# Abstract

 

## Purpose Actinic keratosis lesions (AKs) have the potential to develop into squamous cell carcinoma (SCC) and thus therapies to prevent SCC development from AKs are warranted. The aim of this study was to assess the effects of a 3 month application of a canola phenolic acid-based cream (CPA) on AK lesions. 

## Patients and methods This was a randomized, double-blind, placebo-controlled, 12 week clinical study conducted at a single-center in Santo Domingo, Dominican Republic. Forty-five subjects (30 CPA and 15 placebo), aged 45--85 years with 3--10 AKs within a 20 cm^2^ treatment area (scalp, forehead, dorsal forearm, neck, or back of hand) were enrolled. The primary outcome was complete or partial lesion clearance and the secondary outcome was safety of CPA. 

## Results Although complete AK lesion clearance was not seen in this study, a significant reduction in the mean change from baseline in the average lesion area was observed at weeks 3 ( *P*=0.002), 6 (*P*\<0.001), and 12 (*P*\<0.001) in the CPA group, but only at weeks 6 and 12 in the placebo group (*P*=0.005 and *P*=0.002, respectively). Furthermore, the proportion of participants with a $10% decrease in average lesion area was significantly higher in the CPA group than the placebo group at weeks 3 (*P*=0.05) and 6 (*P*=0.02), and showed a trend at week 12 (*P*=0.06). A subset analysis of the change in average lesion area based upon the total lesion area at baseline revealed that CPA elicited a greater reduction than placebo (2×) in participants with a baseline total AK lesion area of 100--500 mm^2^ than in participants with a total area \<100 mm^2^ (1.3×). 

## Conclusion The results of this study and previous in vitro studies suggest a potential role for CPA in the treatment of AK lesions and the prevention of SCC development. # Results 

## Participant disposition Forty-five eligible subjects (four male and 41 female) were randomized and 42 completed the study ([Figure 1](#)). Three of the 45 participants did not complete the entire treatment period because of loss to follow-up (N=1) or AEs (N=2) ([Figure 1](#)). All enrolled participants were white Hispanic except for one participant of Asian ethnicity. Participants ranged from 45 to 82 years of age and the mean age of those on CPA was 60.0±10.8 years and those on placebo 55.7±9.1 years ([Table 1](#)). All study participants had mild AK lesions and two participants in the CPA group had two moderate lesions along with mild lesions. There was no difference in body mass index, average AK lesion area or total lesion area between the treatment groups at baseline ([Table 1](#)). 

## Efficacy of CPA Although none of the study participants achieved complete clearance, decreases in average lesion area were seen with both CPA and placebo treatment ([Figure 2](#)). The CPA group showed almost twice the decrease in lesion size as the placebo group ([Figure 3](#)). The reduction was significant for both CPA and placebo groups at 6 (*P*\<0.001 and *P*=0.005, respectively) and 12 weeks (*P*\<0.001 and *P*=0.002, respectively), but only significant in the CPA group at 3 weeks (*P*=0.002). The difference in the week 6 change between the CPA and placebo groups approached statistical significance ( *P*=0.09). There was a decrease in average lesion area from week 12 to week 36 (post-treatment) in the CPA group (week 36 assessment was not performed in the placebo group), indicating that the improvement in the CPA group persisted beyond the treatment period ([Figures 2](#) and [3](#)). In the two participants with moderate lesions in the CPA group, lesions decreased to mild in severity at week 6, week 12, and follow-up at week 36. A greater proportion of participants in the CPA group than the placebo group showed a >10% decrease in average lesion size at week 3 (*P*=0.05) and week 6 (*P*=0.02) and showed a trend toward significance at week 12 ( *P*=0.06) ([Figure 4](#)). No difference was seen between the groups in the proportion of participants with>25% reduction in the average lesion size, but >50% reductions were observed only in the CPA group ([Figure 4](#)). Subset analyses based upon the baseline total lesion area (\<100 mm^2^, 100--249 mm^2^ and 250--499 mm^2^) showed differences in treatment response within certain total lesion size groups. Participants in the CPA group with a total lesion area \<100 mm^2^ demonstrated a 1.3× greater mean reduction in average lesion size than placebo (data not shown). Similarly, greater responses were observed for participants in the CPA group compared to placebo for total lesion areas 101--250 mm^2^ (1.9× reduction) and 251--500 mm ^2^ (2.0× reduction). The CPA group showed a trend toward higher prevalence of lesion scabbing, a sign of healing, after 12 weeks of treatment (6.8%) than those treated with placebo (1.3%, *P*=0.09). An analysis of lesion age on responsiveness to treatment suggests that CPA and placebo had comparable reductions in the average lesion area. Although these differences were not statistically significant, the number of years since lesion onset was found to influence the extent of lesion resolution. Average lesion area was examined for participants with lesion onset of ≤5 years, 5--10 years, ≤10 years, and >10 years. Greater reductions in lesion size were seen in the CPA group than the placebo group for all subsets and was found to be more pronounced in participants with lesion onset ≤10 years compared to those with onset >10 years (data not shown). 

## Safety analysis One serious adverse event, a parasitic amoeba infection was reported during this study in a participant receiving placebo. A total of 56 AEs (45 CPA, eleven placebo) were reported in 30 (20 CPA, ten placebo) out of the 45 participants in the safety population (30 CPA, 15 placebo). There were ten events (nine CPA, one placebo) among four participants (three CPA, one placebo) that were judged by the principal investigator to be probably or possibly related to the study product. Of these, five were skin-related, and the other five were eye, gastrointestinal, general, immune, and vascular disorders. The skin-related disorders occurred in three participants, two in the CPA group, and one in the placebo group. This difference was not statistically significant. Blood pressure was significantly reduced compared to baseline by a mean of 7.8 mmHg for systolic blood pressure (*P*=0.01) and a mean of 4.7 mmHg for diastolic blood pressure (*P*\<0.001) after 6 weeks of treatment with CPA. These changes were not clinically significant. No between-group differences were noted for heart rate, blood pressure or safety laboratory parameters with the exception of sodium concentration and red blood cell count. Sodium and red blood cell count were both significantly decreased in the CPA group as compared to the placebo group (*P*=0.02 and *P*=0.03, respectively). However, these changes were of small magnitude and not clinically important. No safety concerns were raised throughout the course of this study.


Extracted trial result:
Outcome: decrease in average lesion (continuous)
Intervention: application of a canola phenolic acid-based cream (CPA)
Comparator: placebo
Intervention group size: 30
Comparator group size: 15
Notes: no raw values given and can only be estimated from figure