Construction of a management and prevention program for targeted therapy-induced hand-foot skin reaction

Abstract

Aims:

To construct a management and prevention program for targeted therapy-induced hand-foot skin reactions (HFSR).

Design:

A systematic review with meta-analysis.

Methods:

Based on a literature review and expert consensus meetings, a two-round expert panel discussion involving 10 experts was conducted to finalize the HFSR management and prevention program.

Data sources:

Articles were systematically searched on the CNKI, Wanfang Database, VIP, PubMed, UpToDate, Embase, and Cochrane Library, and guideline publication websites, NGC, NCCN, NICE, SIGN and ESMO databases from inception up to June 2023.

Results:

The final program comprised 8 primary indicators, 16 secondary indicators, 36 tertiary indicators, and 54 quaternary entries. These include baseline level and hand-foot skin assessment, skin erythema care, skin keratosis care, skin blister management, skin ulcer care, skin pain management, management of other accompanying symptoms, and hand-foot protection and prevention education.

Conclusion:

This management and prevention program, constructed based on evidence and expert discussion, is scientifically sound and clinically applicable, providing reliable guidance for the management and prevention of HFSR in clinical practice.

Impact:

Based on the best available evidence for managing and preventing hand-foot skin reactions induced by targeted therapies, we recommend that nursing leaders implement personalized symptom management plans tailored to the common symptoms of these reactions. Such an approach may help in the early detection of hand-foot skin reactions and alleviate patients’ skin pain effectively.

Highlights

• This study is the first to develop the “Evidence-based management plan for hand-foot skin reaction caused by targeted drugs” through evidence-based methods, which is formulated according to the local cultural background and actual clinical situation. Additionally, this plan offers practical guidelines for clinical skin care practices and delivers personalized symptom management strategies for patients with hand-foot skin reactions.

• On the basis of extensive guidelines and consensuses on skin toxicity reactions caused by targeted drugs, the management evidence of hand-foot skin reaction caused by targeted drugs is scientifically and systematically summarized.

• In this study, we classified items according to common symptoms of hand-foot skin reaction. Compared to conventional nursing, this approach is more systematic and comprehensive, making it easier for clinical staff to learn and apply in practice.

1 Introduction

Hand-foot skin reaction (HFSR), different from traditional chemotherapy-induced hand-foot syndrome (HFS), refers to skin adverse reactions caused by targeted therapy. It is one of the most severe skin toxicities induced by anticancer drugs (1). The typical clinical feature of HFSR is excessive keratinization of the skin on the hands and feet. Other common clinical manifestations include varying degrees of palmar-plantar numbness, swelling, erythema, and burning pain (2). A meta-analysis of the incidence of targeted therapy-induced HFSR reported a total incidence range of 4.5 to 60.5%, with severe cases (grade ≥3) ranging from 1.8 to 21.6% (3). Dose reduction, drug discontinuation, or interruption of cancer treatment are the primary strategies to alleviate or eliminate the burden of HFSR symptoms, which significantly impact the treatment process and quality of life of cancer patients (4). Clinicians tend to focus more on the efficacy of targeted drugs rather than the skin adverse reactions they cause (5). Studies have shown that early prevention, treatment, and education can reduce the incidence and severity of HFSR (6). However, research on nursing interventions for HFSR patients is limited. Additionally, a comprehensive management program for HFSR is yet to be identified, and existing information is fragmented. Therefore, the present study integrates existing evidence from literature and expert clinical experience to develop a comprehensive management and prevention program for HFSR, to provide a scientific basis for healthcare professionals to implement early education and clinical interventions for this patient group.

2 Methods

2.1 Formation of the research team

The research team comprised 8 members, including one master’s supervisor in nursing (Master’s, Chief Nurse), two oncology nurse managers (Bachelor’s, Associate Chief Nurses), one wound and stoma specialist nurse (Bachelor’s, Nurse-in-charge), one oncology physician (Ph.D., Associate Chief Physician), two graduate students in oncology nursing, and one clinical graduate student in oncology surgery. The three master’s students and the wound and stoma specialist nurse conducted the literature search and evidence extraction, integration, and evaluation, and provided materials for the expert meetings. The master’s supervisor chaired the meetings and guided the overall program, while other members collaborated on program formulation and discussion.

2.2 Literature review

2.2.1 Literature search

The Chinese search terms included “Targeted Therapy/Molecular Targeted Therapy”; “Hand-Foot Skin Reaction/Palmar-Plantar Erythrodysesthesia/Hand-Foot Syndrome/Burgdorf Reaction”; “Symptom Management/Management/Nursing”; and “Clinical Practice Guidelines/Best Practices/Systematic Reviews/Expert Consensus/Randomized Controlled Trials/Quasi-Experimental Studies/Cohort Studies.” The English search terms included “Targeted therapy/molecular targeted therapy”; “Hand-foot skin reaction/hand-foot redness and swelling acral erythema/hand-foot syndrome/Burgdorf reaction”; “Symptom management/management/care”; and “Clinical Practice Guide/Best Practice/System Overview/Expert Consensus/Randomized Controlled Study/Quasi-Experimental Study/Cohort Study.” Relevant databases, China National Knowledge Infrastructure (CNKI), Wanfang Database, VIP Database, PubMed, UpToDate, Embase, and Cochrane Library, and guideline publication websites, including the National Guideline Clearinghouse (NGC), National Comprehensive Cancer Network (NCCN), National Institute for Health and Care Excellence (NICE), Scottish Intercollegiate Guidelines Network (SIGN), and European Society for Medical Oncology (ESMO), were systematically searched using a combination of subject terms and free-text terms.

2.2.2 Inclusion and exclusion criteria

Inclusion criteria: Studies involving cancer patients taking targeted drugs; research content including the prevention and management of HFSR; and publications including guidelines, evidence summaries, systematic reviews, expert consensus, basic clinical research trials, etc. Exclusion criteria: Inability to obtain full texts; low-quality literature; and duplicate literature entries. Priority was given to evidence-based, high-quality, and recent publications.

2.2.3 Quality assessment criteria

The quality of the literature was assessed by two nursing graduate students trained in evidence-based research. Any discrepancies were resolved through consensus discussion with a third party. The Appraisal of Guidelines for Research & Evaluation II (AGREEII) tool was used to assess the quality of guidelines (7); the Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) tool was used to evaluate the quality of systematic reviews (8, 9); randomized controlled trials, cohort studies, expert consensus, and opinions were assessed using appropriate tools from the Joanna Briggs Institute (JBI) for Evidence-Based Healthcare (9).

2.2.4 Evidence extraction, integration, and evaluation

The evidence was graded and recommended using the Joanna Briggs Institute (JBI) Levels of Evidence and Grades of Recommendation system (2014). The included evidence was classified according to the type of study design, with levels ranging from 1 to 5, from highest to lowest quality. Based on the clinical significance, feasibility, effectiveness, and appropriateness of the evidence, the strength of recommendations was determined as Grade A (strong recommendation) and Grade B (weak recommendation). After integration and refinement, a preliminary symptom management and prevention plan for targeted therapy-induced HFSR was developed.

2.3 Expert meetings

2.3.1 Selection of meeting participants

Experts were selected using purposive sampling. Inclusion criteria for experts were as follows: (1) professionals engaged in cancer treatment and nursing, with rich knowledge and experience in the field; (2) at least 10 years of work experience; (3) holding a bachelor’s degree or higher; (4) having a professional title of intermediate level or above; (5) able to provide valuable and constructive opinions and suggestions, willing to participate in the study, and capable of completing two rounds of high-quality meetings on time.

2.3.2 Expert meeting planning and facilitation

The expert meeting materials were self-designed as follows:

Expert Meeting Notice: A brief introduction to the background and significance of the study, the process, and the purpose of the meeting.

Self-Evaluation Form: Information on the general situation of the experts, their familiarity with the questionnaire content, and their understanding of the field.

Expert Opinion Consultation Form: Experts rated the “feasibility” and “importance” of primary and secondary indicators in the plan. A Likert five-point scale was used, with 1 point indicating “not important/not feasible” and 5 points indicating “very important/very feasible.” Additionally, each indicator had a suggestion box for experts to provide modifications, additions, or deletions to the content.

Meeting Process: During the meeting, a project leader chaired the session, introducing the background and process of the meeting and explaining the source and scoring instructions for each item in the plan. The main consultation content included: reviewing the general framework of the evidence-based symptom management plan for targeted therapy-induced HFSR and determining whether the detailed content of each item needs optimization or correction.

A preliminary management and prevention plan was developed. After two rounds of expert group discussions, the content of the item pool was revised and summarized based on expert opinions, ultimately forming the symptom management plan for targeted therapy-induced HFSR. Researchers guided the experts without subjective or suggestive prompts to evaluate and discuss the feasibility, applicability, and clinical significance of each piece of evidence based on their work experience and clinical application. Another researcher recorded the meeting and took detailed notes on the discussion.

2.4 Statistical analysis

The results of the two rounds of expert meetings were organized and analyzed using Excel and SPSS 25.0 software. Quantitative data were expressed as mean ± standard deviation and coefficient of variation, whereas categorical data were presented as frequency and composition ratio. The authority coefficient of the experts (Cr) was determined by the coefficient of judgment basis (Ca) and the coefficient of familiarity (Cs). The Cr was calculated using the following formula: Cr = (Ca + Cs)/2.

3 Results

3.1 Basic characteristics of included literature

A total of 469 articles were retrieved and imported into Endnote X8 for deduplication, resulting in 56 articles. After screening the article titles, abstracts, and inclusion/exclusion criteria, 15 articles were included in the final analysis, of which 3 were guidelines (10–12), 2 were systematic reviews (13, 14), 1 was best evidence summary, 6 were expert consensus/opinions (15–20), and 3 were randomized controlled trials (21–23). All three guidelines were rated as Grade A based on quality assessment. The two systematic reviews were rated as “no” for items 7 and 8, whereas the remaining items were rated as “yes.” All six items evaluating the authenticity of the expert consensus/opinions were rated as “yes.” Two randomized controlled trials were rated as “no” for item 5; one trial with an “unclear” rating for items 2 and 3, was rated as Grade B quality, whereas the other trial with a “yes” rating for all items, was rated as Grade A. The general characteristics of the included literature are presented in Table 1.

3.2 General information of experts

Ten experts from three tertiary hospitals in Zhejiang Province were enrolled, of whom 2 were chief physicians, 3 were associate chief physicians, 1 was an attending physician, 1 was a director of the nursing department, 2 were head nurses, and 1 was a specialist nurse in wound and stoma care. The average age was 42.5 ± 5.43 years, ranging from 33 to 52 years. The average years of work experience was 17.8 ± 7.31, ranging from 13 to 31 years. Among them, 3, 6, and 1 held bachelor’s, master’s, and doctoral degrees, respectively. The response rate to the pre-meeting emails was 100%, and the attendance rate at formal meetings was 100%. All experts provided modification suggestions, demonstrating high enthusiasm. The Ca, Cs, and Cr of the two rounds of expert consultation were 0.9125, 0.825, and 0.866, respectively. This confirms a high level of expert authority, supporting the credibility and reliability of the results.

3.3 Suggestions from participating experts on the draft plan

During the meetings, all experts actively participated in the discussions. The experts highlighted the symptom management and prevention plan for HFSR should align with the actual conditions of HFSR patients and clinical practices in China to enhance its clinical guidance value. The summarized suggestions and opinions are as follows:

3.3.1 Modifications

Throughout the document, replace “podiatrist” and “orthopedist” with “foot clinic doctor” to better reflect the standard practice in most hospitals in China, in accordance with the experts’ recommendations. Moreover, revise the blister treatment from a 0.2% benzalkonium chloride solution to povidone-iodine disinfection.

Replace quality of life assessment scales Skindex or Dermatology Life Quality Index with the latest HFSR quality of life assessment scale HF-QoL, adopting the expert’s suggestion.

Change use systemic analgesics (e.g., NSAIDs, codeine, pregabalin, β-aminobutyric acid agonists, anesthetics) and assess bleeding and renal function before use” to “if local drug control is ineffective, systemic analgesics mainly include celecoxib, and if pain intensifies, codeine, pregabalin, or tramadol may be added as appropriate, with liver and kidney function assessed before use.

Replace soak feet in magnesium sulfate to relieve pressure pain with use magnesium sulfate cold spray for local pain relief.

3.3.2 Additions

“Use flurbiprofen gel patches (Babu patches) for pain relief.”

In managing inflammation associated with infection, it is essential to first assess the infection status. If a local infection is present, topical antibiotics such as erythromycin or penicillin ointment should be applied. In cases where systemic infection signs, such as fever, are observed, appropriate oral or intravenous antibiotics should be administered.

To manage unbroken blisters, add small blisters that do not require treatment. Consolidate desquamation, peeling, exudation, bleeding, and inflammation with infection into the management of other accompanying symptoms as a primary indicator.

Recommend psychological care and dietary guidance. Specifically, healthcare professionals should provide psychological counseling and support and, guide patients should avoid spicy and irritating foods, which are common clinical guidance contents for such patients, adopting the experts suggestion.

3.3.3 Deletions

• Remove: “Apply glycolic salicylic acid exfoliating cream to the hyperkeratotic areas of the soles at night to keep the skin soft” as it is repetitive with another entry.

• Remove: In the oral medication intervention section, delete “use low to moderate dose analgesics; apply sunscreen spray to affected areas when needed.”

• Remove: In the footwear recommendations, delete “apply sunscreen to the feet.” This does not align with our national conditions, based on expert recommendations.

3.3.4 Other suggestions

• Suggestion: Move the primary entry “Hand and Foot Protection Education” under “Baseline and Hand-Foot Skin Assessment” to emphasize the importance of health education for HFSR prevention, based on expert recommendations.

• Suggestion: Classify the primary entries according to common HFSR symptoms rather than HFSR grading. This will enable clinical practitioners to perform targeted nursing interventions based on the patient’s actual symptoms, adopting the experts’ suggestions.

3.3.5 Consolidation of expert opinions

• Integrated three expert opinions.

• Merged six entries.

• Deleted 11 entries or redundant content within entries.

• Added eight entries.

• Adjusted the names of eight indicators.

• Proposed three structural adjustments to the plan.

• Ultimately, formed a 52-item management and prevention plan for targeted therapy-induced HFSR symptoms, of which 16 items were classified as Grade A and the remaining as Grade B (Table 2).

4 Discussion

4.1 Clinical significance of the plan

The availability and accessibility of targeted drugs have greatly increased in recent years. The National Healthcare Security Administration is also advocating for the inclusion of antitumor-targeted drugs in the national medical insurance catalog and has introduced several support policies, such as the 2009 “Opinions of the Central Committee of the Communist Party of China and the State Council on Deepening the Reform of the Medical and Health System” (Zhongfa [2009] No. 6) and the 2015 “Pilot Work Plan for Establishing a Drug Price Negotiation Mechanism (Draft for Comments)” (24) by the National Health Commission. The advent of targeted therapy has expanded the range of adverse reactions associated with cancer treatment. In addition to common side effects such as nausea, vomiting, constipation, diarrhea, and organ involvement, new skin toxicities present new challenges for clinical healthcare workers. The mechanism and risk factors of HFSR are yet to be clearly defined. Notably, the occurrence and severity of HFSR are dose-dependent. The continuous use of targeted drugs necessitates effective and scientific handling by healthcare workers, along with the active coping efforts of patients, to manage the symptoms effectively. Early preventive education for patients is crucial to reduce discomfort and prevent complications caused by symptoms.

The primary entries established in the present study include baseline and hand-foot skin assessment, skin erythema care, skin keratosis care, skin blister management, skin ulcer care, skin pain management, management of other accompanying symptoms, and hand-foot protection education, clearly categorizing each treatment measure. To prevent any omissions, a thorough search was conducted utilizing all targeted drug names as keywords. This approach aimed to investigate adverse reactions and identify potential derive intervention measures for HFSR. There is currently no specific nursing plan for HFSR symptom management and prevention, and clinical nursing interventions for HFSR are relatively few. Therefore, extensively soliciting and considering expert opinions is paramount.

A multidisciplinary team was formed during expert panel member selection, including experts from oncology, dermatology, pain management, and wound and stoma care. Such a collaborative multidisciplinary team can provide optimal care and support for cancer patients and their families. The selected experts for this study demonstrated a high level of familiarity with the content and a strong basis for their judgments, indicating good authority and representativeness. All experts provided suggestions and opinions in the two rounds of expert meetings, achieving a 100% positive response rate. The constructed plan is thus practical and valuable for healthcare practitioners.

4.2 Scientific and clinical applicability of the plan facilitates subsequent evidence translation research

With the advancement of molecular technology, targeted drugs have become suitable for the treatment of most tumors (25–27). However, these drugs are associated with a high incidence of skin adverse events, with HFSR being the most common and severe. This significantly impacts the physical and mental health, social well-being, and quality of life of patients, potentially leading to dose reduction or even discontinuation of the medication due to the body’s inability to tolerate these adverse reactions (28). So far, no study has systematically integrated HFSR symptom management and prevention. In addition, existing guidelines have only summarized all targeted therapy-induced skin toxicities without specificity, leading to scattered information on HFSR, which makes it difficult to draw comprehensive conclusions. Management and prevention of HFSR symptoms remain a pressing clinical issue. Introducing evidence into clinical settings and localizing, tailoring, organizing, and integrating this evidence is crucial for its clinical application (29).

Most of the included literature consisted of international guidelines and expert consensus. Given the differences in medical resources, local cultural backgrounds, and the specific needs and baseline characteristics of patients in China, expert meetings were conducted to adjust the content of the plan. For instance, since most hospitals in China do not have dedicated podiatrists and orthotists, the term was revised to “podiatry clinic doctors” in the program. In the original item 2.3.3.2, the suggestion to “apply sunscreen to the feet” was deleted, as patients with HFSR often use protective measures such as wearing thick cotton socks, making this recommendation unsuitable for Chinese patients. Additionally, references to medium- and high-potency corticosteroids in the original plan were changed to hydrocortisone, fluocinolone, and betamethasone propionate, which are frequently used in most hospitals in China. The current study strictly adhered to evidence-based principles, employing scientific and rigorous methods for evaluating the quality of literature. The entire procedure, comprising literature retrieval, evidence extraction, and indicator grading, was carried out independently and objectively by two individuals. This approach ensured the authenticity and reliability of the process.

Related studies indicate an imbalance between patients’ needs for coping with HFSR and the professional support provided by clinical healthcare personnel (30). The present study accounted for the needs of stakeholders, systematically listing the assessment and symptomatic treatment of each common HFSR symptom. Through the expert meeting method, the feasibility and appropriateness of each item were assessed, incorporating the opinions and suggestions from experts’ extensive clinical experience and research in the field. This approach narrows the gap between evidence and actual clinical practice, facilitating evidence translation.

5 Conclusion

In summary, nurses play a crucial role in managing patients’ skin toxic reactions and are ideally positioned to provide supportive care throughout the cancer treatment process. The goal of nursing management is to maintain treatment adherence and improve the quality of life of the patient through proactive and preemptive approaches. This study integrated more high-quality randomized controlled trials and relevant expert guidelines to develop the best management plan for patients with targeted therapy-induced HFSR. However, some of the included literature is relatively outdated, requiring careful discernment and judgment in content extraction. Further clinical application is needed to verify the effectiveness of this plan, and large-scale prospective randomized trials should be conducted to provide more insights into the management of HFSR.

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