Li, J.R., Yang, C.R., Cheng, C.L., Ho, H.C., Chiu, K.Y., Su, C.K., . . . Ou, Y.C. (2013). Efficacy of a protocol including heparin ointment for treatment of multikinase inhibitor-induced hand-foot skin reactions. Supportive Care in Cancer, 21, 907–911. 

To evaluate the efficacy of a protocol including topical heparin therapy for hand-foot skin reactions (HFSR) during multikinase (MKI) treatment

Heparin Z ointment contains 500 IU unfractionated heparin sodium in each 1 g. Heparin, a member of the glycosaminoglycan family, has anti-inflammatory properties and is effective in the treatment of ulcerative wounds. All patients experiencing HFSR received mutifaceted care, including thick socks, shock-absorbing shoes, and topical treatment with heparin Z ointment (Zeria Pharmaceutical Co., Ltd., Japan), twice daily, integrated with urea-containing cream twice daily. Treatment with heparin Z ointment continued daily until grade of toxicity was downgraded to 0. All patients were seen monthly, and those with HFSR were seen weekly. Patients whose grade was downgraded to 0 were considered cured of HFSR. Treatment responders were recorded as the sum of cured and improved patients.

• N = 73 patients, 56 with metastatic renal cell carcinoma (MRCC) and 17 with castration-resistant prostate cancer (CRPC)  
• AGE = 26–86 years
• MALES: 80% of MRCC, 100% CRPC, FEMALES: 20% MRCC, 0% CRPC
• KEY DISEASE CHARACTERISTICS: CRPC and MRCC in patients eligible for MKI therapies
• OTHER KEY SAMPLE CHARACTERISTICS: Twenty-six patients developed HFSR, 16 developed MRCC, and 10 developed CRPC.

• SITE: Single site  
• SETTING TYPE: Not specified    
• LOCATION: Unclear, likely outpatient

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care

• Intent-to-treat study design of patients on MKI therapy

• Percentages reported of four groups of patients experiencing HFSR
• Analysis statistics not clearly defined

Of patients whose grading was downgraded to 0, the highest percentage was in the axitinib group (50%), while 31.8% of the sunitinib group were downgraded to 0, which equated to the cure of HFSR. Patients with CRPC had a higher response rate on sunitinib therapy (80% to MRCC of 66.7%). A higher rate of HFSR was seen in patients with CRPC treated with sunitinib than those with MRCC treated with sunitinib. Only four patients required MKI dose reduction, and none of the 26 patients who experienced HFSR dropped out.

This study provides a new protocol for the treatment of HFSR in patients on MKI therapies who experience HFSR. It would appear beneficial for keeping patients on treatment with minimal need to decrease the dose.

• Small sample (< 100)
• Baseline sample/group differences of import
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment) 
• Risk of bias (no appropriate attentional control condition)
• Unintended interventions or applicable interventions not described that would influence results
• Key sample group differences that could influence results
• Measurement/methods not well described
• Findings not generalizable
• The use of heparin Z ointment as an added intervention appears to improve outcomes, but no control existed to separate the intervention.
• The sample is too small for an intergroup analysis.
• No data on skin pathology or exclusion prior to initiated therapies exist.

Nurses are aware of the need for supportive care to decrease the incidence and severity of skin toxicities with MKI therapies. The use of heparin Z ointment as an additive intervention seems appropriate, particularly in light of heparin use in burned skin and wound healing. However, this study does not allow for inclusion as a new guideline intervention. More investigation with better designed trials is needed.