COX-2 inhibitors are a type of nonsteroidal anti-inflammatory drug that directly affects COX-2, an enzyme involved in inflammation and associated pain. The use of COX-2 inhibitors was evaluated in patients with cancer related to the development of palmar-plantar erythrodysesthesia (PPE) skin effects and as a potential treatment for oral mucositis.
Effectiveness Not Established
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
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
- 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
Research Evidence Summaries
Zhang, R.X., Wu, X.J., Lu, S.X., Pan, Z.Z., Wan, D.S., & Chen, G. (2011). The effect of COX-2 inhibitor on capecitabine-induced hand-foot syndrome in patients with stage II/III colorectal cancer: A phase II randomized prospective study. Journal of Cancer Research and Clinical Oncology, 137, 953–957.doi: 10.1007/s00432-010-0958-9
Capecitabine is hypothesized to cause overexpression of COX-2 in tumor and healthy tissue, inducing hand-foot syndrome (HFS). This prospective clinical trial will address whether the addition of a COX-2 inhibitor plus capecitabine can decrease or ease HFS.
Intervention Characteristics/Basic Study Process:
Patients were randomly assigned to adjuvant treatment with capecitabine plus oxaliplatin or capecitabine alone, with or without celecoxib. The COX-2 inhibitor dose was 200 mg/m2 BID in combination with capecitabine for 14 days. Adverse events were monitored continuously during treatment and for 30 days after the last dose of study drug. The intensity of adverse events was graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
- The study reported on a sample of 101 patients with colorectal cancer.
- Patients were aged 18 years or older.
- The sample was 56% male and 43% female.
- Patients were postcurative surgery and eligible for adjuvant chemotherapy with capecitabine-based therapy.
- Single site
Republic of China
Phase of Care and Clinical Applications:
Patients were undergoing the active treatment phase of care.
This was a randomized, prospective phase 2 clinical trial.
HFS was evaluated according to the NCI CTCAE, version 4.0.
- Patients in the capecitabine plus celecoxib group had a significantly reduced frequency of HFS higher than grade 1 (p < 0.001) and grade 2 (p = 0.024) compared to patients in the groups without celecoxib.
- No significant differences existed between groups in grade 3 HFS.
Celecoxib was safe and convenient for patients receiving chemotherapy and reduced the incidence of lower grade HFS.
- The study was a phase 2 trial and was not placebo controlled.
- The study was no blinded.
- Why lower grade HFS would be affected whereas no differences occurred in higher grade HFS between groups is unclear. This raises questions over the reliability of HFS toxicity grading. The authors stated the incidence of HFS in this study was higher than that reported elsewhere, which may have been caused by the fact that they defined grade 1 HFS as any slight pigmentation change.
- Who did the grading was not described.
In the correct population of patients, COX-2 inhibitors can be suggested. Additional research in this area is warranted.
Zhang, R.X., Wu, X.J., Wan, D.S., Lu, Z.H., Kong, L.H., Pan, Z.Z., & Chen, G. (2012). Celecoxib can prevent capecitabine-related hand-foot syndrome in stage II and III colorectal cancer patients: Result of a single-center, prospective randomized phase III trial. Annals of Oncology, 23, 1348–1353.doi: 10.1093/annonc/mdr400
To compare the incidence and severity of hand-foot syndrome (HFS) in patients who received capecitabine with and without celecoxib.
Intervention Characteristics/Basic Study Process:
Patients were randomized to receive oral celecoxib 200 mg BID or no intervention. Sampling was stratified based on the specific chemotherapy regimen used. Patients were educated on how to prevent side effects of therapy and monitored weekly with telephone calls and monthly clinic visits.
- The study reported on a sample of 139 patients with colorectal cancer.
- Mean patient age was 58 years.
- The sample was 60% male and 40% female.
- Some patients received oxaliplatin as well as capecitabine.
- Single site
Phase of Care and Clinical Applications:
Patients were undergoing the active antitumor treatment phase of care.
This was a randomized, prospective trial.
National Cancer Institute (NCI) common toxicity criteria (CTC), version 4
- The incidence of grade 1 to 2 HFS was lower in the celecoxib group (p < 0.05).
- The mean number of chemotherapy cycles before development of HFS was 4.336 in the celecoxib group versus 5.852 in the control group (p < 0.001).
- No adverse events were associated with use of celecoxib.
Celecoxib as used in this trial may delay the onset and severity of HFS in patients receiving capecitabine-based chemotherapy. In addition, celecoxib was not associated with adverse events.
- No subgroup analysis was conducted between patients who received the two different chemotherapy regimens included; therefore, whether those differences would have affected results is unclear.
- The timeframe and sample characteristics of this study were similar to those of another publication from this group that stated a different sample size and method of HFS rating. Whether this study incorporated the same group of patients is unclear.
- Risk of bias existed in the study design because of the lack of blinding and an appropriate attentional control condition.
Use of anti-inflammatory medications such as celecoxib may help delay the onset and severity of HFS in patients receiving capecitabine-based chemotherapy. In addition, no adverse events were reported with use as long as six months.