bilateral comparison of the efficacy and tolerability of ...

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COPYRIGHT © 2006 JOURNAL OF DRUGS IN DERMATOLOGY

BILATERAL COMPARISON OF THE EFFICACY AND TOLERABILITY OF 3% DICLOFENAC SODIUM GEL AND 5% 5-FLUOROURACIL CREAM IN THE TREATMENT OF ACTINIC KERATOSES OF THE FACE AND SCALP Stacy R. Smith MD, Vera B. Morhenn MD, Daniel J. Piacquadio MD Therapeutics Clinical Research, San Diego, CA, and Division of Dermatology, University of California San Diego, CA

Abstract Actinic keratoses (AKs) are a common precancerous condition and are said to account for 14% of visits to dermatologists in the US each year. Along with cryotherapy, topical treatments are a mainstay of therapy for these lesions. One of the potential benefits of topical therapy is less pain and irritation as compared to cryotherapy. Additionally, topical therapies have a perceived benefit of treating subclinical lesions along with clinically evident keratoses. We conducted a bilateral comparison study of the efficacy and tolerability of diclofenac 3% gel used for 90 days and 5% fluorouracil cream used for 28 days in thirty patients with AK of the face and scalp. The diclofenac gel and 5-fluorouracil cream each demonstrated substantial efficacy in the number of lesions cleared and the proportion of patients with significant lesion clearing. In most patients, diclofenac induced only mild signs of inflammation compared to 5-fluoruracil, despite a longer treatment period. A greater number of patients expressed significant satisfaction with diclofenac gel compared to the 5-fluorouracil cream.

Introduction Hyperplastic, epidermal premalignant lesions called actinic keratoses (AKs) are common in fair skinned individuals. These lesions are the result of overexposure to UV irradiation and, north of the equator, AKs occur in about 18% of the population.1 This problem results in 47 million6 office visits to dermatologists in the US each year.2 Indeed, AKs represents one of the most common reasons for visiting a dermatologist. Since about 8% of metastatic squamous cell carcinomas (SCC) start as AKs, efficacious treatment that has a high compliance rate becomes a very sought after modality.3 Currently, several types of therapies for AKs are available. These include destructive methods such as cryotherapy, chemical peeling or laser resurfacing, and the more recently introduced photodynamic therapy, as well as topical treatments directed at atypical cell growth.4 Topical treatments include 5-fluorouracil products, imiquimod, and diclofenac sodium 3% gel. The advantage of topical treatments is that they facilitate the eradication of subclinical, preinvasive lesions. This study was performed to compare the efficacy and tolerability profiles of 2 currently marketed therapies, diclofenac sodium 3% gel (Solaraze®, Bradley Pharmaceuticals, Fairfield, NJ)(DFS) and 5% fluorouracil cream (Efudex®, Valeant Pharmaceuticals, Costa Mesa, CA) (5-FU).

Materials and Methods In this single center, bilateral, open-label, evaluator blinded study, DFS was compared to 5-FU in patients with at least 3 AKs on each side of the face and/or scalp with relative symmetry of the AK distribution. Thirty patients (23 males, 7 females) with at least 3 AKs on either side of the face and/or scalp were enrolled. Study exclusion criteria included pregnancy or lactation, patient’s unwillingness to use adequate birth control measures if appropriate, use of medications effective against AKs within 4 weeks prior to enrollment, photodynamic therapy within less than 1 month,

treatment with another investigational device or drug within 1 month, systemic retinoid therapy within 6 months, or an allergy or sensitivity to any component of the study medications. A subject who had an untreated cutaneous malignancy within the treatment area was also excluded. The study was overseen by an intuitional review board; all patients gave written informed consent prior to any study-related procedures. Enrolled patients applied DFS twice daily to a randomly selected side of the face and/or scalp for an initial 62 days. On this day, addition of twice daily application of 5-FU to the contralateral side of the face and/or scalp for the final 28 days was initiated. The patients also continued to treat the side of the face that had received DFS for the remaining 28 days. The patients thus received the recommended 90 days of therapy with DFS and 28 days of therapy with 5-FU. Patients underwent evaluations by both a blinded and an unblinded evaluating dermatologist. Initially, patients were evaluated by both the blinded and unblinded investigator to ensure agreement on location and severity of AK lesions. Patients were then evaluated at days 30, 62, and 76 by the unblinded investigator to ensure compliance and assess to lerability. At day 90 (end of treatment) and day 120 (30 days post-treatment), the patients again were evaluated by the investigator that was blinded with respect to the study medication assignment. AKs were graded as unchanged, partially improved, or resolved. Patients were evaluated for efficacy by determining the number and proportion of AK lesions that had resolved as well as through changes in their Global Improvement Score for each side of the face and/or scalp. Tolerability was assessed by evaluator grading of erythema, scaling, edema, and oozing/crusting. Patients were asked to grade the severity of pain and stinging as well as their degree of satisfaction with the treatment.

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JOURNAL OF DRUGS IN DERMATOLOGY FEBRUARY 2006 • VOLUME 5 • ISSUE 2

Figure 1. Efficacy Results

DICLOFENAC AND 5-FU IN AKS

investigator was permitted to view only the baseline photographs during the course of the study to prevent potential unblinding due to varying cutaneous reactions from the therapies.

Results Twenty-nine eligible patients were enrolled in the study and 28 completed the course of treatment. One patient developed a herniated intravertebral disc that required surgery, and another was lost to follow-up. The majority (76%) of patients were male; the average age was 69 years. All were Fitzpatrick skin types I to III.

To ensure verification of lesion location, all selected AKs were marked, mapped, and photographed with high resolution digital photography at baseline and at follow-up visits. These photographs were viewed during follow-up visits to assist in verification of lesion location. The blinded

Efficacy At the end of treatment, a total of 251 AK lesions were evaluated. Of these, 125 were treated with DFS and 126 lesions with 5-FU. Clearance rates determined 30 days after completion of therapy were 111 of 125 (89% clearance) for DFS and 124 of 126 (98% clearance) for 5-FU. The majority of patients with remaining AKs had just a single persistent lesion. Thus, the proportion of patients who cleared at least 2 of the 3 lesions (66% clearance) was similar for both treatments; 93% for the DFS treated sides and 100% for the 5-FU treated sides. The Global Improvement Scores mirrored this outcome with 97% of sides treated with DFS graded as

Figure 2a.

Figure 2c. Moderate to severe erythema

Figure 2b.

Figure 2d.

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Figure 3. A patient treated with DFS on his left side of the face and 5-FU on his right. This is the last day of treatment (day 90); a total of 90 days of DFS and 28 days of 5-FU.

moderately improved or better and with 100% of the 5-FU sides reaching this level of improvement. These results are shown in Figure 1.

Tolerability The two treatments differed markedly in tolerability (Figures 2A-D). Only 27% of patients were graded with moderate or severe erythema on the side treated with DFS at any time through the treatment or follow-up period (Figure 2A). Almost all patients who developed moderate or severe erythema with DFS did so around day 76. By contrast, the sides treated with 5-FU showed moderate or severe erythema in 83% of the patients at the day 76 assessment. The proportion of patients experiencing moderate or severe erythema after 5-FU treatment dropped to 40% by the final day of treatment. At this time, less than 10% of patients treated with DFS showed erythema. A single patient still had moderate erythema on the 5-FU treated side 30 days after completing the treatment.

With respect to scaling, oozing/crusting, and edema, greater proportions of the sides treated with 5-FU were graded as moderate or severe for each of these parameters for most time points during the study as detailed in Figures 2B, C, and D. Although all patients were graded at 30 days of DFS treatment, no significant scaling, oozing or edema was seen and is therefore not displayed in these figures. A representative example of the side effects encountered with both treatments is shown (Figure 3). Patient preference favored DFS over 5-FU treatment. A greater proportion of patients (79%) were either very satisfied or completely satisfied with DFS treatment whereas only 68% of patients indicated this level of satisfaction for the 5-FU treated side. Patients also reported greater pain and stinging on the 5-FU treated sides (22% with moderate or severe pain/stinging compared to 11% for the DFS-treated side).

Safety No new AK lesions were identified in either area through the course of the study and no conversion of lesions to full

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cutaneous malignancies was seen. No adverse events possibly related to the use of the study medications other than the local skin reactions reported above were seen during the study.

Discussion The purpose of this study was to directly compare the tolerability and efficacy of DFS and 5-FU in the treatment of AK. The treatments are similar in efficacy but not identical. Interestingly, the efficacy observed in this study was better than that previously reported for either product.5 This may be a manifestation of the small sample size, differences in methodology of the studies, or perhaps even some synergy due to the products being used simultaneously, albeit in different anatomic locations. Not surprisingly, substantial differences in tolerability were demonstrated. DFS, at its worst, caused only moderate inflammation and irritation. The inflammation known to occur with 5-FU has resulted in various alternate dosing regimens to improve tolerability and compliance.6 However, the data presented here probably overstate the actual inflammation/irritation seen with either product when used alone. It should be noted that the greatest levels of erythema, scaling, and oozing occurred for both products at the day 76 visit (after the first two weeks of 5-FU therapy). It is unlikely that an additional 2 weeks of therapy with DFS (from day 62 to day 76) was the cause of the dramatic increase in inflammatory signs. It is much more likely that the introduction of the second agent (5-FU) made all of the facial and scalp skin more excitable or that some crossover of product occurred. This is an unfortunate consequence of a bilateral study design. Prescribers of these products may expect less inflammation from either product when used alone compared to the findings from this study. Recently, a new form of 5-FU was introduced which utilizes a porous microsphere technology to allow slow release of the active ingredient (Carac, Dermik Laboratories, Berwyn, PA). This allows a reduced dosing frequency and presumably a lower irritation profile. A recent, small comparison study of Carac versus the traditional 5-FU cream has not shown significant differences with respect to tolerability.7 Thus, it is unlikely that this new 5-FU formulation would compare more favorably to DFS with respect to tolerability than the traditional 5-FU cream. Clearly, one of the greatest drawbacks to therapy with DFS is its duration. Between DFS and 5-FU there is a tradeoff of a reduced level of irritation over a significant duration (90 days) versus fairly intense inflammation for only 4 weeks. Each of these paradigms will appeal to different patients and to different physicians. This is exemplified by the satisfaction data where more than two-thirds of patients reported high satisfaction with the 5-FU therapy despite the experience of irritation. Real world compliance and subsequent efficacy may be reduced compared to the values found in this study due to the duration of therapy for DFS and the irritation pro-


file for 5-FU. Armed with this information, clinicians are now better able to choose a therapy that best fits their patient. In summary, DFS offers improved tolerability with perhaps slightly less efficacy. Active, working patients may appreciate an almost innocuous treatment for 90 days while those patients with few or no public obligations may prefer to be treated with a 28-day course of far less tolerable therapy.

Acknowledgement Special thanks to Denise Freeman for her assistance in preparation of this manuscript.

Disclosure Drs. Smith and Piacquadio have received payments and other considerations for competing products to treat actinic keratoses. All authors conduct clinical research studies for a variety of pharmaceutical and device sponsors. This study was conducted under an educational grant from Bioglan Pharmaceuticals (now Doak Dermatologics, Fairfield, NJ)

References 1. Frost CA, Green AC. Epidemiology of solar keratoses. Br J Dermatol. 1994;131:455-64. 2. Lebwohl M. Actinic keratosis: epidemiology and progression to squamous cell carcinoma. Br J Dermatol. 2003;249(Suppl.66):31-33. 3. Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol. 2000;42(2):23-24. 4. Jorizzo JL, Carney PS, Ko WT, Robins P, Weinkle SH, Werschler WP. Treatment options in the management of actinic keratosis. Cutis. 2004;74s:9-17. 5. Nelson C, Rigel D, Smith S, Swanson N, Wolf J. Phase IV, openlabel assessment of the treatment of actinic keratosis with 3% diclofenac sodium topical gel (Solaraze). J Drugs Dermatol. 2004;3:401-7. 6. Labandeira J, Pereiro M Jr, Valdes F, Toribio J. Intermittent topical 5-fluorouracil is effective without significant irritation in the treatment of actinic keratoses but prolongs treatment duration. Dermatol Surg. 2004;30:517-20. 7. Loven K, et al. Evaluation of the efficacy and tolerability of 0.5% fluorouracil cream and 5% fluorouracil cream applied to each side of the face in patients with actinic keratosis. Clin Ther. 2002;24:9901000.

Address for Correspondence Stacy R. Smith MD Therapeutics Clinical Research 9205 Balboa Ave., Suite 105 San Diego, CA 92123 Phone: 858-571-6800 Fax: 858-571-6801 e-mail: [email protected]