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.

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

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

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.

• 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.

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.

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

• 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.

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