UNTHSC RAD Theme REFERENCES COMBINATION THERAPY WITH SHORT CONTACT TOPICAL CALCIPOTRIENE FOAM AND FLUOROURACIL FOLLOWING CRYOTHERAPY FOR ACTINIC KERATOSIS • Actinic keratoses (AKs) are lesions characterized by a proliferation of dysplastic keratinocytes that occur on photoaged skin as a result of ultraviolet radiation. They have malignant potential and are recognized precursors to squamous cell carcinoma (SCC).1,2 • The estimated annual risk of evolution of AK to SCC is between 0.15% and 80% for patients with multiple AKs. Because it is not feasible to predict which AK lesions will become malignant, treatment of all AKs is recommended.1 • Current treatment for AK lesions includes cryotherapy (LN2) and topical 5-fluorouracil (5-FU). Patients have reported local adverse reactions with this therapy including erythema, dryness, pruritus, and irritation.2 • Vitamin D derivatives have demonstrated anti-proliferative properties in cancer treatment via stimulation of the vitamin D3 receptor, which can be found on keratinocytes.3 • Topical vitamin D has been shown to decrease the number of AK lesions. Recent research suggests that topical vitamin D derivatives may be efficacious in the treatment of AKs.3 • A total of fifteen patients (30%) treated with 5-FU cream and five patients (10%) treated with 5-FU cream and topical calcipotriene foam experienced some grade of irritation during their treatment course (Figure 5). Irritation was defined as patient-reported irritation due to the topical treatment. • Reported symptoms of irritation included non-persistent mild erythema, dryness, and/or pruritus. No pain, scabbing, or erosion was reported. • Cases of irritation resolved within two weeks of topical treatment discontinuation. • No patients discontinued treatment due to irritation. • The combination of cryotherapy and short-contact treatment with 5-FU cream and topical calcipotriene foam (Group # 3) resulted in a statistically significant greater decrease in total AK lesions than LN2 alone (Group #1) or LN2 followed by short-contact with topical 5-FU (Group #2) at month 6 (p=0.00952). • A reduction in mean total AK counts was observed at each body site in Group #3 in comparison to Group #1 or Group #2. • Reductions in total mean AK lesion counts were demonstrated at months 1 and 3, with statistically significant decrease in total AK lesion count at month 6 (p=0.03383). • Greater percent reduction in mean total AK lesion counts was also observed in patients treated with LN2 followed by short- contact combination therapy of calcipotriene foam with 5-FU than patients being treated with LN2 alone and LN2 followed by short- contact 5-FU. • Treatment with LN2 followed by the short-contact treatment with calcipotriene foam in addition to 5-FU was associated with a lower rate of irritation (10%) than treatment with LN2 followed by short-contact treatment with topical 5-FU alone (30%). • Irritation rates were also markedly lower than those reported in clinical trials (39%).4 It is likely that the short-contact method of application resulted in tolerability improvement. • Cryotherapy followed by short contact topical calcipotriene foam in combination with 5-fluorouracil cream may offer increased efficacy and safety in the treatment of actinic keratoses. • Multicenter, randomized, placebo-controlled trials are needed to confirm these findings. • A decrease in total AK lesion count was noted at months1, 3, and 6 using measures of central tendency, but a statistically significant decrease in total lesion count was only observed at month 6 compared to baseline count (p=0.03383). • Upon further analysis, treatment with LN2 followed by short- contact topical 5-FU and calcipotriene foam (group #3) showed a greater mean decrease in number of AKs than treatment with LN2 alone (group #1) or LN2 followed by short-contact topical 5-FU (group #2) (Figure 1). • Using Tukey Contrasts, a statistical difference in total AK lesions counts was only observed in group #3 (LN2 followed by short-contact 5-FU and calcipotriene foam) (p=0.0255) (Figure 2). -25% -15% -5% 5% 15% 25% 35% Month 1 Month 3 Month 6 Figure 3. Percent Reduction in Mean* Total Lesions by Treatment at 1-, 3-, and 6-Month Follow-Up Visits LN2 LN2 + 5-FU LN2 + 5-FU + Calcipotriene foam INTRODUCTION RESULTS CONCLUSIONS 1. Dodds, A., A. Chia, and S. Shumack, Actinic keratosis: rationale and management. Dermatol Ther (Heidelb), 2014. 4(1): p. 11-31. 2. Seckin, D., et al., Can topical calcipotriol be a treatment alternative in actinic keratoses? A preliminary report. J Drugs Dermatol, 2009. 8(5): p. 451-4. 3. Seckin, D., et al., Can topical calcipotriol be a treatment alternative in actinic keratoses? A preliminary report. J Drugs Dermatol, 2009. 8(5): p. 451-4. 4. Cunningham, T.J., et al., Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy. J Clin Invest, 2017. 127(1): p. 106-116. METHODS • This was a retrospective analysis of patients presenting with AKs in a clinical dermatology office setting. • Three treatment groups were evaluated with 50 patients per group: 1) LN2, 2) LN2 with short-contact topical 5-FU 1% cream, 3) LN2 with short-contact topical 5-FU 1% cream and calcipotriene foam • Lesion count was assessed and cryotherapy was administered on AK lesions at baseline visit. Patients in the groups #2 and #3 were then instructed to begin short-contact topical therapy cycles: nightly for 5 days on the face and 7 days on other affected areas, off for 2-week interval, and then repeat, with 5-FU (group #2) or both 5-FU and calcipotriene foam (group #3) Follow-up visits were scheduled for 1, 3, and 6 months. • At each follow-up visit, AK lesion count was assessed and AK’s treated with cryotherapy. Patients were also asked to report any side effects. • Patient assessments and lesion counts were only performed at scheduled follow-up evaluation visits. • ANCOVA analysis was used to adjust for imbalances in baseline AK lesion count. Angela Yen Moore, MD 1 2, 3; Madalyn Nguyen, OMS-II4 1Arlington Research Center, Arlington, TX; 2Baylor University Medical Center, Dallas, TX; 3University of Texas Medical Branch at Galveston, TX; 4Texas College of Osteopathic Medicine, UNTHSC, Fort Worth, TX 0 5 10 15 20 25 Face Chest Back Arms Figure 4. Mean Lesion Count Per Body Site at Each Visit for LN2 + 5-FU + Calcipotriene foam Baseline (N=50) Month 1 (N=24) Month 3 (N=22) Month 6 (N=19) 0% 5% 10% 15% 20% 25% 30% 35% LN2 + 5-FU (N=50) LN2 + 5-FU + Calcipotriene foam (N=50) Figure 5. Treatment-Associated Irritation Figure 1. ANCOVA Summary Table 6 Months Treatment p-value Mean Change in Lesion Count Confidence Interval (95%) LN2 4.21e-07 17.212 11.055 – 23.369 LN2 + 5-FU 0.16420 -4.741 -11.467 – 1.985 LN2 + 5-FU + Calcipotriene foam 0.00952 -8.818 -15.415 – -2.221 • A greater percent reduction in total AK lesion count was observed in patients treated with LN2 followed by short-contact combination therapy of calcipotriene foam with 5-FU than patients being treated with LN2 alone and LN2 followed by short- contact 5-FU (Figure 3). • Compared with baseline, the mean lesion count decreased over the course of treatment at each body site evaluated (Figure 4). • Two patients in group #1 (treated with LN2 alone), one patient in group #2 (treated with LN2 and short-contact topical 5-FU), and two patients in group #3 (treated with LN2 and short-contact topical calcipotriene foam with 5-FU) were determined to be noncompliant due to failure to maintain regularly scheduled follow-up visits at 1, 3, or 6 months. *Means after controlling for variations in baseline lesion count. Figure 2. Tukey Contrasts 6 Months Treatment p-value LN2 + 5-FU – LN2 0.3434 LN2 + 5-FU + Calcipotriene foam – LN2 0.0255 **Research partially funded by unrestricted educational grant from Mayne Pharma