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.

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).

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

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

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).

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.

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.

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.