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Dermatologic Adverse Events Associated With Systemic Anticancer Agents

Dermatologic Adverse Events Associated With Systemic Anticancer Agents

  • Acneiform Rash Stage 1 (Sensory disturbance)
    Figures 1–4. "Acneiform" Rash, Stages 1–4: Treatment consists of a tetracycline antibiotic (minocycline or doxycycline 100 mg bid) in addition to low-medium potency topical corticosteroid creams (hydrocortisone 2.5% or triamcinolone 0.1%). Figure 1 (above). Stage 1 (Sensory disturbance): Within the first few days of starting an EGFR inhibitor, diffuse erythema with underlying edema may appear in the central area of the face.
  • Acneiform Rash Stage 2 (papules and pustules)
    Figure 2. Stage 2 (papules and pustules): Lesions may be tender or pruritic, and appear during weeks 1 to 3.
  • Acneiform Rash Stage 3 (crust formation)
    Figure 3. Stage 3 (crust formation): Crusting of the papules and pustules is usually indicative of resolution.
  • Acneiform Rash Stage 4 (residual erythema)
    Figure 4. Stage 4 (residual erythema): Post-inflammatory erythema or hyperpigmentation, localized to previously affected areas. This is a common sequela, which may persist for several months.
  • Trichomegaly of the eyelashes
    Figure 5. Trichomegaly of the eyelashes: An increased thickness and waviness of the eyelashes and facial hair may be noted in up to 33% of patients, after 3 to 4 months of EGFR inhibitor therapy. Eyelashes should be regularly trimmed, as their inward growth may lead to corneal complications (eg, erosions, ulcerations). Development of meibomitis (due to plugging of meibomian glands) warrants antibiotics.
  • Skin fissures
    Figure 6. Skin fissures: Fissuring of the fingertips and heels is a manifestation of severe xerosis in response to treatment with EGFR inhibitors. The condition is very painful and may limit activities of daily living. Liquid bandages and topical zinc oxide cream (20% to 30%) qid are recommended. Wearing of cotton gloves after application of creams provides occlusion, and facilitates retention of moisture in the skin.
  • Xerosis
    Figure 7. Xerosis: Dry skin (xerosis) develops in almost all patients on EGFR inhibitor therapy, and usually manifests after the second month of treatment initiation. Depending on the severity, treatment with topical moisturizing creams, ammonium lactate (palms/soles), and topical corticosteroid creams is usually effective.
  • Radiation dermatitis
    Figure 8. Radiation dermatitis: Concurrent treatment with EGFR inhibitors and radiation therapy increases the risk of developing severe, in-field radiation dermatitis. Prophylactic treatment of risk-prone areas with high-potency topical corticosteroid creams (eg, mometasone 0.1%) is beneficial.
  • Hand-foot skin reaction
    Figure 9A. Hand-foot skin reaction: Occurs in 10% to 60% of patients on the multikinase inhibitors (sorafenib, sunitinib, pazopanib, axitinib, regorafenib, and cabozantinib). Usually, it develops within the first 2 weeks of treatment and may be associated with blisters or hyperkeratosis overlying areas of pressure, which may impair activities of daily living in up to 10% of patients. Prophylactic therapy with urea 10% cream tid reduces all grade events by 24%. Treatment with topical corticosteroid creams (eg, clobetasol 0.05%), keratolytics (eg, salicylic acid 6%, urea 40%) that soften the skin, and analgesia with oral nonsteroidal anti-inflammatory drugs (NSAIDs) or opioids may be necessary. Topical lidocaine (Lidoderm patches) is also effective when there are painful localized areas. Friction or trauma to the palms and soles should be minimized with use of thick cotton socks, and cushioned footwear.
  • Hand-foot skin reaction
    Figure 9B. Hand-foot skin reaction: Occurs in 10% to 60% of patients on the multikinase inhibitors (sorafenib, sunitinib, pazopanib, axitinib, regorafenib, and cabozantinib). Usually, it develops within the first 2 weeks of treatment and may be associated with blisters or hyperkeratosis overlying areas of pressure, which may impair activities of daily living in up to 10% of patients. Prophylactic therapy with urea 10% cream tid reduces all grade events by 24%. Treatment with topical corticosteroid creams (eg, clobetasol 0.05%), keratolytics (eg, salicylic acid 6%, urea 40%) that soften the skin, and analgesia with oral nonsteroidal anti-inflammatory drugs (NSAIDs) or opioids may be necessary. Topical lidocaine (Lidoderm patches) is also effective when there are painful localized areas. Friction or trauma to the palms and soles should be minimized with use of thick cotton socks, and cushioned footwear.
  • Periarticular thenar erythema with onycholysis (PATEO) syndrome
    Figure 10. Periarticular thenar erythema with onycholysis (PATEO) syndrome: Paclitaxel and docetaxel-induced erythema on the dorsum of the hands, along with subungual hemorrhages leading to nail separation and infection, may occur in up to 30% of treated patients. This may be accompanied by tenderness or pruritus. Therapy consists of cold gloves during infusion, high-potency topical corticosteroid creams for erythematous areas, antiseptic soaks, and antimicrobials for nail infections.
  • Hand-foot syndrome
    Figure 11. Hand-foot syndrome (HFS): Erythema and edema, with pain and sensation of tightness and cracking in the palms and soles may occur in up to 30% of patients treated with liposomal doxorubicin, fluorouracil (5-FU), and capecitabine. Treatment consists of topical corticosteroid creams (eg, clobetasol 0.05%) bid, and tapering doses of oral corticosteroids (eg, dexamethasone at 8 mg bid for 5 days from day 1, followed by 4 mg bid for 1 day, then 4 mg od for 1 day). Capecitabine (Xeloda)-related HFS can be prevented with oral celecoxib 200mg daily.
  • Temsirolimus and everolimus-induced rash
    Figure 12A. Rash: Temsirolimus and everolimus-induced rash in the trunk and extremities develops in approximately 45% and 25% of patients, respectively. Usually it is mild in severity and responds to topical corticosteroid creams (eg, clobetasol, fluocinonide bid). These drugs have also been associated with peripheral edema and mucositis.
  • Temsirolimus and everolimus-induced rash
    Figure 12B. Rash: Temsirolimus and everolimus-induced rash in the trunk and extremities develops in approximately 45% and 25% of patients, respectively. Usually it is mild in severity and responds to topical corticosteroid creams (eg, clobetasol, fluocinonide bid). These drugs have also been associated with peripheral edema and mucositis.
  • Cutaneous neoplasms
    Figure 13. Cutaneous neoplasms: During treatment with Raf inhibitors (vemurafenib, sorafenib), between 4% to 31% of patients develop cutaneous neoplasms, and in 9%, there can be multiple lesions. Lesions usually appear within 8 to 12 weeks of beginning therapy and favor sun-exposed skin of the head and neck. Most of the lesions are keratoacanthomas (Figure). Patients may also develop benign skin lesions, including milia and verrucae. Treatment consists of local destructive or surgical measures—dose modifications are usually not necessary.
  • Excoriations
    Figure 14. Excoriations: Ipilimumab-induced intense pruritus develops after the first or second cycle, initiating an urge to scratch which results in excoriations. Treatment with oral (eg, prednisone, dexamethasone) or topical corticosteroids, oral antihistamines (eg, diphenhydramine, hydroxyzine, doxepin) will usually control symptoms and permit consistent dosing of ipilimumab. If these measures are not effective, GABA agonists (eg, pregabalin, gabapentin) or aprepitant may be used.
  • Brittle nails during therapy
    Figure 15. Brittle nails during therapy: Splitting and nicking at the distal (free) end of the nail plate can occur during treatment with EGFR/HER2/mTOR inhibitors. The nail thickness is reduced which predisposes them to damage. Nails tend to break off easily and may also separate from the nail bed. Patients are advised to minimize use of nails for daily tasks and protect them from trauma. Biotin 2.5 mg a day, and topical poly-ureaurethane 16% (Nuvail) may improve strength.
  • Photosensitivity reactions
    Figure 16. Photosensitivity reactions: Majority of these reactions are grade 1 with an early onset (about 24 hours), and have been reported in 30% to 52% of patients being treated with vemurafenib, vandetanib, and voriconazole. Generous use of broad spectrum, SPF30 sunscreens, protective clothing, and minimizing outdoor activities between 10 a.m. to 4 p.m. are advised. Treatment with topical corticosteroid creams is useful in symptomatic cases.
  • Aphthous stomatitis
    Figure 17. Aphthous stomatitis: Stomatitis and mucositis has been reported in up to 40% and 20% of patients on mTOR inhibitors (everolimus, temsirolimus), respectively. Treatment consists of dexamethasone oral rinses tid or triamcinolone in orabase tid. Patients should avoid drinking or eating for 30 minutes after using these topical steroids.
  • Paronychia
    Figure 18. Paronychia: Inflammation of the nail folds (fingers, toes) is commonly seen in patients on EGFR inhibitors. Incidence may vary with different agents (eg, panitumumab, 24%; cetuximab/gefitinib, 10% to 15%; lapatinib, < 1%). Paronychia can significantly impact the quality of life in these patients. Management includes topical antibiotics (eg, mupirocin), antiseptics (eg, povidone-iodine), chemical cautery (eg, silver nitrate), and oral antibiotics in case of a secondary infection confirmed by microbial cultures.
  • Keratosis pilaris-like rash
    Figure 19. Keratosis pilaris-like rash: Erythematous folliculocentric keratotic papules (similar to goose bumps), sometimes accompanied by scaling. The incidence varies from 22% to 62% with nilotinib, and 6% to 57% with dasatinib. The rash is usually low-grade, and topical corticosteroids and keratolytics (eg, ammonium lactate, urea, salicylic acid) are advised.
  • Maculopapular rashes
    Figure 20. Maculopapular rashes: Rashes usually appear early (about 2 weeks) during the course of treatment, and are seen in up to 35% of patients on sorafenib and 20% of patients on vemurafenib. Antibiotics and NSAIDs are also common culprits. Treatment consists of topical or oral corticosteroids, gentle skin care, and in intolerable grade 2/3 cases, dose reductions or interruptions may be required.
  • Inflammatory and scarring alopecia
    Figures 21–24. Alopecia (hair loss): Treatment consists of topical minoxidil 5% bid and biotin 2.5 mg qd. Ensuring that TSH, vitamin D, ferritin, and zinc levels are normal is part of the workup for alopecia. Prophylactic use of minoxidil 2% bid may reduce the duration of complete alopecia from chemotherapy by approximately 50 days. Figure 21 (above). Inflammatory and scarring alopecia: Sequela to EGFR inhibitor therapy-induced follicular inflammation/superinfection. Treatment consists of topical corticosteroid foam or solution (clobetasol 0.05%), and oral antibiotics, if infection is suspected or evidenced.
  • Female pattern alopecia
    Figure 22. Female pattern alopecia: Aromatase inhibitors and tamoxifen (Figure) can result in hair loss in 2% to 10% and 9% of patients, respectively.
  • Persistent alopecia
    Figure 23. Persistent alopecia: Chemotherapy-induced alopecia may rarely persist after treatment with gemcitabine, busulfan, docetaxel, and paclitaxel.
  • Textural hair abnormalities
    Figure 24. Textural hair abnormalities: Curly hair and partial alopecia is commonly seen with vismodegib (Figure), vemurafenib, and sorafenib.

Novel cancer agents have brought about significant improvements in patient survival while reducing systemic toxicities, when compared with cytotoxic chemotherapy. Therefore, other components of cancer management have come forward, such as supportive care and psychosocial well-being. Most notably, dermatologic adverse events have gained considerable attention due to their high frequency, appearance in functional and cosmetically sensitive areas, and association with symptoms of pain and pruritus—all of which lead to decreased quality of life and inconsistent dosing. In turn, clinical outcomes may be affected with dose modifications, in response to these untoward events.

TABLE 1: Dermatologic adverse events from select newer anticancer agents (common and clinically significant examples)

Additionally, therapies targeting specific pathways and proteins critical to cancer cells are noteworthy for inducing dermatologic adverse events, which may affect up to 90% of treated patients. These toxicities are usually class effects, and may be noted with the use of monoclonal antibodies or small-molecule kinase inhibitors sharing similar targets. These effects may occur at different cycles during therapy, and not all patients develop the archetypal toxicities (Table1).

Suggested Reading

Baas JM, Krens LL, Guchelaar HJ, et al: Recommendations on management of EGFR inhibitor-induced skin toxicity: a systematic review. Cancer Treat Rev 38:505–514, 2012.

Balagula Y, Lacouture ME, Cotliar JA: Dermatologic toxicities of targeted anticancer therapies. J Support Oncol 8:149–161, 2010.

Belum VR, Fischer A, Choi JN, Lacouture ME: Dermatological adverse events from BRAF inhibitors: a growing problem. Curr Oncol Rep 15:249–259, 2013.

Drucker AM, Wu S, Busam KJ, et al: Rash with the multitargeted kinase inhibitors nilotinib and dasatinib: meta-analysis and clinical characterization. Eur J Haematol 90:142–150, 2013.

Fischer A, Rosen AC, Ensslin CJ, et al: Pruritus to anticancer agents targeting the EGFR, BRAF, and CTLA-4. Dermatol Ther 26:135–148, 2013.

Gandhi M, Kuzel T, Lacouture M: Eosinophilic rash secondary to temsirolimus. Clin Genitourin Cancer 7:E34–36, 2009.

Jatoi A, Rowland K, Sloan JA, et al: Tetracycline to prevent epidermal growth factor receptor inhibitor-induced skin rashes: Results of a placebo-controlled trial from the North Central Cancer Treatment Group (N03CB). Cancer 113:847–853, 2008.

Lacouture ME: Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 6:803–812, 2006.

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 19:1079–1095, 2011.

Lacouture ME, Duvic M, Hauschild A, et al: Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist 18:314–322, 2013.

Lacouture ME, Wu S, Robert C, et al: Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist 13:1001–1011, 2008.

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 28:1351–1357, 2010.

Scotte F, Tourani JM, Banu E, et al: Multicenter study of a frozen glove to prevent docetaxel-induced onycholysis and cutaneous toxicity of the hand. J Clin Oncol 23:4424–4429, 2005.

Scope A, Agero AL, Dusza SW, et al: Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol 25:5390–5396, 2007.

von Moos R, Thuerlimann BJ, Aapro M, et al: Pegylated liposomal doxorubicin-associated hand-foot syndrome: Recommendations of an international panel of experts. Eur J Cancer 44:781–790, 2008.

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Wozel G, Sticherling M, Schön MP: Cutaneous side effects of inhibition of VEGF signal transduction. J Dtsch Dermatol Ges 8:243–249, 2010.

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