Journal of Clinical and Aesthetic Dermatology

OCT 2017

An evidence-based, peer-reviewed journal for practicing clinicians in the field of dermatology

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32 JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY October 2017 • Volume 10 • Number 10 O R I G I N A L R E S E A R C H clearance. This difference in clearance rate (17% vs. 69%) was also statistically significant (P<0.0001) (Figure 3) and demonstrates the efficacy of the treatment. Finally, when comparing the original study with this extension study, the overall difference in clearance rates of all clinical and subclinical lesions (79% vs 69%) that received treatment was not statistically significant (P=0.2336) (Figure 4) and again emphasizes that the medication was effective in treating field cancerization. LSRs were assessed as mild in 12 patients, moderate in two patients, and severe in one patient. There was no statistically significant correlation between LSR severity and clearance. DISCUSSION Our original study, published in 2016, was innovative in that we correlated noninvasive imaging with histopathology and revealed the concept of field cancerization beyond what can be visualized clinically. After performing biopsies on areas that appeared normal ("subclinical lesions"), we found that 79 percent of these normal-appearing areas actually contained actinic damage, which was clearly diagnosed on OCT. This finding demonstrated the importance of noninvasive imaging in diagnosing early precancerous lesions that would otherwise go unnoticed. Based on the high correlation between histopathologic and OCT diagnoses (100% for clinical lesions and 79% for subclinical lesions), we were able to monitor reliably the response of clinical and subclinical lesions that were either treated with ingenol mebutate 0.015% or left untreated. Considering that some AKs can be refractory to cryotherapy, 13 the findings in our original study prompted us to pursue an extension study to assess the durability of clearance after one year and offer patients the benefit of clearing their originally untreated lesions. In addition to knowing that they can treat AKs effectively, it is also important to clinicians to know that lesion clearance can be maintained long term. Among treated lesions, we found that there was no statistically significant difference in the average number of treated clinical and subclinical lesions between the end of the original study and the beginning of the extension study, which suggests that clearance was maintained throughout 12 months. In contrast, the majority of lesions not treated in the original study, both clinical and subclinical (which represent the field of cancerization), were still largely present one year later. However, once these same areas subsequently received treatment in the extension study, they exhibited a clearance rate of 69 percent. The difference between these clearance rates (17% vs 69%) was statistically significant. For overall clearance rates, the difference between those rates in the original study and the extension study (79% vs 69%) was not statistically significant, thereby suggesting that we achieved similar levels of efficacy in both studies. In a similar study conducted by Lebwohl et al that assessed the 12-month recurrence rates following treatment of AK on the face or scalp with ingenol mebutate gel 0.015%, 14 there was a sustained clearance rate of 46 percent at one year after lesions had been treated and an overall reduction in the number of lesions. Another long-term follow-up study of AKs after treatment was conducted by Garbe et al, who enrolled 450 patients with 4–8 clinically visible AKs on the face or scalp. 15 These patients were also treated with ingenol mebutate gel 0.015%, and they received follow-up at 26 and 44 weeks. After the initial treatment, 277 patients (61.6%) were completely clear at Week 8, 141 had persistent AKs at Week 8, and 62 had emergent AKs at Week 26 or Week 44. Those patients with emergent AKs were then randomized and treated with ingenol mebutate gel or vehicle. Complete clearance rates were s ignificantly higher with ingenol mebutate than with vehicle (59.5% vs 25.0%; P=0.01), demonstrating a long-term benefit of ingenol mebutate for initial and follow-up treatment of AKs. An interesting finding in both our original study and the extension study involved treatment-resistant lesions, as they provided insight into characteristics of AKs that might render some lesions more refractory to FIGURE 5. Optical coherence tomography (OCT) images of nonclearing actinic keratosis (AKs)—(A) prior to treatment, (B) following treatment (Day 60 of the original study), and (C) when evaluated at the start of the extension study 12 months later; during all stages, AKs featured characteristics seborrheic keratoses, with areas of thickened and very well-defined architectural plateaus (yellow arrows)

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