Tolerability of Ingenol Mebutate Gel, 0.05%, for Treating Patients with Actinic Keratosis on the Scalp in a Community Dermatology Practice

| March 1, 2016
Spread the word.
Email this to someonePrint this pageShare on FacebookTweet about this on TwitterShare on LinkedInShare on Google+Pin on PinterestShare on TumblrBuffer this pageDigg thisFlattr the authorShare on RedditShare on StumbleUponShare on YummlyShare on VK

Miriam S. Bettencourt, MD Advanced Dermatology and Cosmetic Surgery, Henderson, Nevada; Assistant Clinical Professor of Dermatology, University of Nevada, Las Vegas, Nevada

Disclosure: Dr. Bettencourt reports no relevant conflicts of interest.


Abstract

Objective: To describe the safety, tolerability, and efficacy of treatment of actinic keratosis on the scalp with two consecutive, once-daily applications of ingenol mebutate gel, 0.05%. Design: Retrospective chart review. Setting: Community dermatology practice. Participants: Male patients (N=78) with a long history of recurrent and relapsed scalp actinic keratosis. Measurements: This chart review extracted non-identifying information on patients’ medical history, pertinent history of actinic keratosis and skin cancer, and prior actinic keratosis treatments. Also collected was information on patients’ treatment of scalp actinic keratosis with ingenol mebutate gel, 0.05%, including the occurrence of local skin reactions and their treatment, adverse events, and efficacy results at short-term and additional follow-up. Results: In these patients, a significant proportion of the scalp had numerous actinic keratoses that were often recurrent and/or hyperkeratotic. Most patients (83%) received cryosurgery to visible scalp actinic keratoses two weeks before ingenol mebutate treatment. Local skin reactions developed on the first day of topical treatment, were predominantly mild or moderate in intensity, and generally were resolved by 10 to 14 days. Local skin reactions were treated with a topical moisturizing product in 44 percent of the patients. Nearly half (45%) of the patients experienced application-site reactions, described as a combination of burning, itching, pain, and/or tenderness; the reactions were mild or moderate in intensity and lasted only a few days. Conclusions: Ingenol mebutate gel, 0.05%, had a good safety and tolerability profile when used to treat scalp actinic keratosis in patients who had a prolonged history of actinic keratosis. (J Clin Aesthet Dermatol. 2016;9(3):20–24.)


 

Actinic keratosis (AK) is one of the most common conditions encountered by dermatologists. In a survey of dermatologist visits from 1993 to 2010, AK was the leading diagnosis in patients aged 45 years and older.[1] The majority of AKs are found on skin sites that have received chronic, long-term sun exposure, such as the head, neck, forearms, and hands.[2] The primary concern over AK is that it may progress to squamous cell carcinoma (SCC). Although the progression of a specific AK lesion to SCC cannot be predicted, the majority of clinically diagnosed SCCs do, in fact, originate from concomitant or contiguous AKs.[3–5] This association supports the importance of dermatologic evaluation of AKs and the initiation of treatment.[6],[7]

Comprehensive management of AK to reduce the risk of progression to SCC often includes both lesion-directed methods, such as cryosurgery,[8],[9] and topical field therapies, which treat large numbers of visible and subclinical lesions present in contiguous areas of sun-damaged skin.10,11 Ingenol mebutate gel, 0.015%, a topical treatment indicated for the treatment of AK of the face and scalp, is applied once daily for three consecutive days. When used to treat AK on the trunk and extremities, a 0.05% formulation is applied once daily for two consecutive days.[12],[13]

Some evidence suggests that AKs on the scalp are not cleared as completely as those on the face with use of the ingenol mebutate, 0.015%, formulation. In a pooled analysis of two Phase 3 studies, rates of complete and partial clearance of AKs, assessed by anatomic location on the face and scalp, were statistically higher with ingenol mebutate gel, 0.015%, than with vehicle gel, but clearance rates on the scalp were noted to be lower than those on the face.[14] A retrospective chart review of patients in the author’s practice also showed that the rate of complete clearance of AKs with ingenol mebutate gel, 0.015%, was lower on the scalp than on the face.[15] These observations suggested that AKs on the scalp may be more difficult to treat with the 0.015% strength of ingenol mebutate gel and led the author to speculate that scalp AK might respond better to the higher 0.05% formulation of ingenol mebutate. Therefore, over the course of 20 months, the author treated male patients in her community dermatology practice with ingenol mebutate gel, 0.05%, for AK on the scalp. This retrospective chart analysis describes the results with this treatment.

Methods

The chart review extracted non-identifying information on the patient’s medical history, pertinent history of AK and skin cancer, and prior AK treatments. Information collected from the charts on the patient’s course of treatment of scalp AK with ingenol mebutate gel, 0.05%, included the occurrence of local skin reactions (LSRs) and their treatment, adverse events (AEs), short-term efficacy (generally 2–8 weeks), and long-term follow-up (ranging from 2–14 months). Complete clearance was defined as the absence of any baseline or emergent scalp AKs (100%). The percentages of patients who achieved 100 percent, ?75 percent but <100 percent, or ?50 percent but <75 percent short-term clearance of AKs were summarized.

Results

Baseline characteristics. From January 2013 to August 2014, 78 male patients received ingenol mebutate gel, 0.05%, for treatment of AKs of the scalp. The mean age of the patients was 70 years; median (range) was 70 (55–85) years. Overall, patients had a high burden of sun-damaged skin (Table 1 ). More than half of the patients had a history of nonmelanoma skin cancer (n=43, 55%), and a similar proportion had had a history of AK for ?10 years (n=44, 56%). Nearly all patients had received cryosurgery (n=76, 97%), and only approximately one-quarter of the patients had not previously used any topical therapy (n=19, 24%).

The most commonly used prior topical treatment was diclofenac (n=34, 44%). A substantial proportion of patients had treated AKs on their scalp with at least one course of ingenol mebutate gel, 0.015% (n=32, 41%). Several patients had used ingenol mebutate treatment to treat AKs on areas other than the scalp: 14 (18%) patients had treated AKs on the face with the 0.015% gel, and one patient (1%) had treated the forearms with the 0.05% gel.

Current treatment course. At the time that the patients began treatment of scalp AKs with ingenol mebutate, 0.05%, most patients (n=64, 82%) had AK affecting an area that involved ?50 percent of their scalp (Table 2). A majority of patients had lesions that were recurrent (n=71, 91%) and/or hyperkeratotic (n=41, 53%). Most of the patients (n=65, 83%) received cryosurgery to all visible scalp AKs before beginning treatment with ingenol mebutate. Approximately two weeks following cryo-surgery, patients applied ingenol mebutate gel, 0.05%, once daily for two consecutive days. All patients applied the doses for the two days.

LSRs. LSRs were characterized by six parameters (erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration).[13],[16] Each parameter was descriptively assessed as mild, moderate, or severe based on clinical judgment (Figure 1). All patients ex-perienced LSRs that began on the first treatment day. All patients experienced erythema (n=78, 100%), almost all experienced flaking/scaling (n=76, 97%), and a majority experienced crusting (n=48, 66%). All of these LSRs were judged as mild or moderate, with the exception of severe crusting in two (3%) patients (Figure 2). Approximately one-third of patients experienced vesiculation/pustulation (n=25, 32%), while fewer had erosion/ulceration (n=10, 13%) or swelling (n=5, 6%). Thirty-four patients (44%) treated LSRs with at least one topical product. Treatments included moisturizers (n=16), Neosalus® (n=9), Hylatopic Plus® (n=3), Atrapo® (n=3), Cetaphil® (n=2), CeraVe® (n=2), and Aurstat® (n=1). LSRs were resolved by 10 to 14 days in most patients; in one patient, LSRs did not resolve until Day 20.

AEs. Application-site reactions, which were described as a combination of burning, itching, pain, and/or tenderness, occurred in 35 patients (45%). Most application-site reactions were mild (n=17) or moderate (n=16) in intensity; severe reactions were infrequent (n=2). AEs occurred within the first 10 days of the start of treatment and resolved in the same time frame as, or more quickly than, the visible LSRs.

AK clearance. Short-term assessment of AK clearance in most patients occurred at follow-up visits taking place at 2 to 8 weeks after treatment initiation. The majority of the patients (n=58) were evaluated within one month of treatment; seven patients were evaluated at between four weeks and eight weeks, 12 patients at later than eight weeks, and one patient had no evaluation.

Short-term assessment showed that complete clearance or partial clearance (100% or ?75%) of scalp AK occurred in 94 percent of patients (61 of 65) treated with a sequential combination of cryosurgery and ingenol mebutate (Figure 3) and in 85 percent of patients (11 of 13) treated only with topical treatment (Figure 3). The number of remaining AKs was low, at a median of three lesions (range, 1–13). Most patients with residual AKs were treated with cryosurgery. A small number of patients (n=11, 14%) underwent a second treatment course with ingenol mebutate gel, 0.05%.

Approximately two-thirds of the patients (n=51, 65%) had at least one additional follow-up assessment that occurred at a visit from two months to 14 months from the time of treatment. Among this group, one-third of the patients (n=17) were completely clear of AKs on the scalp. Among the other 34 patients, the small number of remaining AKs (median=3; range, 1-8) were treated with cryosurgery.

Limitations

This report describes the therapeutic management of real-life patients with a long history of scalp AK, for whom a combination of treatment with lesion-directed cryosurgery and a topical field therapy is regarded as prudent. Rates of AK clearance in these patients were not compared with those for patients treated with cryosurgery alone or with the 0.015% ingenol mebutate formulation, which is indicated for face or scalp. Therefore, the author cannot know to what extent the 0.05% formulation contributed to AK clearance. However, the author notes that 41 percent of the patients had received prior treatment of scalp AK with the 0.015% formulation, and the persistence of their AK prompted the author to evaluate use of the higher- strength formulation and its tolerability.

Conclusion

Ingenol mebutate gel, 0.05%, was used to effectively treat AKs of the scalp of 78 male patients in a community dermatology setting who had a long history of scalp AK that had been previously treated with cryosurgery and a variety of topical agents. Most of the patients (65 of 78 [83%]) began treatment with ingenol mebutate gel, 0.05%, at approximately two weeks after cryosurgery. At short-term evaluation, more than 90 percent of the patients had achieved 75- to 100- percent clearance of AKs and had few remaining lesions.

Among the patients the author studied, approximately 40 percent had received previous treatment of scalp AK with ingenol mebutate gel, 0.015%, which is the recommended dose for treating AKs of the scalp as well as the face. The generally greater thickness of AKs on the scalp, however, may reduce the absorption of ingenol mebutate,[17] leading to the lower clearance rates observed. The 0.05% formulation, having a 3.3-fold higher concentration of ingenol mebutate gel than the 0.015% formulation, may provide an effective means for increasing exposure to the active agent.

Various investigations also suggest that effective clearance of scalp AK requires higher exposure to therapeutic topical agents. A subgroup analysis of two studies with imiquimod (using both the 3.75% and the 2.5% formulations) demonstrated lower rates of AK clearance on the scalp than on the face, and lower rates of clearance on the scalp with the 2.5% strength than with the 3.75%.18 Similarly, with 5 fluorouracil, 1% cream formulation, scalp AKs required a longer treatment period for clearance than did facial AKs.[19]

LSRs are common with topical treatments for AK. In the present analysis, visible LSRs developed on the first day of treatment with ingenol mebutate gel, 0.05%. They were predominantly mild or moderate in intensity, and they generally resolved by 10 to 14 days. The most common LSR responses were erythema, flaking/scaling, and crusting. A good proportion of the patients (34 of 78) treated their LSRs with a moisturizer or emollient; this was a higher proportion than the author has seen among patients in her practice who have treated scalp AK with the 0.015% gel (6 of 45).[15] Nevertheless, visible LSRs and any accompanying itch or tenderness in both sets of patients resolved within a similar time frame.

Limitations of this analysis are those inherent to a retrospective chart review of patients from a single practice. All evaluations were based on clinical assessments alone, as no histopathologic analysis of biopsy samples was performed.

The experience gained from this community dermatology practice showed that treatment of scalp AK with two consecutive, once-daily applications of ingenol mebutate gel, 0.05%, was well-tolerated. The associated LSRs from this short treatment regimen were of brief duration. Ingenol mebutate gel, 0.05%, may thus be a useful treatment option for men with AK on the scalp.

References

1. Landis ET, Davis SA, Taheri A, Feldman SR. Top dermatologic diagnoses by age. Dermatol Online J. 2014;20(4):22368.

2. Frost CA, Green AC. Epidemiology of solar keratoses. Br J Dermatol. 1994;131:455–464.

3. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009;115:2523–2530.

4. Czarnecki D, Meehan CJ, Bruce F, Culjak G. The majority of cutaneous squamous cell carcinomas arise in actinic keratoses. J Cutan Med Surg. 2002;6:207–209.

5. Mittelbronn MA, Mullins DL, Ramos-Caro FA, Flowers FP. Frequency of pre-existing actinic keratosis in cutaneous squamous cell carcinoma. Int J Dermatol. 1998;37:677–681.

6. Berman B, Bienstock L, Kuritzky L, et al. Actinic keratoses: sequelae and treatments. Recommendations from a consensus panel. J Fam Pract. 2006;55(Suppl):1–8.

7. Stockfleth E, Ferrandiz C, Grob JJ, et al. Development of a treatment algorithm for actinic keratoses: a European Consensus. Eur J Dermatol. 2008;18:651–659.

8. Balkrishnan R, Cayce KA, Kulkarni AS, et al. Predictors of treatment choices and associated outcomes in actinic keratoses: results from a national physician survey study. J Dermatolog Treat. 2006;17:162–166.

9. Halpern AC, Hanson LJ. Awareness of, knowledge of and attitudes to nonmelanoma skin cancer (NMSC) and actinic keratosis (AK) among physicians. Int J Dermatol. 2004;43:638–642.

10. Berman B, Cohen DE, Amini S. What is the role of field-directed therapy in the treatment of actinic keratosis? Part 1: Overview and investigational topical agents. Cutis. 2012;89:241–250.

11. Stockfleth E. The paradigm shift in treating actinic keratosis: a comprehensive strategy. J Drugs Dermatol. 2012;11(12):1462–1467.

12. Picato gel 0.015%, 0.05% [package insert]. Parsippany, NJ: LEO Pharma Inc; 2015.

13. Lebwohl M, Swanson N, Anderson LL, et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012;366:1010–1019.

14. Berman B, Marmur E, Melgaard A. Three-day topical treatment with ingenol mebutate gel 0.015% for actinic keratoses on the face and scalp: analysis of data pooled from two trials. Poster no. P5623. Presented at the annual meeting of the American Academy of Dermatology; March 16–20, 2012; San Diego, California.

15. Bettencourt MS. Use of ingenol mebutate gel for actinic keratosis in patients in a community dermatology practice. J Drugs Dermatol. 2014;13(3):269–273.

16. Rosen R, Marmur E, Anderson L, et al. A new, objective, quantitative scale for measuring local skin responses following topical actinic keratosis therapy with ingenol mebutate. Dermatol Ther (Heidelb). 2014;4:207–219.

17. Goldenberg G, Berman B. Assessment of local skin reactions with a sequential regimen of cryosurgery followed by ingenol mebutate gel, 0.015%, in patients with actinic keratosis. Clin Cosmet Investig Dermatol. 2015;8:1–8.

18. Swanson N, Smith CC, Kaur M, Goldenberg G. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: two phase 3, multicenter, randomized, double-blind, placebo-controlled studies. J Drugs Dermatol. 2014;13(2):166–169.

19. Simmonds WL. Topical management of actinic keratoses with 5-fluorouracil: results of a 6-year follow-up study. Cutis. 1972;10:737–741.

Spread the word.
Email this to someonePrint this pageShare on FacebookTweet about this on TwitterShare on LinkedInShare on Google+Pin on PinterestShare on TumblrBuffer this pageDigg thisFlattr the authorShare on RedditShare on StumbleUponShare on YummlyShare on VK

Category: Original Research, Past Articles

Comments are closed.