Antibiotics

Antibiotics

PEP Topic 
Skin Reactions
Description 

Antibiotics are medicines that combat bacterial infections by killing or slowing the growth of bacteria. Specific antibiotic agents or classes may be identified within the Oncology Nursing Society Putting Evidence Into Practice (PEP) resources as individual interventions, depending on the specificity of the evidence synthesized. Prophylactic administration of antibiotics has been examined for the prevention of infection in patients with cancer. In addition, systemic antibiotics and topical application of antibiotics have been evaluated in patients with cancer for the management of skin effects.

Effectiveness Not Established

Systematic Review/Meta-Analysis

Anderson, R., Jatoi, A., Robert, C., Wood, L.S., Keating, K.N., & Lacouture, M.E. (2009). Search for evidence-based approaches for the prevention and palliation of hand-foot skin reaction (HFSR) caused by the multikinase inhibitors (MKIs). Oncologist, 14, 291–302.

doi: 10.1634/theoncologist.2008-0237
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Purpose:

To systematically review the literature on the prevention and palliation of multikinase inhibitor (MKI)-associated hand-foot syndrome (HFS) to identify areas for further clinical study and to provide a foundation for evidence-based guidelines for HFS management

Search Strategy:

DATABASES USED: PubMed, Cochrane Database of Systematic Reviews, BIOSIS, and CANCERLIT

KEYWORDS: Hand foot syndrome, hand foot skin reaction, acral erythema, palmar-plantar erythrodysesthesia, acral erythrodysesthesia, Burgdorf reaction, toxic erythema of the palms and soles. Medical subject headings (MeSH) included skin disease, hand injuries, chemically induced, antineoplastic agents, and protein kinase inhibitors. Names of specific agents also were entered into the MeSH search.

INCLUSION CRITERIA: English language clinical studies; meta-analysis, reviews, or practice guidelines; literature through August 31, 2008. Literature was categorized (C) according to the type of agent and cutaneous reaction.

  • C1—Articles pertaining to MKI-associated HFS containing histology, pathogenesis, incidence, quality of life, impact, treatment, or prevention
  • C2—Articles focused on MKI-associated skin reactions other than HFS
  • C3—Articles focused on antineoplastic agents other than MKIs and HFS
  • C4—Articles that did not focus on clinical details of pathophysiology or treatment of HFS (e.g., health policy, study design issues)

EXCLUSION CRITERIA: Conditions other than HFS, topics unrelated to antineoplastic therapy

Literature Evaluated:

TOTAL REFERENCES RETRIEVED = 2,069 abstracts 

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: After screening for inclusion, 350 abstracts (17%) met criteria for inclusion in C1–C4 categories.

Sample Characteristics:

  • FINAL NUMBER STUDIED INCLUDED = 56 articles categorized as C1 were reviewed and evaluated. Only those that fell into this category were discussed in this review. None of the citations on prevention or palliation approaches to HFS were randomized, controlled trials.

Results:

Prevention approaches for MKI-associated HFS included

  • Screening for preexisting plantar hyperkeratosis (e.g., podiatry care)
  • Prophylactic removal of hyperkeratotic areas (e.g., manicure or pedicure before and during treatment to remove hyperkeratosis)
  • Use of prophylactic skin care (e.g., emollients, topical exfoliating products applied to calluses, pedicures, manicures)
  • Protection of pressure-sensitive areas of the hands and feet (e.g., wearing well-fitting, soft shoes; cushioning of callused areas by soft or padded shoes)
  • Use of prophylactic systemic treatments (e.g., administration of prophylactic pyridoxine [vitamin B6], glucocorticoids, cyclooxygenase-2 inhibitors).

The following are recommendations on patient education prior to MKI therapy.

  • Providers are encouraged to listen to patient concerns, offer options to enhance patient comfort, and identify treatment issues early.
  • No studies were found that tested efficacy of patient education approaches for preventing hand-foot skin reactions (HFSRs) (e.g., written materials, videos).

Treatment and palliation for management of HFS symptoms:

  • Grade 1 HFS
    • Dermatology referral and management, as appropriate
    • Use of keratolytics (e.g., 40% urea and/or salicylic acid) to aid in exfoliation of callused areas
    • Cushioning of affected regions with gel inserts in shoes or use of loose-fitting shoes or slippers
    • Frequent application of emollients and creams, especially to palms and soles, to maintain moisture and prevent breaks in skin integrity
    • Analgesics
    • Local/regional cooling (e.g., cool compresses)
    • Foot soaks in magnesium sulfate to soften calluses and reduce pain upon pressure
  • Grade 2 HFS
    • All interventions as outlined for grade 1
    • Dosage or regimen adjustments of MKIs
    • Continue to control symptoms and relieve patient discomfort
  • Grade 3 HFS
    • Topical therapy to reduce symptoms and prevent further progression (e.g., frequent use of creams and lotions, especially to palms and soles of feet; wet disinfectant to treat blisters and erosions; cortisone creams and topical antibiotics for severe forms of HFSRs)
    • Systemic strategies to reduce symptoms and prevent further progression (e.g., pyridoxine may be beneficial in doses of 50–150 mg/day)
    • Dosage or regimen adjustments of MKIs (e.g., interruption of MKI therapy for a minimum of seven days until toxicity is resolved to grade 0 or 1)

Authors stated that no evidenced-based treatment algorithms exist for cutaneous toxicities of the MKIs in the dermatologic or oncologic literature. It was noted that none of these recommendations were based upon strong evidence-based data and that none of the C1 articles were randomized, controlled trials designed to test HFS reactions management. It was revealed that clinical approaches to HFS are largely anecdotal, from case reports, based on practices during clinical trials of antineoplastic treatment, obtained from post-marketing practices, or extrapolated from approaches often used with chemotherapeutic treatments.

Conclusions:

No actual convincing evidence was found in this review for any recommendation identified.

Limitations:

  • Among all the C1 articles reviewed, none were randomized, controlled trials designed to test HFS management approaches.
  • None of the ancillary, observational, or case control studies described in the literature reviewed were designed to test the effectiveness of HFS management interventions.
  • Most information being used is anecdotal or based upon individual provider experience and preference.

Nursing Implications:

This review points to the need for research to test and compare various recommendations for prevention and management of HFS on clinical and patient-centered outcomes.

Research is needed in the following.

  • Appropriate and effective patient education for prevention
  • How often the patient should be seen and assessed for HFS
  • How to accurately diagnose mild HFS and recognize subsequent skin complications
  • How to effectively treat without leading to increased HFS damage and symptoms
  • Providing guidance on the best types of gel inserts, cushions, and soft footwear
  • Identifying treatment strategies that are most effective at all grades of HFS
  • Testing specific emollients or creams for preventive or reactive treatment of MKI-associated HFS

Baas, J.M., Krens, L.L., Guchelaar, H.-J., Ouwerkerk, J., de Jong, F.A., Lavrijsen, A.P., & Gelderblom, H. (2012). Recommendations on management of EGFR inhibitor-induced skin toxicity: A systematic review. Cancer Treatment Reviews, 38, 505–514.

doi: 10.1016/j.ctrv.2011.09.004
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Purpose:

To evaluate evidence regarding the prevention and management of epidermal growth factor receptor–inhibitor (EGFRI)-related skin toxicities. Secondary objectives were to review current knowledge on (a) the pathophysiology of this type of skin toxicity, (b) prediction of the occurrence of (severe) skin toxicity in individual patients, (c) the need for adequate management of skin toxicities, and (d) the possibility of any interference between management of skin toxicities and the antitumor effect of EGFRIs.

Search Strategy:

The database searched was MEDLINE.

Search keywords were skin toxicity, rash, acneiform rash, acne, exanthema, cetuximab, panitumumab, erlotinib, gefitinib, lapatinib, monoclonal antibodies, EGFR, antibiotics, antibody dependent cell mediated cytotoxicity, ​and NK cells.

Studies were included in the review if they reported on the testing any type of management (prophylactic as well as reactive) using topical agents, systemic agents, or both.

Exclusion criteria were not specified.

Literature Evaluated:

A total of 283 references were retrieved. No quality rating or method of study evaluation was described.

Sample Characteristics:

  • Eighty final studies were included, with five randomized controlled trials comprising 338 patients.
  • The samples across studies ranged from 16 to 110 patients.

Phase of Care and Clinical Applications:

Patients were undergoing the active antitumor treatment phase of care.

Results:

  • Reviews with findings regarding the pathophysiology of skin toxicities, factors that predict skin toxicity, and potential interactions between the management of skin toxicities and antitumor effects of EGFRIs concluded that skin toxicities should be prevented or managed because of their impact on quality of life.
  • The studies also provided a review of clinical trials for the prevention and management of skin toxicities. They noted the lack of a strong evidence base, and that tetracycline derivatives have the strongest evidence, despite review findings of conflicting results in this area.

Conclusions:

A strong evidence base is lacking for any recommendations on the prevention and management of skin toxicities with EGFRIs.

Limitations:

  • How evidence was evaluated or graded is unclear.
  • Recommendations were made for tetracyclines, despite the review of evidence showing conflicting results.
  • The search was limited, with only one database used.

Nursing Implications:

This review adds to the current observation that a lack of strong evidence exists for any specific set of interventions to prevent or manage skin toxicities in patients receiving EGFRIs. However, the review suggests that the prior belief in letting skin effects go uncontrolled, as they were seen as an indicator of an antitumor treatment effect, is not appropriate.

Tan, E.H., & Chan, A. (2009). Evidence based treatment options for the management of skin toxicities associated with epidermal growth factor receptor inhibitors. Annals of Pharmacology, 43, 1658–1666.

doi: 10.1345/aph.1M241
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Purpose:

To compile evidence from randomized controlled trials, case series, and case reports to identify the effectiveness of various therapeutic agents for prevention and treatment of skin toxicities associated with epidermal growth factor receptor (EGFR) inhibitor therapy

Search Strategy:

DATABASES: PubMed (January 2002–May 2009) and SCOPUS (January 2002–March 2009), manual searching for retrieval of additional references from articles reviewed

KEYWORDS: EGFR inhibitor, cetuximab, erlotinib, gefitinib, panitumumab, management, skin toxicity, and cutaneous effects

INCLUSION CRITERIA: Clinical trial, case series, case report, or clinical management guideline that studied treatment options of EGFR inhibitor-induced skin toxicities; EGFR inhibitor dosing regimen and treatment outcomes included in the publication

Literature Evaluated:

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Authors do not state the total volume of literature reviewed or decision-making regarding article exclusion processes. Authors report that randomized controlled trials, case series, and case reports were retrieved.

Sample Characteristics:

  • FINAL NUMBER STUDIES INCLUDED = Final reports included in the analysis were two randomized controlled trials, three case series, and 10 case reports.
  • TOTAL PATIENTS INCLUDED IN REVIEW = 156

Results:

Interventions were categorized as preventive intent or treatment intent. Interventions included in the review were topical antibiotics, systemic antibiotics, antiseptics, topical corticosteroids, retinoids, and other products. The majority of interventions were reported regarding effectiveness with EGFR inhibitor rash. Pruritus associated with the EGFR inhibitor-induced rash was documented in 47 patients in seven case reports; however, only three reports addressed pruritus treatment. Management of xerosis was mentioned in three case reports and one case series, for a total of 20 patients.

Preventive intent findings:

  • Interventions found included topical erythromycin solution, systemic tetracyclines, and topical retinoid (tazarotene cream in combination with systemic antibiotics).
  • Erythromycin solution was provided to two patients. These patients experienced only slight erythema without pustules, suggesting a protective effect.
  • Two randomized controlled trials investigated the use of systemic tetracyclines to prevent EGFR inhibitor rash. In the total 51 patients across these trials, systemic antibiotic treatment did not prevent rash. Findings did suggest that the use of systemic antibiotic treatment along with EGFR inhibitor can decrease the severity of the rash during the first month of EGFR inhibitor treatment.
  • Tazarotene cream, in combination with minocycline, demonstrated no effect on rash severity in 39 patients. The retinoid also was associated with significant skin irritation, causing one-third of the patients to discontinue its use.

Treatment intent findings:

  • Interventions found for treatment of EGFR inhibitor skin toxicity included topical antibiotics, systemic antibiotics, antiseptics, topical corticosteroids, retinoids, colloidal sulfur galenic cream, and cream containing urea and vitamin K.
  • Topical antibiotics were the most common treatments and were most often used in combination with other topical agents or systemic antibiotics. This intervention was reported in 49 patients.
    • Topical antibiotics used included clindamycin, erythromycin, fusidic acid, and metronidazole.
    • The majority of cases had either partial or complete responses with treatment.
  • Systemic antibiotics were used to treat more severe EGFR inhibitor-induced rash in a total of 16 patients in several case reports and case series. Systemic tetracyclines were used in 12 patients in combination with topical medications for treatment of rash. In seven patients, non-tetracycline compounds (e.g., penicillin, clindamycin, fusidic acid) were used in combination with various topical agents.
    • Mixed results were seen. Some patients had complete or partial response, but in 58% of cases, results were confounded by concomitant delay or dose reduction in EGFR inhibitor treatment.
    • Results with non-tetracycline compounds also were confounded by withdrawal of EGFR inhibitor treatment.
  • Antiseptics, including povidone iodine, hexamidine, benzoyl peroxide, and boric acid were reported in seven cases. In all cases, these were used in combination with other topical or systemic drugs. Response to these interventions was confounded by concomitant EGFR inhibitor dosage reduction in two patients who had a “complete response” to intervention with antiseptics.
  • Retinoid interventions for rash treatment included oral isotretinoin in four patients and topical adapalene in three patients.
  • Other intervention reports were retrieved that involved use of topical sulfur galenic cream and a cream containing urea and vitamin K. Improvement in these three patients was reported.

Strong evidence supports the use of topical antibiotics to manage EGFR inhibitor skin toxicities. Antibiotics are the most common treatment option. Use of anti-acne medications such as benzoyl peroxide and retinoids is controversial. Steroids are not recommended until well-designed clinical trials can demonstrate efficacy because steroid use can aggravate and induce acne.

Conclusions:

This review did not identify strong evidence for any of the interventions reported for the management of skin toxicities associated with EGFR inhibitors. Antibiotics are most frequently used to manage EGFR inhibitor-induced skin toxicities, and more reports are available on the use of antibiotics than on the use of other approaches. The authors concluded that the evidence in support of the use of antibiotics is questionable. In this review, the total number of cases involved in the use of topical antibiotics was 49, and the total number of cases involved in the use of systemic antibiotics was 68. In many of the cases for systemic antibiotic use, reported findings were confounded by the additional intervention of dose modification (i.e., EGFR inhibitor dosages were reduced, delayed, or stopped).

Limitations:

  • Reports reviewed involved a variety of mixed interventions, so identifying the combinations of interventions that appear to have the greatest promise for successful management of EGFR inhibitor-induced skin toxicities is difficult.
  • This review only focused on skin toxicities associated with EGFR inhibitors. Little information on toxicities other than skin rash was found.
  • This review, as well as the current literature evaluating the interventions, had a number of limitations. The review was limited by a lack of information found on pruritus and xerosis, as well as a lack of substantive, well-controlled research in this area. Most reports gave information about the resolution of rash in terms of lesion count but did not evaluate patient symptoms or specific patient-centered outcomes.
  • Most reports did not provide a determination or measurement of the severity of skin problems. Most studies did not conduct a follow-up to determine long-term resolution. Reports of complete resolution of skin rash often involved discontinuation or dose reduction of the EGFR inhibitor, so efficacy of the intervention is likely to have been overestimated.

Nursing Implications:

This review emphasized the need for well-designed research in this area that includes appropriate follow-up strategies. This review also discusses the widespread use of antibiotics to treat EGFR-induced skin toxicities. It notes that topical antibiotics are recommended for treatment of milder skin reactions, and systemic antibiotics (e.g., minocycline or doxycycline) are recommended for treatment of more severe rash. The authors state that their recommendations are aligned with several proposed treatment algorithms that have been obtained from international and interdisciplinary EGFR inhibitor dermatologic toxicity forums. As evident in this review, these recommendations are not based on strong evidence.

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.  

Bracarda, S., Ruggeri, E.M., Monti, M., Merlano, M., D'Angelo, A., Ferrau, F., ... Sorafenib Working Group. (2012). Early detection, prevention, and management of cutaneous adverse events due to sorafenib: Recommendations from the Sorafenib Working Group. Critical Reviews in Oncology/Hematology, 82, 378–386. 

PROFESSIONAL GROUP: Sorafenib Working Group (SWG)

doi: 10.1016/j.critrevonc.2011.08.005
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Purpose & Patient Population:

PURPOSE: To provide practicing physicians with the specific information necessary to diagnose, prevent, and manage the dermatological events related to treatment with sorafenib, with particular reference to the hand-foot skin reaction (HFSR)
 
TYPES OF PATIENTS ADDRESSED: No relevant set of participants

Type of Resource/Evidence-Based Process:

RESOURCE TYPE: Expert opinion  

PROCESS OF DEVELOPMENT: The SWG was a multidisciplinary team of experts in the field who were closely involved in the sorafenib clinical development program. The group was established with the objective of developing recommendations to allow the early detection, prevention, and management of cutaneous adverse events in everyday clinical practice.

Phase of Care and Clinical Applications:

PHASE OF CARE: Active antitumor treatment

Results Provided in the Reference:

The SWG aims to collect the experience of each clinician in order to develop detailed, practical guidelines for the prevention and management of dermatological adverse events associated with sorafenib.

Guidelines & Recommendations:

For grade 1 HFSR on the hands, apply zinc oxide and magnesium silicate lenitive cream without Vaseline. For feet, wear comfortable shoes with a latex insole if possible. Wash with non-foaming cleansing creams, apply same cream as hands, and wear perspiring socks without seams. For grades 2–3 HFSR, aspirate fluid inside blister and then medicate with a PEG-based cicatrizing ointment. Avoid antibiotics. General erythema should be treated also with zinc oxide and magnesium silicate lenitive cream. For follicular rash, apply a cold compress of potassium permanganate 0.0125% solution followed by 2% sulfosalicylic cream without Vaseline. No antibiotics recommended.

Limitations:

  • Unknown

Nursing Implications:

Nurses should consider these recommendations, especially for HFSR. Certainly, the preventative measures are worthy. However, one also needs to be familiar with any trials using the products that are recommended from this expert group.

Burtness, B., Anadkat, M., Basti, S., Hughes, M., Lacouture, M.E., McClure, J.S., . . . Spencer, S. (2009). NCCN Task Force Report: Management of dermatologic and other toxicities associated with EGFR inhibition in patients with cancer. Journal of the National Comprehensive Cancer Network, 7(Suppl. 1), S5–S21.

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Purpose & Patient Population:

To describe commonly used therapies that National Comprehensive Cancer Network (NCCN) Task Force members agreed are appropriate standards of care to manage dermatologic and ocular toxicities that occur in patients with cancer being treated with epidermal growth factor receptor (EGFR) inhibitors.

Type of Resource/Evidence-Based Process:

NCCN Task Force members reviewed available published data on treating toxicities associated with EGFR inhibitors, reviewed data from the treatment of clinically similar toxicities from different etiologies, and shared their expert opinions. Through this process, they developed recommendations for managing dermatologic and ocular toxicities associated with EGFR inhibition in patients with cancer. 

The databases searched were not identified specifically. The authors stated their recommendations were supported only by anecdotal evidence.

Search keywords, inclusion criteria, and exclusion criteria were not provided.

Phase of Care and Clinical Applications:

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

Guidelines & Recommendations:

Modifying EGFR Inhibitor Therapy

  • Brief dosing interruptions can be helpful in managing high-grade EGFR-inhibitor–associated skin and ocular toxicities. These toxicities may lessen over the course of one to two weeks, and then reintroduction of the EGFR inhibitor often is feasible.
  • The role of dose reduction remains uncertain. The reproducible relationship between rash and survival for all EGFR antagonists suggests, but does not prove, that maintaining full dose in patients with rash may be beneficial.

Topical Therapies for Rash

Prophylactic/Mitigating Treatments:

  • Long-term prophylactic topical mupirocin ointment can be used in the nose to prevent Staphylococcus aureus colonization, especially for patients with recurrent infection.

Reactive Treatments: 

  • Topical steroids (low-strength on the face; medium strength on the body) and topical antibiotics (e.g., clindamycin, erythromycin) are based on expert reference and clinical experience, rather than data from randomized clinical trials.
  • Petroleum jelly, ammonium lactate, or dilute hydrogen peroxide soaks with gentle debridement may remove excessive formation of yellow crusts and debris in severe skin rash.
  • If superinfection is suspected (because of excessive induration and erythema, the presence of a dominant lesion that appears larger and more inflamed than the remainder of the lesions, or purulent drainage), then the site should be cultured to determine the organism and sensitivity. Positive cultures may be evidence of infection or colonization, and clinical judgment is needed to evaluate culture results.
  • Pulsed dye laser and intense pulsed light may effectively decrease the erythema and prominence of telangiectatic vessels (dilated blood vessels).
  • Postinflammatory hyperpigmentation may fade through the use of hydroquinone, azelaic acid, topical retinoids, or laser-based therapies.

Systemic Therapies for Rash

Prophylactic/Mitigating Treatments:

  • These treatments are used to decrease the severity of rash.
  • Oral antibiotics include tetracycline (500 mg BID), minocycline (100 mg daily), and doxycycline (100 mg BID).
  • Multiagent prophylactic skin treatment (Skin Toxicity Evaluation Protocol With Panitumumab [STEPP] study—randomized trial) includes oral doxycycline (100 mg BID), topical corticosteroids (1% hydrocortisone), skin moisturizer, and sunscreen.
  • Sunscreens that are non–alcohol based and physical sunblocks (e.g., zinc oxide, titanium dioxide) with 30 sun protection factor (SPF) that block ultraviolet A (UVA) and ultraviolet B (UBV) light should be applied thickly. 
  • A topical vitamin K3 analog, menadione, is being investigated in a phase 1 trial for use in reducing the skin rash associated with EGFR inhibitors.

Reactive Treatments:

  • The following treatments are based on anecdotal reports or nonrandomized studies.
    • Oral antibiotics:  tetracycline, minocycline, and doxycycline
    • Retinoids:  isotretinoin (problem with paronychia) and low-dose acitretin (oral 10 mg per day)
    • Systemic steroids: May be appropriate in some settings (usually in the inpatient setting) with careful supervision.

Paronychia:

  • For bacterial and fungal cultures, treat infection with appropriate oral antibiotics.
  • Apply Monsel’s (ferric subsulfate) solution or silver nitrate to bleeding, overgrown tissue.
  • Soaks for symptomatic relief include 4% thymol in alcohol, aluminum acetate (Burow's solution), white vinegar (1:10), and bleach (1/4 cup bleach: 3 gallons water).
  • Use topical corticosteroid cream (e.g., methylprednisolone) for inflammatory, noninfected paronychia.
  • Clip nails, remove embedded nails or possibly the nail plate, and pack the area with cellulose sponge (Surgifoam®).
  • Wear well-fitted shoes or sandals.
  • Cushion nail beds for symptomatic comfort.
  • Use topical corticosteroid cream (e.g., methylprednisolone) for inflammatory paronychia.

Pruritus:

  • Apply cool compresses, sedating antihistamines (diphenhydramine) at evening or bedtime, topical steroids, and topical menthol lotions.
  • Give oral gabapentin or pregabalin (100 mg BID).
  • For dry skin, minimize the use of soap, increase use of emollients, avoid alcohol-based agents and topical antipruritics (e.g., Aveeno® Anti-Itch, Sarna® Ultra).
  • Topical agents for the scalp include fluocinonide 0.05%, clobetasol foam, or steroid shampoo.

Xerosis:

  • Frequently apply zinc oxide (30%), petroleum jelly, and other thick emollients (e.g., Aquaphor®, Aveeno, Bag Balm®, Cetaphil®, Cutemol®, Eucerin®, Vanicream®).
  • Avoid alcohol-based lotions, antibacterial soaps, long baths or frequent water immersion, and contact with harsh chemicals.

Fissuring on the heels or fingertips:

  • Do not use Monsel’s solution (ferric subsulfate) on the face. Some NCCN Task Force members believed this solution may increase the size of the fissures and stain tissue.
  • Silver nitrate
  • Aluminum chloride solution
  • Zinc oxide cream (20%–30%)
  • Bleach soaks (10 minutes per day) to prevent infection (1/4 cup bleach: 3 gallons water)
  • Protective coverings
  • Apply cyanoacrylate glue (e.g., Krazy Glue®, Super Glue®) to fissures to relieve pain and promote healing. Some patients and healthcare providers prefer cyanoacrylate glue because liquid cyanoacrylate coverings may increase the sensation of burning and delay healing.
  • Antibiotics (e.g., doxycycline) for infected fissures

Desquamation:

  • Petroleum jelly or other thick emollients (e.g., Bag Balm)
  • Mild (neutral pH) soap
  • 12% ammonium lactate, 6% salicylic acid, and 20% urea

Nursing Implications:

The NCCN Task Force report described the management of dermatologic and ocular toxicities that occur in patients receiving EGFR inhibitors. Few recommendations were evidence based; however, some commonly used therapies have data supporting their use. 

Implications for nursing practice include integrating the recommendations of the NCCN Task Force into facility algorithms for preventing or managing several types of EGFR-induced skin reactions. Well-designed research is needed in this area.

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
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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.  

Lacouture, M.E., Anadkat, M.J., Bensadoun, R.-J., Bryce, J., Chan, A., Epstein, J.B., Eaby-Sandy, B., . . . MASCC Skin Toxicity Study Group. (2011). Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Supportive Care in Cancer, 19, 1079–1095.

doi: 10.1007/s00520-011-1197-6
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Purpose & Patient Population:

To develop first-generation, evidence-based recommendations for eight epidermal growth factor receptor inhibitor (EGFRI)-associated dermatologic toxicities: papulopustular (acneform) rash, hair changes, radiation dermatitis, pruritus, mucositis, xerosis, fissures, and paronychia.

The type of patients addressed was those receiving EGFRIs.

Type of Resource/Evidence-Based Process:

In this guideline, topic review committees were formed according to expertise to review the literature and develop guidelines for each dermatologic toxicity. Each review committee comprised three members, with a primary reviewer to present the findings of the committee to the Skin Toxicity Study Group. Each committee reviewed from 17 to 35 articles to formulate the recommended guidelines. Randomized clinical trials were considered the best source. The level of evidence and grade of the recommendation were considered. In the absence of experimental evidence, pertinent studies and case reports were presented in conjunction with expert opinion derived from clinical practice. When available, data were extrapolated from other dermatologic conditions with similar clinical or pathologic characteristics (e.g., xerosis, alopecia, hirsutism, pruritus, paronychia, radiation dermatitis).

Databases searched were Ovid, MEDLINE, and Embase.

Search keywords were rash, hair changes, radiation dermatitis, pruritus, mucositis, xerosis, fissures, paronychia, EGFR inhibitors, and recommendations (this information was not stated directly in the article).

Studies were included in the review if they were published before December 2010. 

Studies were excluded if they were published during or after December 2010.

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:

Eight tables outlining prophylactic and reactive recommendations were included for papulopustular (acneform) rash, hair changes, radiation dermatitis, pruritus, oral complications, xerosis, fissures, and paronychia.

Guidelines & Recommendations:

Papulopustular (Acneform) Rash

Preventive (Weeks 1–6 and 8 of EGFRI Initiation): 

  • Systemic: minocycline 100 mg daily (less photosensitizing) and doxycycline 100 mg BID (preferred in patients with renal impairment)
  • Topical: hydrocortisone 1% cream with moisturizer and sunscreen BID 

Treatment:

  • Systemic: minocycline 100 mg daily (less photosensitizing), doxycycline 100 mg BID (preferred in patients with renal impairment), and isotretinoin at low doses (20–30 mg per day).
  • Topical: alclometasone 0.05% cream, fluocinonide 0.05% cream BID, and clindamycin 1% cream

Hair Changes (Hair Loss)

Preventive:

  • Topical and Systemic: Follow rash recommendations for scarring alopecia.

Treatment:

  • Topical: minoxidil 2% or 5% BID (nonscarring alopecia); class 1 steroid lotion, shampoo, or foam, or antibiotic lotion (scarring alopecia)

Hair Changes (Increased Hair)

Preventive:

  • Support interventions (e.g., patient education)
  • Treatment: eflornithine and lasers (facial hypertrichosis) and eyelash trimming (eyelash trichomegaly)

 Radiation Dermatitis

Preventive:

  • Topical: maintenance of appropriate skin hygiene with gentle cleansing in radiated areas prior to radiation treatment; high-potency topical steroids

 Treatment:

  • Topical: maintenance of appropriate skin hygiene with gentle cleansing in radiated areas prior to radiation treatment, moisturizers, antibacterial moisturizers, drying gel or antiseptics (chlorhexidine), hydrophilic dressings, and antibiotics if infected
  • Systemic: doxycycline
  • Other: blood cultures for fever or signs of sepsis

Pruritus

Preventive:

  • Topical: gentle skin instructions

Treatment:

  • Systemic: antihistamines (first generation, sedating: hydroxyzine and diphenhydramine; second generation, nonsedating: loratadine), anti-epileptic agents (gabapentin or pregabalin), and doxepin
  • Topical: menthol (0.5%–3%), cooling, pramoxine 1%, doxepin, and medium-to-high–potency steroids (triamcinolone acetonide 0.025%, desonide 0.05%, fluticasone propionate 0.05%, and alclometasone 0.05%)

Mucositis

Preventive:

  • Topical: benzydamine, steroids, cryotherapy or ice chips, and low-level laser therapy
  • Systemic: patient-controlled analgesia
  • Other: radiation blocks and intensity-modulated radiation therapy

Treatment:

  • Topical: No topical treatments are recommended.
  • Systemic: doxycycline

Xerosis

Preventive:

  • Topical: bathing techniques: using bath oils or mild moisturizing soaps and bathing in tepid water; regular moisturizing creams
  • Other: Avoid extreme temperatures and direct sunlight.

Treatment:

  • Topical (mild to moderate): emollient creams packaged in a jar or tub that lacks fragrance or potential irritants; occlusive emollients containing urea, colloidal oatmeal, and petroleum-based creams; exfoliants for scaly areas: ammonium lactate 12% or lactic acid cream 12%; urea creams (10%–40%); salicylic acid 6%; zinc oxide (13%–40%)
  • Topical (severe): Use medium-to-high–potency steroid creams (triamcinolone acetonide 0.025%, desonide 0.05%, fluticasone propionate 0.05%, and alclometasone 0.05%).

Fissures

Preventive:

  • Topical: Wear protective footwear and avoid friction with fingertips, toes, and heels.

Treatment:

  • Topical: thick moisturizers or zinc oxide (12%–40%) creams; liquid glues or cyanoacrylate to seal cracks, steroids or steroid tape, hydrocolloid dressings, and topical antibiotics; bleach soaks to prevent infection; and zinc oxide

Paronychia

Preventive:

  • Topical: Diluted bleach soaks; avoid irritants.

Treatment:

  • Systemic: tetracyclines, antimicrobials (reserved for culture-proven infection), and biotin for brittle nails
  • Topical: corticosteroids and calcineurin inhibitors
  • Other: silver nitrate chemical cauterization weekly; nail avulsion

Limitations:

Recommendations were based on randomized clinical trials with control groups when possible. However, because of the lack of high-quality studies investigating EGFRI-associated dermatologic changes, many recommendations were based on expert opinion and consensus.

Nursing Implications:

The authors developed first-generation, evidence-based recommendations for eight EGFRI-associated dermatologic toxicities: papulopustular (acneform) rash, hair changes, radiation dermatitis, pruritus, mucositis, xerosis, fissures, and paronychia. In addition, the authors rated each intervention according to the level of evidence (I–V) and the recommendation grade (A–D). 

The authors proposed that multidisciplinary teams, including radiation and medical oncologists, nurses, dermatologists, pharmacists, oral healthcare providers, and wound care specialists, should assess the occurrence and management of EGFRI-associated dermatologic toxicities. In addition, the Multinational Association for Supportive Care in Cancer (MASCC) EGFRI Skin Toxicity Tool (MESTT) should be used in clinical trials and practice.

Nurses should provide patient education prior to EGFRI therapy to ensure patients can expect, prepare for, and use preventive and treatment approaches to manage the eight toxicities described. In addition, nurses should encourage the multidisciplinary team to collaborate on management of EGFRI-associated dermatologic toxicities.

Pinto, C., Barone, C.A., Girolomoni, G., Russi, E.G., Merlano, M.C., Ferrari, D., Maiello, E. (2011). Management of skin toxicity associated with cetuximab treatment in combination with chemotherapy or radiotherapy. Oncologist, 16, 228–238.

doi: 10.1634/theoncologist.2010-0298
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Purpose & Patient Population:

To identify appropriate prophylactic and therapeutic interventions for the assessment and management of skin toxicities including rash, dryness, pruritus, paronychia, hair abnormality, and mucositis in patients with cancer receiving treatment including epidermal growth factor receptor inhibitors (EGFR-Is) (e.g., cetuximab) alone or in combination with chemotherapy or radiotherapy.

Type of Resource/Evidence-Based Process:

In the absence of definitive evidence from clinical trials, a group of Italian expert clinicians produced recommendations for skin toxicity management in patients receiving EGFR-Is. The RAND Corporation/University of California, Los Angles (UCLA) Appropriateness Method was used for obtaining consensus on the expert opinions.

The consensus panel comprised an advisory board of nine expert clinicians from different clinical settings (six medical oncologists, two radiation oncologists, and one dermatologist). A group of 40 panelists was identified.

The database searched was MEDLINE (2005 to October 2009). Potentially relevant abstracts presented at annual meetings or gastrointestinal symposia of the American Society of Clinical Oncology and the European Society of Medical Oncology were examined.

Search keywords were EGFR inhibitors, cetuximab, skin toxicity, skin rash, and radiation dermatitis.

Studies were included in the review if they were

  • In English language
  • Observational, prospective studies about assessment and treatment
  • Randomized, double-blind, placebo-controlled, or uncontrolled
  • Retrospective and uncontrolled
  • Systematic reviews and meta-analyses
  • Consensus guidelines
  • Reporting on available data for drugs tested in phase 3 (including abstracts).

Studies were excluded if they were published before 2005.

Phase of Care and Clinical Applications:

Patients were undergoing the active treatment phase of care.

Guidelines & Recommendations:

General Prophylactic Measures Before Starting Cetuximab Treatment:

  • Perform medical history and full-body skin evaluation with attention to xerosis, atopic dermatitis, and severe acne vulgaris.
  • Education and general interventions may include the following.
    • Use sunscreens.
    • Avoid habits or products that can produce dry skin (e.g., hot water, alcohol-based cosmetics).
    • Enhance skin hydration (e.g., use bath oils).
    • Use alcohol-free moisturizing creams frequently.
    • Use tocopherol oil or gel.
    • Avoid tight shoes.
    • Avoid excessive beard growth, shaving with a regular shaving razor (e.g., sharp multiblade), using pre–shaving cream emollients and moisturizing aftershave, using alcohol and aftershave, or using an electric razor.

Rash

Management of Grade 1 Skin Rash (Adapted From the National Cancer Institute [NCI] Common Toxicity Criteria [CTC], Version 3):

  • For skin lesions and symptoms including papules, pustules, or symptom-free erythema, do not modify cetuximab dose, interrupt treatment, or use topical or systemic treatment.
  • Administer general educational and prophylactic measures.

Management of Grade 2 Skin Rash:

  • Skin lesions include eruption with papules (grade 2A) or pustules (grade 2B) covering less than 50% of the body surface, with moderate symptoms and that do not interfere with daily activities.
  • Do not modify cetuximab dose or interrupt treatment.
  • Topical treatments include the following.
    • Antibiotics: clindamycin 1% gel, erythromycin 3% gel or cream, and metronidazole 0.75%–1% cream or gel, BID until improvement to grade 1.
    • Avoid benzoyl peroxide products.
    • Use erythromycin 2% lotion for lesions of the scalp.
  • Systemic treatments include the following.
    • Prevalence of pustules (grade 2A): No systemic treatment is recommended.
    • Prevalence of pustules (grade 2B): Antibiotics include oral semisynthetic tetracyclines. Use minocycline or doxycycline 100 mg orally once per day for more than four weeks and until the rash is asymptomatic.

Management of Grade 3 Skin Rash:

  • Skin lesions and symptoms include eruption with papules (grade 3A) or pustules (grade 3B) covering more than 50% of the body surface, with severe symptoms that interfere with daily activities.
  • Cetuximab dose modification or treatment interruptions include the following.
    • First occurrence: Delay cetuximab infusion for less than 21 days until the skin rash improves to grade lower than 2. If the rash improves, continue at 250 mg/m2. If the rash does not improve, discontinue therapy.
    • Second occurrence: Delay cetuximab infusion for less than 21 days until the skin rash improves to lower than grade 2. If the rash improves, continue at a reduced dose of 200 mg/m2. If the rash does not improve, discontinue therapy.
    • Third occurrence: Delay cetuximab infusion for less than 21 days until the skin rash improves to lower than grade 2. If the rash does not improve, continue at a reduced dose of 150 mg/m2. If the rash still does not improve, discontinue therapy.
    • Fourth  occurrence: Discontinue therapy definitively.    
  • Topical treatment:
    • Antibiotics: Use clindamycin 1% gel, erythromycin 3% gel or cream, and metronidazole 0.75%–1% cream or gel BID until improvement to grade 1. Avoid benzoyl peroxide products. 
    • Use erythromycin 2% lotion for lesions of the scalp.
  • Systemic treatment:
    • Antibiotics include oral semisynthetic tetracyclines. Use minocycline or doxycycline 100 mg orally once per day for more than four weeks and until the rash is asymptomatic.
    • Corticosteroids: Use methylprednisolone 0.4 mg/kg orally or prednisone 0.5 mg/kg orally for up to 10 days.
  • Systemic treatment for grade 3, highly symptomatic or nonresponsive patients:
    • Retinoids: isotretinoin 0.3–0.5 mg/kg orally
    • Corticosteroids: methylprednisolone or dexamethasone via IV
    • Antihistamines: clorfenamine intramuscularly (IM) or via IV
    • Antibiotics: amoxicillin or clavulanic acid and gentamicin via IV

Management of Grade 4 Skin Rash:

  • Skin lesions include generalized rash with severe symptoms that require emergency treatment.
  • Discontinue therapy immediately and definitively.
  • Topical treatment:
    • Antibiotics: Use clindamycin 1% gel, erythromycin 3% gel or cream, and metronidazole 0.75%–1% cream or gel BID until improvement to grade 1. Avoid benzoyl peroxide products.
    • Use erythromycin 2% lotion for lesions of the scalp.
  • Systemic treatment:
    • Retinoids:  isotretinoin 0.3–0.5 mg/kg orally
    • Corticosteroids:  methylprednisolone or dexamethasone via IV
    • Antihistamines: chlorpheniramine IM or via IV
    • Antibiotics: amoxicillin or clavulanic acid and gentamicin via IV
    • Hydration via IV
    • Hospitalization

Xerosis, Fissures, and Eczema

Prevention:

  • General educational and prophylactic measures are important.
  • Regular use of emollient ointments, almond oil, and preparation of polyethylene glycol is recommended.

Management:

  • For eczema, use topical treatment with medium-potency corticosteroids for one to two weeks.
    • Betamethasone dipropionate 0.05%–0.1% cream
    • Clobetasone 0.05% cream
    • Ointment fluocinolone acetonide
    • Hydrocortisone butyrate 0.1% cream
    • Consider simple or occlusive dressing for the extremities.
    • Topical antibiotic is recommended for superinfection.
      • Fusidic acid 2% cream
      • Bacitracin cream
      • Mupirocin 2% cream

Paronychia

Prevention:

  • Avoid friction and pressure on the nail fold (e.g., avoid tight shoes).

Management:

  • Wash with antiseptics including diluted hydrochloric acids solution or boric acid solution 3%.
  • Use creams containing corticosteroids and antiseptics.
    • Betamethasone 0.05% plus clioquinol 3% ointment
    • Betamethasone 0.1% plus gentamicin 0.05% cream
    • Betamethasone 0.1% plus gentamicin 0.1% cream
    • Betamethasone valerate 0.1% plus fusidic acid 2% cream
    • Triamcinolone acetonide 3% plus chlortetracycline 0.1% ointment
    • Triamcinolone benetonide 2% plus fusidic acid 0.03% cream
  • Use oral antibiotics for superinfection.
    • Amoxicillin or clavulanic tablets
    • Cefalexin tablets
    • Clindamycin capsules
  • Use analgesic drugs (nonsteroidal anti-inflammatory drugs) orally.

Nursing Implications:

The use of cetuximab in treating colorectal and head and neck cancer has significantly affected patient outcomes. A strategic approach to managing skin toxicities that includes consensus recommendations from experts will guide clinicians in minimizing the incidence of skin rash, improve compliance, and optimize patient outcomes.

Nurses who will be managing grade 1 and 2 skin toxicities should receive education. In addition, use of a multidisciplinary approach when managing skin rashes is paramount. Facilities may choose to create algorithms as an effective strategy to establish consistent processes for the assessment and management of skin toxicities induced by EGFR-I therapy.

Potthoff, K., Hofheinz, R., Hassel, J.C., Volkenandt, M., Lordick, F., Hartmann, J.T., Karthaus, M., . . . Wollenberg, A. (2011). Interdisciplinary management of EGFR-inhibitor-induced skin reactions: A German expert opinion. Annals of Oncology, 22, 524–535.

doi: 10.1093/annonc/mdq387
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Purpose & Patient Population:

To provide interdisciplinary expert recommendations on how to treat patients with skin reactions undergoing anti–epidermal growth factor receptor (EGFR) treatment.

Type of Resource/Evidence-Based Process:

The task force prepared the first manuscript based on the data retrieved. All panel members were then asked to agree on a consensus statement following a period of meetings and discussions.

The search strategy included literature published until April 8, 2010, and data presented during the Annual Meeting of the American Society of Clinical Oncology (ASCO) 2008; the World Congress of Gastrointestinal (GI) Cancer, Barcelona 2008; the European Cancer Organisation–15 Congress 2008; ASCO GI 2009; and ASCO 2009.

Databases searched were MEDLINE, the Cochrane Library, Cochrane Central Register of Controlled Trials, and EMBASE: Drugs and Pharmacology.

Guidelines & Recommendations:

Acneform Rash:

  • Moisturize.
  • Begin topical antibiotic treatment (erythromycin, metronidazole, or nadifloxacin) twice daily for early-stage skin reactions.
  • Systemic treatment should be started if grade 2 or higher skin reactions occur. Oral tetracyclines (doxycycline or minocycline) are recommended.

Xerotic Skin:

  • Avoid hot showers and excessive use of soaps.
  • Return moisture by applying emollients.

Pruritus:

  • Skin moisturizer
  • Urea or polidocanol-containing lotions

Fissures:

  • Treat topically with propylene glycol 50% in water for 30 minutes under plastic occlusion every night, followed by application of hydrocolloid dressing.

Paronychia:

  • Daily antiseptic baths to avoid bacterial superinfection.

Dermatology Referral:

  • Lesions classified as grade 3 or higher should be managed collaboratively by an oncologist and a dermatologist.

Treatment Adjustments:

  • Perform if skin reaction is grade 3 or higher.

Prophylactic Treatment:

  • A number of unresolved issues remain, including whether or not to give prophylactic agents, and if given, whether to use topical or systemic approaches.

Nursing Implications:

To date, no evidence-based treatment algorithms exist for the management of these skin reactions. The most important conclusion from this panel is that EGFR-inhibitor–induced skin reactions can be effectively treated at all stages and grades. The panel recommends to intervene as early as possible at the first sign of dermatologic reactions. Basic skin care combined with a specific therapy adapted to the stage and grade of the skin reaction is recommended. Randomized phase 3 trials are needed to make recommendations on prophylactic treatment.

Reguiai, Z., Bachet, J.B., Bachmeyer, C., Peuvrel, L., Beylot-Barry, M., Bezier, M., . . . Bouche, O. (2012). Management of cutaneous adverse events induced by anti-EGFR (epidermal growth factor receptor): A French interdisciplinary therapeutic algorithm. Supportive Care in Cancer, 20, 1395–1404.

doi: 10.1007/s00520-012-1451-6
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Purpose & Patient Population:

To draft an algorithm for optimal management of cutaneous adverse events with epidermal growth factor receptor (EGFR)-inhibitors in patients receiving EGFR treatment.

Type of Resource/Evidence-Based Process:

The quality of publications was analyzed using the Oxford scale for methodology. Information about practices was collected through a questionnaire developed by a steering committee. The questionnaire was completed by 67 individuals including oncologists, gastroenterologists, and radiotherapists via regional meetings in seven towns in France, chaired by three to five local experts. A national meeting was held to build an algorithm. Participants comprised 20 members who were on the steering committee, were regional meeting chairs, and were in a bibliographic study group.

Databases searched were PubMed, Embase, and the Cochrane Collaboration. Reference lists of articles retrieved were manually searched.

Search keywords were EGFR inhibitor (and each specific drug name), skin toxicity, rash, acne, aceneiform, nail, paronychia, hair, alopecia, hirsutism, hypertrichosis, trichomegaly, xerosis, pruritus, and itch.

Inclusion and exclusion criteria were not stated.

Guidelines & Recommendations:

  • Recommendations regarding the use of preventive doxycycline on initiation of EGFR are level II. All other recommendations are level IV, expert opinion only.
  • Preventive measures on introduction of EGFR inhibitors include the following.
    • Systemic cyclines (doxycycline 100–200 mg per day, lymecycline 300 mg, or minocycline 100 mg) for at least six weeks
    • Moisturizing skin cream
    • Perfume-free cleanser with pH close to skin pH
    • Conventional photoprotection with clothing or an anti-ultraviolet with a sun protector factor (SPF) of 15 or higher
    • Cut nails straight, but not too short.
    • Nonaggressive shaving, with caution
    • Avoid harsh manicure or pedicure, ordinary soap, alcohol-based products, and physical irritation.
  • Provide care for folliculitis according to grade and paronychia according to the level of symptoms. Use the same types of interventions as outlined for prevention, with the addition of topical steroids in paronychia.
  • Additional recommendations with xerosis by grade are provided, including use of emollients (e.g., bath oil), occlusive dressing, and skin adhesive with fissures.
  • Topical steroids are not indicated for xerosis, and the efficacy of antihistamines has not been demonstrated.

Limitations:

  • Most recommendations had expert opinion–level evidence only, and comprised general skin and nail care recommendations.
  • The investigators noted that few data exist regarding dose reduction with EGFRs to evaluate the impact on skin lesions.
 

Nursing Implications:

This algorithm recommended prophylactic use of systemic cyclines with EGFR treatment across the board. Additional skin and nail care recommendations provided generally are seen elsewhere and are in agreement with expert consensus. A lack of clarity exists regarding dose reduction or treatment delays and the impact on skin symptoms. In addition, a lack of research evidence exists for interventions other than cyclines.

Research Evidence Summaries

de Noronha e Menezes, N.M., Lima, R., Moreira, A., Varela, P., Barroso, A., Baptista, A., & Parente, B. (2009). Description and management of cutaneous side effects during erlotinib and cetuximab treatment in lung and colorectal cancer patients: A prospective and descriptive study of 19 patients. European Journal of Dermatology, 19, 248–251.

doi: 10.1684/ejd.2009.0650
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Study Purpose:

To evaluate the effectiveness of treating epidermal growth factor receptor–inhibitor (EGFRI)-induced rash using a topical antibiotic or a combination of an antibiotic and benzoyl peroxide for grade 1 rash, or systemic treatment (oral antibiotics) for grade 2 or higher rash eruption.

Intervention Characteristics/Basic Study Process:

On initiation of EGFRIs, all patients started sunscreen, a mild skin cleanser, and oatmeal cream daily. Patients with a grade 1 rash were treated with a topical antibiotic or an antibiotic and benzoyl peroxide. Patients with a grade 2 or higher rash eruption were treated with systemic treatment (oral antibiotics).

Sample Characteristics:

The study reported on a sample of 19 patients with lung and colorectal cancer who initiated therapy with EGFRI agents (erlotinib or cetuximab) and had skin alterations.

Setting:

Portugal

Study Design:

This was a prospective, descriptive study.

Measurement Instruments/Methods:

  • Clinical and photographic evaluation
  • National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3

Results:

  • Eighteen of 19 patients developed a grade 2 rash.
  • Of those 18 patients, 50% had a complete response to treatment with tetracyclines (mainly doxycycline).
  • Only one patient had grade 3 rash, which did not respond to minocycline.
  • None of the patients had to stop treatment with EGFRI therapy.

Conclusions:

Tetracyclines were effective in completely resolving grade 2 EGFRI-induced rash in 50% of the sample.

Limitations:

  • This was a small, noncontrolled study.
  • No statistical analysis of the difference in prevalence rates was reported.

Gerber, P.A., Meller, S., Eames, T., Buhren, B.A., Schrumpf, H., Hetzer, S., ... Homey, B. (2012). Management of EGFR-inhibitor associated rash: A retrospective study in 49 patients. European Journal of Medical Research, 17(1), 4.  

doi:10.1186/2047-783X-17-4
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Study Purpose:

To compare the effectiveness of three established rash-management strategies in EGFR-inhibitor (EGFRI) associated rash development

Intervention Characteristics/Basic Study Process:

Rash severity was assessed during the initial presentation to clinic by applying the EGFR-Induced Rash Severity Score (ERSS). Three different EGFRI rash-management strategies were compared, and each targeted the inflammatory and/or the infectious characteristics of the rash. In stage 1 of the study, 21 patients (ERSS 10.3 to 77.9) were treated topically with mometasone furoate cream (a topical anti-inflammatory) twice daily. In stage 2 of the study, 23 patients (ERSS 12.5 to 67.1)  were treated topically with nadifloxacin 1% cream (a potent topical fluoroquinolone antibiotic) once daily in the morning, in combination with prednicarbate 0.25% cream (a topical glucocorticosteroid) once daily in the evening. In stage 3 of the study, five patients (ERSS > 50) received topical nadifloxacin and prednicarbate 0.25% cream in combination with the systemic retinoid isotretinoin 10–20 mg/day. Rash severity was reassessed after three weeks of specific therapy to manage the dermatologic reaction.

Sample Characteristics:

  • N = 49            
  • AGE = Not reported
  • MALES: Not reported, FEMALES: Not reported
  • KEY DISEASE CHARACTERISTICS: Not reported
  • OTHER KEY SAMPLE CHARACTERISTICS: (1) DRUG: Patients who were treated with either cetuximab (a monoclonal anti-EGFR antibody) or erlotinib (a small molecule EGFR tyrosine kinase inhibitor), and who developed an EGFRI-associated rash at the time of referral to the physician’s clinic. (2) TIMING: Selection was limited to initial patients, and their follow-up visits were made in the timeframe of March 2007 to October 2009. (3) RASH SEVERITY: Patients who presented with ERSS of 10 or higher.  

Setting:

  • SITE: Multi-site      
  • SETTING TYPE: Outpatient          
  • LOCATION: Germany

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active antitumor treatment

Study Design:

Retrospective, uncontrolled, comparative study

Measurement Instruments/Methods:

The EGFR-induced rash severity score (ERSS or WoMoScore) is a skin-specific scoring system that was introduced in 2008. The ERSS is a combined score of the severity of five different aspects of the EGFRI rash (i.e., color of erythema, distribution of erythema, population, postulation, and scaling crusts), and the extent of affected facial area and the total body area involved.  
 
ERSS score ranges are 0 (no skin reaction), 1–20 (mild), 21–40 (moderate), and more than 40 (severe). Rash severity was assessed during initial presentation to the clinic and at three weeks of specific therapy to manage the dermatologic reaction. Statistical analysis was performed using the Student’s t-test.   

Results:

Patients' EGFRI-associated rash severity improved significantly with all three dermatological treatments, which are aligned with recent expert recommendations: topical mometasone furoate cream (p = 0.00009); nadifloxacin 1% cream and prednicarbate 0.25% cream (p = 0.03); and nadifloxacin 1% cream and prednicarbate 0.25% cream plus systemic isotretinoin (p = 0.015).

Conclusions:

In summary, the results demonstrate that EGFRI-associated rashes can be effectively managed by specific dermatologic interventions, including topical glucocorticosteroids, topical antiseptics/antibiotics, and systemic retinoids. Topical mometasone furoate cream was the only therapy that resulted in a complete resolution of all rash symptoms in one patient.

Limitations:

  • Small sample (< 100)
  • Risk of bias (no control group)
  • Risk of bias (no blinding)  
  • Risk of bias (no random assignment)
  • Other limitations/explanation
    • For the sample population, age, sex, and diagnosis were not reported.
    • Statistical comparison of different therapy regimens is limited due to variations in patient numbers and rash severity in each of the three test groups before therapy. Specifically, group 3 had only five patients and the rash severity in all five patients was ERSS > 50 (severe).
    • The study design did not include a control group, which would have been a subgroup of patients with EGFRI rash that was left untreated for the study period (three weeks).
    • In the abstract, the authors state that mild to moderate rashes should be treated with basic measures in combination with other dermatologic treatments. In the discussion section, the authors state, “Notably, all approaches that were analyzed in this study are in line with recent expert recommendations that suggest an escalating strategy for the management of the EGFRI rash with a succession of treatments, as indicated, summarized as follows: intensive skin care in combination with mild cleansers ... .”   The components of “basic measures” or “intensive skin care” were not described, and whether intensive skin care and mild cleansers were included with the other interventions is not delineated in the article.
    • The ERSS system was designed with a non-linear affected area scale emphasizing minor variations in mild patients with face involvement only.   

Nursing Implications:

Nurses should consider treating mild to moderate EGFRI skin rashes with basic skin care measures in combination with topical glucocorticosteroids or combined regimens using glucocorticosteroids and antiseptics/antibiotics. Nurses should be aware that more severe or therapy-resistant rashes may respond with the addition of systemic retinoids.

Jatoi, A., Dakhil, S.R., Sloan, J.A., Kugler, J.W., Rowland, K.M., Jr., Schaefer, P.L., . . . Loprinzi, C.L. (2011). Prophylactic tetracycline does not diminish the severity of epidermal growth factor receptor (EGFR) inhibitor-induced rash: Results from the North Central Cancer Treatment Group (Supplementary N03CB). Supportive Care in Cancer, 19, 1601–1607.

doi: 10.1007/s00520-010-0988-5
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Study Purpose:

To attempt to confirm the benefit of the antibiotic tetracycline in decreasing the severity of epidermal growth factor receptor (EGFR)–inhibitor-induced rash.

Intervention Characteristics/Basic Study Process:

Eligible patients who were starting an EGFR inhibitor and were rash free were randomly assigned to tetracycline 500 mg orally BID for 28 days, versus placebo. Rash development and severity, quality of life, and adverse events were monitored during the four-week intervention and for an additional four weeks. The primary objective was to compare the incidence of grade 2 or worse rash between the study arms.

Sample Characteristics:

  • The study reported on a sample of 65 patients aged 18 years or older.
  • The sample was 63% male and 36% female.
  • All patients had a cancer diagnosis and were starting an EGFR inhibitor.

Phase of Care and Clinical Applications:

Patients were undergoing the active treatment phase of care.

Study Design:

This was a randomized, double-blind, placebo-controlled clinical trial.

Measurement Instruments/Methods:

  • Patients were monitored for rash severity by physician report using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.   
  • Patient-reported questionnaire regarding rash
  • Patient-reported quality of life as per the Skindex-16 questionnaire
  • Patient-reported series of linear analogue self-assessment (LASA) scales
  • Adverse events reported by the patient and physician
  • Patient diary regarding compliance with EGFR inhibitor consumption

Results:

  • The cumulative incidence of grade 2 or worse rash was comparable across study arms.
  • Quality of life also was not significantly different between study arms.

Conclusions:

This randomized, double-blinded, placebo-controlled study did not find that tetracycline decreased rash incidence or severity in patients who were taking EGFR inhibitors.

Limitations:

The sample size was small (fewer than 100 patients).

Nursing Implications:

Quality of life was comparable and tetracycline was well tolerated, but the current results did not support what prior studies had suggested.

Jatoi, A., Rowland, K., Sloan, J.A., Gross, H.M., Fishkin, P.A., Kahanic, S.P., . . . Loprinzi, C.L. (2008). 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.

doi: 10.1002/cncr.23621
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Study Purpose:

To compare the effectiveness of tetracycline 500 mg orally BID versus placebo for 28 days starting on day 1 of treatment with any epidermal growth factor receptor–inhibitor (EGFRI) agent to prevent or reduce EGFRI-induced rash in patients with cancer.

Intervention Characteristics/Basic Study Process:

Patients were randomized to either the tetracycline arm (500 mg orally BID for 28 days) or the placebo arm.

Sample Characteristics:

  • The study reported on a sample of 61 adult men and women with cancer.
  • Thirty-one patients were randomized to the tetracycline arm, and 30 patients were randomized to the placebo arm.
  • Median patient age was 71 years in the tetracycline arm and 63 years in the placebo arm.

Setting:

This study was a collaborative effort of the North Central Cancer Treatment Group (including centers in Illinois, Iowa, Kansas, South Dakota, and Ohio) and the Mayo Clinic (Rochester, MN).

Study Design:

This was a placebo-controlled, doubled-blind trial.

Measurement Instruments/Methods:

Three patient-reported assessments were used.

  • A brief rash incidence questionnaire
  • SKINDEX-16 questionnaire relevant to rash development and its implications on patients' quality of life (this tool was previously validated)
  • Questionnaire regarding patient compliance with EGFRI therapy

Those three questionnaires were completed at baseline and weekly for eight weeks after initiation of tetracycline or placebo. Oncologists performed an evaluation at the end of four weeks and eight weeks. The evaluation included a history and physical examination, an assessment of patient performance status, and an assessment of adverse events (e.g., gastrointestinal toxicity, rash development) as per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

Results:

  • At week 4, 70% of patients in the tetracycline arm (n = 16) and 76% of patients in the placebo arm (n = 22) developed a rash (p = 0.61).
  • At week 8, 87% of patients in the tetracycline arm (n = 13) and 84% of patients in the placebo arm (n = 16) developed a rash (p = 0.84).
  • By week 4, physician-reported grade 2 rash or rash covering more than 50% of body surface area (BSA) occurred in 17% of patients in the tetracycline arm (n = 4) and 55% of patients in the placebo arm (n = 16) (p = 0.04).
  • By week 8, when 44% of the cohort had dropped out, physician-reported grade 2 rash or rash covering more than 50% of BSA occurred in 27% of patients in the tetracycline arm (n = 4) and 47% of patients in the placebo arm (n = 9) (p = 0.5).
  • Of note, the worst physician reported rash (grade 3) occurred in one patient in the tetracycline arm.
  • Results of the SKINDEX-16 questionnaire did not demonstrate uniform, statistically significant differences, with a few exceptions. Tetracycline exerted positive effects on quality of life in four questions (skin itching, skin burning or stinging, skin irritation, and being bothered by a persistence or recurrence of the skin condition). Tetracycline exerted a negative effect on one question (bothered about being annoyed about your skin). No statistical significance was found for the remaining 11 questions.
  • Tetracycline was well tolerated with no significant difference in adverse events between study arms.

Conclusions:

Administration of tetracycline prophylactically did not significantly affect the incidence of rash development in patients receiving EGFRI drugs. Indicators suggest administration of tetracycline prophylactically may have a favorable influence with regard to rash severity in patients receiving EGFRI drugs. In addition, the results suggested these rashes bother patients, who must contend with itching, burning, and other types of skin irritation.

Limitations:

  • The sample size was relatively small.
  • The measurement method for clinician grading of rash symptoms was not described.
  • Six patients, including three patients from each study arm, stopped taking EGFRI medication within the first month because of the development of skin rash.

Katzer, K., Tietze, J., Klein, E., Heinemann, V., Ruzicka, T., & Wollenberg, A. (2010). Topical therapy with nadifloxacin cream and prednicarbate cream improves acneiform eruptions caused by the EGFR-inhibitor cetuximab–A report of 29 patients. European Journal of Dermatology, 20, 82–84.

doi:10.1684/ejd.2010.0806
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Study Purpose:

To evaluate the clinical efficacy of nadifloxacin and prednicarbate cream for treatment of cetuximab-induced acneiform eruptions

Intervention Characteristics/Basic Study Process:

Patients who had acneiform eruptions of varying severity were treated with nadifloxacin 1% cream and prednicarbate 0.25% cream once daily for six weeks. Patients continued their usual use of sunscreens, cleansers, and antihistamines. The severity of eruptions was scored at baseline and after one, two, and six weeks of treatment.

Sample Characteristics:

  • N = 29
  • MEAN AGE = 64.6 years (range = 38–89 years)
  • MALES: 76%, FEMALES: 24%
  • KEY DISEASE CHARACTERISTICS: All patients were receiving cetuximab

Setting:

  • SITE: Single site 
  • SETTING TYPE: Outpatient 
  • LOCATION: Germany

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active antitumor treatment

Study Design:

  • Open-label trial

Measurement Instruments/Methods:

Investigator developed skin score calculated from percentage body involvement, percentage facial involvement, and skin lesion scoring on a 3-point scale for erythema and other lesion characteristics.

Results:

A significant reduction in skin score was seen at all time points (p < .05). Subjective symptoms such as pruritus, pain, and tenderness were reported to be improved. The treatment was well tolerated. Two patients reported mild burning and erythema following application of the nadifloxacin cream.

Conclusions:

The combination of topical quinolone and corticosteroid was effective in reducing acneiform eruptions in this group of patients.

Limitations:

  • Small sample (< 30)
  • Risk of bias (no control group) 
  • Risk of bias (no blinding)  
  • Risk of bias (no random assignment)
  • Measurement validity/reliability questionable
  • Other limitations/explanation: The skin score used is well described, but validity and reliability is not clear.

Nursing Implications:

The combination of topical quinolone and steroid may be helpful in treating EGFR-inhibitor associated acneiform rash. This study had several methodological limitations, so it does not provide strong support. Further research in this combination is warranted.

Molinari, E., De Quatrebarbes, J., Andre, T., & Aractingi, S. (2005). Cetuximab-induced acne. Dermatology, 211, 330–333.

doi: 10.1159/000088502
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Study Purpose:

To evaluate the effectiveness of systemic antibiotic treatments (oral doxycycline) and local treatment for skin rash in patients receiving cetuximab.

Intervention Characteristics/Basic Study Process:

Patients were prospectively evaluated by dermatologists from two phase 2 trials between October 2003 and May 2004. Dermatologists determined they would treat four patients with oral doxycycline; in three of those patients, a topical treatment (retinoid) was given as well. Other patients were treated with benzoyl peroxide (n = 1) or fusidic acid (n = 1).

Sample Characteristics:

  • The study reported on a sample of 13 patients with metastatic colorectal cancer who were receiving cetuximab once per week (400 mg/m2 on week 1 and 250 mg/m2 thereafter).
  • The cetuximab treatment was associated with oxaliplatin, 5-fluorouracil, and fusidic acid, or irinotecan.

Setting:

Service de Dermatologie et Service d’Oncologie, Hôpital Tenon, in Paris, France

Study Design:

This was a prospective trial.

Measurement Instruments/Methods:

Rash intensity was graded as mild, moderate, or severe.

Results:

  • Eleven patients treated with cetuximab (85%) developed skin lesions.
  • The six treated patients responded to classical modalities of doxycycline (n = 4), benzoyl peroxide (n = 1), and fusidic acid (n = 1). Skin lesions resolved in four weeks.
  • Five patients were not treated because the acneform rash was mild. In those patients, the rash resolved spontaneously, although cetuximab was continued at the same dose.

Conclusions:

Antibiotic treatments (oral doxycycline) and local treatments given to six patients receiving cetuximab were effective in resolving skin lesions.

Limitations:

  • This was a very small, nonrandomized trial.
  • The description of the measurement tool or method used to grade rash symptoms was inadequate, with no reliability and validity.
  • Treatment was determined by the dermatologist.
  • A combination of interventions was used; therefore, determining the effectiveness of the individual interventions is difficult.

Scope, A., Agero, A.L., Dusza, S.W., Myskowski, P.L., Lieb, J.A., Saltz, L., . . . Halpern, A.C. (2007). Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. Journal of Clinical Oncology, 25, 5390–5396.

doi: 10.1200/JCO.2007.12.6987
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Study Purpose:

To compare the effectiveness of placebo versus minocycline 100 mg every day for eight weeks, beginning on day 1 of cetuximab infusion, to prevent or reduce cetuximab-induced rash in patients with metastatic colorectal cancer.

To compare the effectiveness of receiving tazarotene cream BID for eight weeks on one side of the patient’s face versus not receiving the topical treatment on the other side of the patient’s face.

Intervention Characteristics/Basic Study Process:

Twenty-four patients were randomized to the oral minocycline (100 mg per day) arm, and 24 patients were randomized to the oral placebo arm. Treatment was administered starting on day 1 of cetuximab therapy and continued for eight weeks.

All patients received open-label, topical tazarotene 0.05% cream (Tazorac®) application to one side of their face, starting on day 1 of cetuximab therapy and continuing for eight weeks.

Sample Characteristics:

  • The study reported on a sample of 48 adult men and women with stage IV metastatic colorectal cancer, who were preparing to initiate treatment with cetuximab.
  • Mean patient age was 61 years (range 39–83 years).

Setting:

  • Single center
  • Memorial Sloan-Kettering Cancer Center

Study Design:

This was a randomized, double-blind, placebo-controlled trial.

Measurement Instruments/Methods:

Follow-up clinical assessment was completed at weeks 1, 2, 4, and 8, with questionnaires and skin examination, including skin lesion counts and digital photos.

Results:

  • Initially, 48 patients were randomized in this study. At the end of the eight-week trial, 35 patients were included in the final analysis (18 patients in the minocycline arm and 17 patients in the placebo arm).
  • A significant overall difference existed in log lesion counts between the minocycline arm (fewer lesions) and the placebo arm (p = 0.005). The difference was apparent by week 1, peaked at weeks 2 and 4, and tapered by the end of the study (week 8).
  • At week 4, a decreased proportion of patients in the minocycline arm reported moderate-severe itch compared to those in the placebo arm.
  • Patients in the minocycline arm trended toward decreased frequency of moderate-severe rash compared to those in the placebo arm. Those differences diminished by week 8.
  • In four patients in the placebo arm (8%), cetuximab treatment was interrupted because of grade 3 dermatologic adverse events. Cetuximab treatment was not interrupted for any patients in the minocycline arm.
  • Topical treatment with tazarotene did not translate into a meaningful clinical benefit.
  • Of the 43 patients available for at least one clinical evaluation, 14 (33%) discontinued tazarotene prematurely as a result of local irritation.
  • Three additional patients (7%) reported stopping tazarotene after one month because of subjective lack of efficacy compared to the control side of the face.
  • In a review of facial photography at week 4 (n = 39), no difference existed in rash severity between the tazarotene and observation sides of the face (n = 34, 87%), and the rash was assessed as more severe in four patients (10%) who received tazarotene.

Conclusions:

Prophylactic treatment with minocycline appears to significantly decrease the severity of acneform rash during the first eight weeks of cetuximab therapy. Continuation of this therapy beyond eight weeks is not beneficial.

Results suggest that topical tazarotene has no role in the management of cetuximab-induced rash.

Limitations:

  • The sample size was small (48 at the start of the study; reduced to 35 by the end of eight weeks).
  • The measurement tool or method used to grade rash symptoms was not described.
  • A combination of interventions was used; therefore, determining the effectiveness of the individual interventions is difficult.

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