Urea-Based Topical Treatment

Urea-Based Topical Treatment

PEP Topic 
Skin Reactions
Description 

Urea-containing lotion and creams are emollients for topical use that have keratolytic properties. Urea hydrates, as well as breaks down the intercellular matrix, resulting in mild debridement and normal healing of surface lesions. Urea lotion and urea-based products were evaluated in patients with cancer for the prevention and management of radiodermatitis and skin effects.

Effectiveness Unlikely

Guideline/Expert Opinion

Balagula, Y., Garbe, C., Myskowski, P.L., Hauschild, A., Rapoport, B.L., Boers-Doets, C.B., & Lacouture, M.E. (2011). Clinical presentation and management of dermatological toxicities of epidermal growth factor receptor inhibitors. International Journal of Dermatology, 50, 129–146.

doi: 10.1111/j.1365-4632.2010.04791.x
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Purpose & Patient Population:

To describe the underlying mechanisms, clinical presentation, National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (version 4.0) severity grading, and strategies to prevent and manage epidermal growth factor receptor inhibitor (EGFRI)-associated skin side effects, emphasizing evidence based practice approaches.

The type of patients addressed was those receiving EGFRIs, including monoclonal antibodies (e.g., cetuximab, panitumumab) and low-molecular-weight tyrosine kinase inhibitor (e.g., gefitinib, erlotinib, lapatinib).

Type of Resource/Evidence-Based Process:

The search strategy in this expert opinion article was not defined.

Phase of Care and Clinical Applications:

  • Patients were undergoing the active treatment phase of care.
  • The study has clinical applicability for late effects.

Results Provided in the Reference:

The article provided a table with results from four randomized controlled trials. Algorithms for the treatment of papulopustular rash, xerosis, hyperpigmentation, and paronychia were provided. Each algorithm was based on the grading defined in the NCI CTCAE (version 4.0, May 2009).

Guidelines & Recommendations:

General Skin Reactions

Preventative:

  • General preemptive or prophylactic recommendations for all patients starting therapy with EGFRIs include the following.
    • Patient education prior to the start of therapy
    • Lifestyle modifications
      • Use thick alcohol–free emollients for overall skin moisturization (e.g., creams, ointments).
      • Avoid frequent, prolonged, hot showers, and use tepid water when showering and washing dishes to minimize xerosis.
      • Avoid excessive sun exposure.
      • Use a broad spectrum of sunscreens (ultraviolet A [UVA] and ultraviolet B [UVB]).
      • Avoid alcohol-based products (e.g., lotions).

Rash

Preventative:

  • The authors developed an algorithm for preventing and managing EGFRI–induced papulopustular rash. The various treatments were based on severity grading in the NCI CTCAE scale.
  • Grade 0:
    • Minocycline 100 mg orally once on the day of chemotherapy for the first eight weeks of therapy
    • Doxycycline 100 mg orally BID one day prior to the start of chemotherapy for the first six weeks of therapy, skin moisturizer, and sunscreen (para-aminobenzoic acid [PABA] free, sun protection factor [SPF] ≥ 15, and UVA and UVB protection)
    • 1% hydrocortisone cream BID for the first six weeks of therapy
    • Skin moisturizing cream
    • Give gentle skin care instructions.

Treatment:

  • Grade 1:
    • Continue anticancer agent at current dose and monitor for changes in severity.
    • Give hydrocortisone 2.5% cream and clindamycin 1% gel daily.
    • Reassess after two weeks (either by healthcare professional or patient self-report); if the reactions worsen or do not improve, proceed to the next step.
  • Grade 2:
    • Continue anticancer agent at current dose and monitor for change in severity.
    • Give hydrocortisone 2.5% cream and doxycycline or minocycline 100 mg BID.
    • Reassess after two weeks (either by healthcare professional or patient self-report); if reactions worsen or do not improve, proceed to the next step.
  • Grade 3:
    • Modify dose as per package insert.
    • Obtain bacterial or viral cultures if infection is suspected and continue treatment of skin reactions with the following.
      • Give hydrocortisone 2.5% cream, doxycycline or minocycline 100 mg BID, and prednisone 0.5 mg/kg for five days.
      • Reassess after two weeks. If reactions worsen or do not improve, then dose interruption or discontinuation per the package insert may be necessary.

Xerosis

Prevention:

  • The authors developed an algorithm for preventing and managing EGFRI–induced xerosis. The various treatments were based on severity grading using the NCI CTCAE scale.
  • Grade 0: Prophylactic therapy with sunscreen SPF (≥ 30), moisturizing creams, gentle skin care instructions, use of tepid water when showering or washing dishes, use of oil-in-water creams, and avoidance of alcohol–based skin care products or antibacterial soaps.

Treatment:

  • Grade 1:
    • Continue anticancer agent at current dose and monitor for changes in severity.
    • Apply over-the-counter (OTC) moisturizing cream or ointment to the face BID and ammonium lactate 12% cream to the body BID.
    • Reassess after two weeks (either by healthcare professional or patient self-report); if reactions worsen or do not improve, proceed to the next step.
  • Grade 2:
    • Continue anticancer agent at current dose and monitor for changes in severity.
    • Apply OTC moisturizing cream or ointment to the face BID and ammonium lactate 12% cream or salicylic acid 6% cream to the body BID.
    • Reassess after two weeks (either by healthcare professional or patient self-report); if reactions worsen or do not improve, proceed to the next step.
  • Grade 3:
    • Modify dose as per package insert; obtain bacterial or viral cultures if infection is suspected.
    • Continue treatment of skin reactions with the following. Apply OTC moisturizing cream or ointment to the face BID, ammonium lactate 12% cream or salicylic acid 6% cream to the body BID, and triamcinolone 0.25% cream to eczematous areas BID.
    • Reassess after two weeks. If reactions worsen or do not improve, then dose interruption or discontinuation per the package insert may be necessary.

Hyperpigmentation

Prevention:

  • The authors developed an algorithm for preventing and managing hyperpigmentation. The various treatments were based on severity grading in the NCI CTCAE scale.
  • Grade 0: Prophylactic therapy includes applying sunscreen (SPF ≥ 30) to the face, ears, neck, arms, and hands when exposed to the sun, as well as use of hats and protective clothing.

Treatment:

  • Grade 1:
    • Continue anticancer agent at current dose and monitor for changes in severity.
    • Ensure no associated dermatitis (e.g., erythema, rash, edema) exists that should be treated with triamcinolone 0.1% cream.
    • Treat with hydroquinone 4% cream BID and use sunscreen.
    • Reassess after two weeks (either by healthcare professional or patient self-report); if reactions worsen or do not improve, proceed to the next step.
  • Grade 2:
    • Interrupt treatment until severity decreases to grade 0 to 1.
    • Continue treatment of skin reactions with application of hydroquinone 4% cream BID to affected areas and strict sun protection.
    • Reassess after two weeks (either by healthcare professional or patient self-report). If reactions worsen or do not improve, then dose interruption or discontinuation per protocol may be necessary.

Paronychia

Prevention:

  • The authors developed an algorithm for preventing and managing paronychia. The various treatments were based on severity grading using the NCI CTCAE scale.
  • Grade 0: Prophylactic therapy with moisturizing creams, gentle skin care instructions, teaching patients to avoid wearing tight shoes that will exert excessive friction and pressure on the periungual tissues, and teaching patients to avoid frequent water immersion or touching harsh chemicals with their hands and feet.

Treatment:

  • Grade 1:
    • Continue anticancer agent at current dose and monitor for changes in severity.
    • Use topical antibiotics and vinegar soaks (soaking fingers or toes in a solution of white vinegar in water [1:1 concentration] for 15 minutes daily).
    • Reassess after two weeks (either by healthcare professional or patient self-report); if reactions worsen or do not improve, proceed to the next step.
  • Grade 2:
    • Continue anticancer agent at current dose and monitor for changes in severity.
    • Treat with systematic (oral) antibiotics, vinegar soaks, and silver nitrate or Monsel‘s solution, applied weekly.
    • Reassess after two weeks (either by healthcare professional or patient self-report); if reactions worsen or do not improve, proceed to the next step.
  • Grade 3:
    • Modify dose as per package insert.
    • Obtain bacterial or viral cultures if infection is suspected and continue treatment of skin reaction with systematic (oral) antibiotics, vinegar soaks, and silver nitrate or Monsel‘s solution, applied weekly; consider nail avulsion.
    • Reassess in two weeks. If reactions worsen or do not improve, then dose interruption or discontinuation per package insert may be necessary.

Limitations:

This expert opinion article cannot be considered a consensus guideline because it lacks clear comprehensive search and design strategies, clear evaluation of evidence, and a description of the method used to apply that evidence in the development of the recommendation.

Nursing Implications:

A variety of interventions have been studied to prevent or manage various EGFRI-induced skin reactions, including papulopustular rash, xerosis, hyperpigmentation, and paronychia. Although 76 references were cited, this is an expert opinion article based on the lack of clear comprehensive search and design strategies, unclear evaluation of the evidence, and lack of description of the method to apply that evidence in development of the recommendation.

The authors commented on the lack of evidence-based practice recommendations for preventing and managing skin reactions caused by EGFRIs. The authors stated, “The overall lack of adequate data from prospective RCTs and lack of evidence-based standardized guidelines is reflected by differences in treatment methods utilized by clinicians.” The authors also stated, “The relative paucity of clinical data arising from prospective, large, and placebo-controlled randomized controlled trials has been the major limitation of the currently available treatments.”

Considering the frequent use of EGFRIs, healthcare providers should be familiar with these toxicities, as well as available prevention and management strategies.

Implications for nursing practice include using the tables and algorithms in this article as practical tools to prevent or manage several types of EGFRI-induced skin reactions.  

Gutzmer, R., Becker, J.C., Enk, A., Garbe, C., Hauschild, A., Leverkus, M., . . . Homey, B. (2011). Management of cutaneous side effects of EGFR inhibitors: Recommendations from a German expert panel for the primary treating physician. Journal der Deutschen Dermatologischen Gesellschaft, 9, 195–203.

doi: 10.1111/j.1610-0387.2010.07561.x
Print

Purpose & Patient Population:

To describe the underlying mechanisms, clinical presentation, severity grading (according to National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], version 4.0), and strategies to prevent and manage epidermal growth factor receptor inhibitor (EGFRI)-associated skin side effects, emphasizing evidence-based practice.

The type of patients addressed was adults receiving an EGFRI, including monoclonal antibodies (e.g., cetuximab, panitumumab) and tyrosine kinase inhibitors (e.g., erlotinib, gefitinib, lapatinib).

Type of Resource/Evidence-Based Process:

In this expert opinion article, a panel of German dermatologists met in June 2009 in Frankfurt am Main, Germany, to generate mutual recommendations on the management of cutaneous side effects of EGFRIs. Those recommendations were passed after an internal revision in July 2010. The authors stated the basis of the recommendations was the physicians’ long-term personal experiences with affected patients.

Databases searched were not reported.

Search keywords were EGFR, cutaneous side effects, and papulopustular exanthema.

Studies were included in the review if they were published up to April 2010.

Exclusion criteria were not reported.

Phase of Care and Clinical Applications:

Patients were undergoing the active treatment phase of care.

Guidelines & Recommendations:

General and Preventive Measures for All Patients Receiving EGFRI Therapy:

  • Give patient education regarding various cutaneous side effects, usual time points for manifestation, and positive correlation between early occurring papulopustular exanthems and therapy success and general measures. 
  • The following advice was recommended for preventive skin care procedures for all patients receiving therapy with EGFRIs:
    • Avoid frequent hand washing; daily, long showers; or frequent, long baths.
    • Use mild bath or shower oils or syndets (no soap).
    • Use moisturizers or urea-containing skin care products (e.g., ointment, cream) without fragrances or other skin irritants (no lotion or gel).
    • Avoid sun-tanning parlors, and consistently use sun protection products (light exposure factor > 20) or clothing protection from ultraviolet radiation.
    • Avoid skin contact with irritants such as solvents, disinfectants, and polishes.
    • Avoid activities that mechanically stress the skin (e.g., garden work, carrying heavy objects, hot hair drying).
    • For adequate treatment of preexisting skin diseases, refer to a dermatologist.

Medicinal Prophylaxis of EGFRI Cutaneous Lesions:

  • A few studies on medicinal prophylaxis of papulopustular exanthema have been performed, and their results do not allow for reliable recommendations.
  • Prophylactic treatments included oral tetracycline, minocycline, and doxycycline; topical pimecrolimus; skin moisturizer; and topical sunscreen, glucocorticosteroids, and vitamin K3.

Therapy of the Papulopustular Exanthems on the Face and Trunk:

  • Initiate combined therapy with a topical metronidazole or nadifloxacin-containing ointment and a systemic tetracycline (doxycycline: 50 or 100 mg BID;  minocycline: 50 mg BID; tetracycline: 2–4 x 250 mg daily).
  • Treatment of rash with wound gel containing collagen or lidocaine and topical vitamin K3 is being studied.

Advanced Diagnostics and Therapy for Rash (Usually With a Dermatologist):

  • Obtain microbial diagnostics in papulopustular exanthema.
  • If Demodex mites are detected in the lesions, employ topical metronidazole, a short course of an azelaic acid cream, or a cream containing permethrin.
  • If Pityrosporum yeasts are identified, ciclopirox olamine, clotrimazole, or ketoconazole is recommended.
  • In bacterial superinfection, depending on the antibiogram (usually identification of Staphylococcus aureus), topical therapy with an antiseptic agent (e.g., octenidine) and targeted systemic antibiotic therapy are recommended.
  • For eczematous skin lesions with scaling and pruritus on the trunk, mild-to-moderate potency topical glucocorticosteroids (e.g., hydrocortisone butyrate, methylprednisolone aceponate) are recommended.
  • When clinical features of seborrheic dermatitis or perioral dermatitis are present in the face, pimecrolimus or tacrolimus and a topical antifungal agent (e.g., ciclopirox) may be used.

Therapy of Papulopustular Exanthems on the Scalp:

  • Early treatment with a systemic antibiotic usually offers effective protection from the development of a severe papulopustular rash on the scalp.
  • In patients who develop a superinfection despite administration of a systemic antibiotic, microbiological diagnostics should be performed and therapy based on the antibiogram should be changed to an antibiotic effective against S. aureus (e.g., flucloxacillin).
  • Antimicrobial shampoos may be used.

Treatment Recommendations: Dry Skin and Pruritus:

  • Use of emollients (e.g., urea-containing products), perhaps with the addition of an antiseptic (e.g., triclosan) can be used for dry, sensitive skin.  
  • If marked inflammation exists, a short course of glucocorticosteroid ointment is recommended.
  • If severe inflammation exists, a short course of glucocorticosteroid ointment and an antiseptic is recommended.
  • Topical products containing polidocanol and oral antihistamines can be used on a supplemental basis for dry skin and pruritus.
  • If inflamed skin fissures exist, obtain a referral to a dermatologist.

Treatment Recommendations: Paronychia:

  • In early stages of paronychia, treatment with a topical antifungal agent (e.g., ciclopirox olamine) and a topical antibiotic (fusidic acid) is recommended.
  • In the event of damage to the cuticle, a nail lacquer containing ciclopirox should be applied every two days.
  • Combination of a topical glucocorticosteroid and a disinfectant can be considered.
  • Systemic therapy can include one of the oral tetracyclines, or an oral cephalosporin or quinolone.
  • In advanced or persistent inflammation, the patient should be referred to a dermatologist for further treatment.
  • For severe inflammation, microbiological tests and targeted antibiotic therapy are recommended.
  • Excessive granulation tissue should be removed surgically or with silver nitrate.
     

Nursing Implications:

Effective management of frequent cutaneous side effects is important for tumor therapy. The present recommendations developed by a German expert panel are based on a three-step concept.

  • Patient education and general preventive measures
  • Measures that should be initiated as early as possible by the primary treating physician at the first sign of skin lesions
  • Advanced diagnostics and therapy by a specialized dermatologist

Although the article had 36 references, several interventions (especially in rash—advanced diagnostics and therapy, rash—therapy on scalp, measures for dry skin and pruritus, and therapy of paronychias) do not have a specific reference.

Adequate management of cutaneous side effects is necessary for optimal therapeutic benefit and enhanced quality of life. Because of their visibility, cutaneous side effects are experienced by many patients as a psychological burden that can impair quality of life and often endangers compliance with therapy, or leads to a dose reduction or discontinuation. This article provided nurses with practical recommendations for the prevention and management of cutaneous side effects of EGFRIs.  

Research Evidence Summaries

Ocvirk, J., & Rebersek, M. (2008). Managing cutaneous side effects with K1 vitamin creme reduces cutaneous toxicities induced by cetuximab. Journal of Clinical Oncology, 26(15, Suppl.), 20750.

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Intervention Characteristics/Basic Study Process:

Patients receiving cetuximab were seen weekly and started with topical 0.1% vitamin K1 cream with urea applied BID, beginning with first noted rash.

Sample Characteristics:

  • The study reported on a sample of 30 patients.
  • The sample comprised patients with colorectal cancer being treated with cetuximab who experienced acne-like rash (grade 3: n = 6; grade 2: n = 18; grade 1: n = 6).

Setting:

Department of Medical Oncology at the Institute of Oncology Ljubljana in Slovenia

Study Design:

This was a case report series.

Measurement Instruments/Methods:

Severity was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.

Results:

Rash was improved in all patients after eight to 18 days of initiating cream with urea and 0.1% vitamin K1 applied BID.

Conclusions:

Application of cream with urea and 0.1% vitamin K1 BID was effective in managing cetuximab-induced rash.

Limitations:

  • This was a case report series.
  • Various grades of rash existed with additive interventions dependent on grade.

Wolf, S.L., Qin, R., Menon, S.P., Rowland, K.M., Jr, Thomas, S., Delaune, R., . . . Loprinzi, C.L. (2010). Placebo-controlled trial to determine the effectiveness of a urea/lactic acid-based topical keratolytic agent for prevention of capecitabine-induced hand-foot syndrome: North Central Cancer Treatment Group Study N05C5. Journal of Clinical Oncology, 28, 5182–5187.

doi: 10.1200/JCO.2010.31.1431
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Study Purpose:

To determine the effectiveness of a urea/lactic acid–based topical keratolytic agent (ULABTKA) for the prevention of capecitabine-induced hand-foot syndrome (HFS).

Intervention Characteristics/Basic Study Process:

Eligible patients received their first dose of capecitabine at 2,000 or 2,500 mg/m2 per day for 14 days, every 21 days. Patients then were randomized to the ULABTKA arm or placebo cream. Creams were applied to the hands and feet BID for 21 days over four consecutive cycles. Patients kept a daily diary. Toxicity data were collected at baseline and the end of each 21 day cycle. The primary end point was incidence of moderate or severe HFS in the first cycle, based on patient report. Secondary end points included the incidence of moderate or severe HFS by physician grading, times to grade, and physician determination.

Sample Characteristics:

  • The study reported on a sample of 127 patients. Of 137 total patients enrolled, only 67 on study drug and 60 on placebo reported characteristics and outcomes.
  • Twenty patients were aged younger than 50 years, 36 were aged from 50 to 60 years, and 71 were aged older than 60 years.
  • The sample was 84% female, 16% male, and 96% Caucasian.
  • Sixty-five percent of the sample had breast cancer, 23% had lung cancer, and 11% had colon cancer.
  • All patients were to receive their first cycle of capecitabine; 85% were on metastatic treatment and 14% were on adjuvant treatment.

Setting:

  • Multi-site
  • Outpatient
  • North Central Cancer Treatment Group (NCCTG)

Phase of Care and Clinical Applications:

Patients were undergoing the active treatment phase of care.

Study Design:

This was a randomized, double-blind, phase 3 clinical trial.

Measurement Instruments/Methods:

  • All patients were provided information regarding initial signs and symptoms of HFS.
  • Patients completed a self-reported HFS diary daily.
  • Physicians determined HFS grades for symptoms with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, at baseline and the end of each 21-day cycle.
  • Patients completed a symptom experience diary at baseline and each week.
  • Patients were queried about the occurrence of rash and diarrhea at each visit.

Results:

  • No significant differences were observed in toxicities between the two groups across all visits.
  • With regard to primary end point, the difference between the two study arms was not statistically significant. In fact, the incidence of moderate-to-severe HFS was higher in the treatment arm.

Conclusions:

The use of urea/lactic acid for the prevention of HFS in patients receiving capecitabine therapy cannot be supported on the basis of this trial.

Limitations:

The primary end point only concerned the first 21-day cycle, rather than looking over the planned four cycles. This raises the question over whether more power could have existed to detect smaller differences. More patients received the lower dose of capecitabine.

Nursing Implications:

Nurses should educate patients to limit or not use urea/lactic acid cream if starting on capecitabine.


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