Treatment of palmar-plantar erythrodysesthesia (PPE) with topical sildenafil: a pilot study

Abstract

Purpose: Palmar-plantar erythrodysesthesia (PPE) is a common chemotherapy and anti-VEGF multi-kinase inhibitor class-related toxicity that often results in debilitating skin changes and often limits the use of active anti-cancer regimens. Mechanistic and anecdotal clinical evidence suggested that topical application of sildenafil cream may help reduce the severity of PPE. Therefore, we conducted a randomized, double-blind, placebo-controlled pilot study to evaluate the feasibility, safety and efficacy of topical sildenafil cream for the treatment of PPE.

Methods: Eligible subjects were required to have grade 1-3 PPE associated with either capecitabine or sunitinib. Subjects were randomized to receive 1 % topical sildenafil cream to the left extremities or right extremities and placebo cream on the opposite extremity. Two times per day, 0.5 mL of cream was applied to each affected hand/foot. The primary endpoint was improvement in PPE grading at any point on study. Clinical assessments were evaluated by NCI-CTC 4.0 grading and patient self-reported pain.

Results: Ten subjects were enrolled, nine were evaluable for safety and efficacy. Five of nine subjects reported some improvement in foot pain and three of eight subjects for hand pain improvement. One of these subjects noted specific improvement in tactile function. No treatment-related toxicities were observed.

Conclusions: In this limited, single-center study, topical cream containing 1 % sildenafil is feasible to administer, is well-tolerated, and may mitigate PPE-related symptoms due to anti-cancer therapeutic agents. Further validation is necessary.

Conflict of interest statement

Conflict of Interest

The authors have no financial conflicts of interest to disclose and have full control of all primary data. The authors agree to allow the journal to review the data if requested.

Figures

Figure 1

Figure 1

Figure 2. Patterns of Pain Reporting

Placebo pain scores were graphed to assess parameters that influenced pain reporting. X axis represents days on treatment; Y axis represents mean placebo pain scores for all patient extremities (n=9 for hands, n=8 for feet). Pain scores used a scale of 1–10, 0 (none) to 10 (severe). A.) For the amount of pressure, the solid line represents pain scores at rest, the dotted line represents pain scores when stressed. B.) For type of extremity, the solid line represents feet pain scores; the dotted line represents hand pain scores.

Figure 2. Patterns of Pain Reporting

Placebo pain scores were graphed to assess parameters that influenced pain reporting. X axis represents days on treatment; Y axis represents mean placebo pain scores for all patient extremities (n=9 for hands, n=8 for feet). Pain scores used a scale of 1–10, 0 (none) to 10 (severe). A.) For the amount of pressure, the solid line represents pain scores at rest, the dotted line represents pain scores when stressed. B.) For type of extremity, the solid line represents feet pain scores; the dotted line represents hand pain scores.

Figure 3. Evaluation of Study Cream Efficacy

Mean differences in pain scores are shown for each extremity in the AM: A) stressed and rested feet and B) stressed and rested hands. Each bar represents one individual. The average of the difference was calculated across the first 40 days on protocol. Difference in pain score was defined as placebo minus active score; thus, efficacy of the treatment is reflected by a positive difference.

Figure 3. Evaluation of Study Cream Efficacy

Mean differences in pain scores are shown for each extremity in the AM: A) stressed and rested feet and B) stressed and rested hands. Each bar represents one individual. The average of the difference was calculated across the first 40 days on protocol. Difference in pain score was defined as placebo minus active score; thus, efficacy of the treatment is reflected by a positive difference.

Figure 3. Evaluation of Study Cream Efficacy

Mean differences in pain scores are shown for each extremity in the AM: A) stressed and rested feet and B) stressed and rested hands. Each bar represents one individual. The average of the difference was calculated across the first 40 days on protocol. Difference in pain score was defined as placebo minus active score; thus, efficacy of the treatment is reflected by a positive difference.

Figure 3. Evaluation of Study Cream Efficacy

Mean differences in pain scores are shown for each extremity in the AM: A) stressed and rested feet and B) stressed and rested hands. Each bar represents one individual. The average of the difference was calculated across the first 40 days on protocol. Difference in pain score was defined as placebo minus active score; thus, efficacy of the treatment is reflected by a positive difference.

Figure 4. Pain Improvement for Patient 7

Daily pain scores are plotted for patient 7 with pain improvement on treatment for stressed feet. X axis represents days; Y axis represents daily pain scores The solid line represents pain scores on the foot with study cream; the dotted line represents the pain score for the foot receiving placebo cream.