the inferior edge of the eyelid (trichiasis), it can result in corneal abrasion or scarring and will require removal through electrolysis or other methods. Importantly, abnormalities in tear film formation and meibomian gland inflammation can coexist, requiring an ophthalmologic consultation.8 In addition to modifications of hair growth, changes to hair coloration have also been observed with the use of targeted inhibitors. Sunitinib, a low molecular weight receptor TKI, has been found to have direct antitumor and antiangiogenic activity via targeting of the vascular endothelial growth factor (VEGF), platelet-derived growth factor, c-Kit, FMS-like TK 3, colony-stimulating factor–1R, and the neurotrophic factor receptor.44 Patients in phase I studies of sunitinib exhibited bands of depigmentation and pigmentation in their scalp hair that corresponded, respectively, to periods of treatment and dosing rest periods.45 Pigment of the hair shaft is formed by the follicular melanocytes. Stem cell factor (SCF) and its TK receptor c-Kit are critically important for the maintenance of hair follicle melanocytes.46 The period of active hair growth of the hair follicle (anagen) is the most significant for hair pigmentation, and during early anagen, SCF/c-Kit signaling is vitally important for melanocyte proliferation/differentiation and proper pigment production. Regeneration of the hair pigmentation unit requires c-Kit, and without SCF/c-Kit signaling during anagen, melanocytes are absent or unable to pass melanin to the growing ke-
ratinocytes, resulting in a follicle partially or completely devoid of color. The changes in hair pigmentation observed with the use of sunitinib raise the possibility that hair color can serve as a dose-dependent, dynamic, biologic readout for c-Kit inhibition, and perhaps, as a surrogate marker of drug activity.45
Periungual and Nail Alterations There have been several reports of EGFR inhibitor–induced periungual inflammation (also known as paronychia).14,23,29,47,48 Paronychia affects the area around the fingernail or toenail and occurs in 12%-16% of patients, typically after 4-8 weeks of treatment with EGFR inhibitors (Figure 4).17,49,50 It is another typical side effect of EGFR inhibitors that has been observed with any of the inhibitors currently in use.23,51 It is characterized by crusted lesions, with inflammation of the nail fold usually appearing as the first sign and eventually progressing into painful lateral nail-fold pyogenic granuloma-like lesions.14,23,29 The nails tend to grow slower, become brittle, and sometimes crack.24 Paronychia can affect any fingernail or toenail, and the reason why some fingers are affected when others are not is unknown.29 The condition might be severe enough to impair the ability to perform simple manual work or prevent the patient from wearing any shoes other than sandals. The pathogenesis of paronychia in patients treated with EGRF inhibitors is unknown. Histologic examination shows granulation tissue with prominent capillaries and a diffuse inflammatory infiltrate that consists of plasma cells, lymphocytes, and some neutrophils within an edematous stroma.12,52 Although occasional cultures have been positive for Staphylococcus aureus, there has been no report of infection with Candida albicans.29,52 Paronychia is clinically similar to the lesions that can arise with the use of antiretroviral drugs and retinoids.53 As with retinoids, skin fragility with retention and penetration of nail-plate fragments or desquamation into the periungual tissues might lead to a foreign-body reaction. Further findings include a brittle, slower-growing nail plate that might result from EGFR inhibition in the nail matrix.
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Non-Rash Skin Toxicities Associated with Novel Targeted Therapies Figure 6 Hand-Foot Skin Reaction to the Multitargeted Antitumor and Antiangiogenic Agent Sorafenib29
Figure 7 Cyst-Like Lesion Observed in a Patient Receiving Sorafenib; Histology Showed Abundant Neutrophils
Paronychia can resolve spontaneously and always disappears within a few days of discontinuation of EGFR-inhibitor treatment.29 Topical corticosteroids and oral synthetic tetracyclines, such as minocycline and doxycycline, have shown success in the management of paronychia, in addition to destructive measures such as electrodesiccation or partial nail-plate excision.4,47 Advanced lesions that appear with excessive granulation tissue in the nail sulci should be treated with silver nitrate, antiseptic soaks, and cushioning.29 Patients should be encouraged to refrain from putting pressure on their nails, biting them, and cutting them too short, as well as wearing shoes that fit too tightly during treatment. Alterations in the hair and nails that develop in patients treated with EGFR inhibitors are reported less frequently than the papulopustular rash.11 Whether this is because of fewer incidences of these cases or underreporting remains to be determined.
Hand-foot skin reaction typically develops after 2-4 weeks of treatment with these agents, and the condition seems to be dose dependent and disappears after treatment discontinuation, although tachyphylaxis is seen in some patients in whom full doses can be restored after dose reduction.16,29 Histology shows a decreased or absent granular layer, with some areas of parakeratosis in the stratum corneum.29 Epidermal cells are edematous in the stratum spinosum. Many mitoses are seen in the basal layers and also above the basal and suprabasal layers, suggesting altered differentiation. Apoptotic keratinocytes are also observed, and deep bullous lesions are present. A nonspecific dermal inflammatory infiltrate is usually evident. The pathogenesis of HFSR is not well understood, but the dose dependence in most cases suggests a direct toxic effect of the agent. Sunitinib and sorafenib inhibit VEGFR and FMS-like TK 3, but neither of these receptors is known to be expressed on keratinocytes.29,55 Hand-foot syndrome (HFS) is a condition marked by pain, swelling, numbness, tingling, or redness of the hands or feet. It is often reported as a complication of various traditional chemotherapies, including 5-fluorouracil,56 capecitabine,57 liposomal doxorubicin,58 and docetaxel.59 Although HFSR can sometimes clinically resemble HFS, most patients with the reaction induced by kinase inhibitors seem to have more localized and hyperkeratotic lesions that are distinct from classic HFS.29 Histologic examination of HFSR shows epidermal changes that suggest maturation modifications unlike those seen with HFS, in which cell death seems to play a major role.29,55 Hand-foot syndrome had not been previously described with biologic agents or small molecule TKIs until 3 cases were recently reported in patients treated with the EGFR inhibitor gefitinib.55 However, each of these patients had been previously treated with liposomal doxorubicin, and it was proposed that the observed HFS could be a “recall reaction” as a result of previous exposure to liposomal doxorubicin. Recall dermatitis of the HFS type was described in patients who received several chemotherapeutic agents after originally developing HFS be-
Subungual Splinter Hemorrhages Subungual splinter hemorrhages (Figure 5) are small areas of bleeding under the fingernails or, less commonly, the toenails.29 They take the shape of straight lines of red or reddish-black color that are similar to wood splinters in appearance. They appear in the epidermis of the nail bed and consist of a small area of blood that adheres to the undersurface of the nail plate.54 They vary in their pattern of appearance, color, location (distal or proximal), frequency, and might or might not be associated with pain.29 Subungual splinter hemorrhages have been observed in patients treated with the kinase inhibitors sunitinib and sorafenib, which target the VEGF receptor (VEGFR) and the platelet-derived growth factor receptor, both of which have been implicated in angiogenesis. It has been proposed that subungual splinter hemorrhages occur as a result of elective VEGFR blocking and might reflect the antiangiogenic effects of therapy with these agents.54 There is no particular care for splinter hemorrhages.
Hand-Foot Skin Reaction There have been reports of hand-foot skin reaction (HFSR) with the kinase inhibitors sunitinib and sorafenib (Figure 6).29
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Mario E. Lacouture et al cause of troxacitabine and liposomal doxorubicin.60 Physicians treating patients with targeted agents who have previously undergone chemotherapeutic therapy known to cause HFS should be aware of the possibility of such a recall reaction. For HFSR and HFS, patient education in the early phases of treatment is vital for minimizing discomfort and preventing complications. Patients should be instructed to avoid wearing tightfitting clothes and shoes as well as to avoid excessive sun exposure, hot baths and showers, and excessive rubbing of the soles of the feet and palms of the hands.61 Sandals or shock absorbers in shoes can be worn to relieve painful pressure points.29 Control of symptomatic pain can occur through the use of cold compresses or ice packs and frequent application of highly occlusive emollients.61 For thick, hyperkeratotic areas, keratolytics such as 40% urea or salicylic acid are beneficial in decreasing lesion thickness.
Abscesses and Neutrophil-Rich Lesions The multitargeted TKIs (sunitnib, sorafenib) have been associated with the development of tender, well-defined, subcutaneous nodules. The exact incidence is unknown, but they are probably infrequent. These lesions are reminiscent of abscesses, and they occur most commonly in the trunk, groin, and buttocks. Histologic examination reveals an abundant neutrophilic infiltrate with no microorganisms, suggesting a noninfectious origin (Figure 7).
Conclusion It has become increasingly clear that many novel targeted agents present themselves with unique toxicities relative to standard cytotoxic agents. Included among these toxicities, especially for agents targeting the signal transduction pathways, are dermatologic toxicities that can manifest as more than a rash. It is important to be aware of these untoward events, so that they can be diagnosed early and treatment or dose modification can be initiated, if necessary. It is also essential to educate the patient so that the patient knows when it is important to communicate toxicity development with the physician. Initiation of therapy to treat these toxicities early might delay treatment interruption or discontinuation, thus allowing for potentially greater success of the anticancer therapy.
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Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 2005; 16:1425-1433. Tavakkol A, Varani J, Elder JT, et al. Maintenance of human skin in organ culture: role for insulin-like growth factor-1 receptor and epidermal growth factor receptor. Arch Dermatol Res 1999; 291:643-651. Ahmad T, Eisen T. Kinase inhibition with BAY 43-9006 in renal cell carcinoma. Clin Cancer Res 2004; 10:6388S-6392S. Lee MW, Seo CW, Kim SW, et al. Cutaneous side effects in non-small cell lung cancer patients treated with Iressa (ZD1839), an inhibitor of epidermal growth factor. Acta Derm Venereol 2004; 84:23-26. Dick S, Crawford GH. Managing cutaneous side effects of epidermal growth factor receptor (HER1/EGFR) inhibitors. Commun Oncol 2005; 2:492-496. Perez-Soler R, Delord JP, Halpern A, et al. 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