c1 jcad 1108 winter clinical cover1...4 supplement a to [november 2008 • volume 1 • number 4] 4...

Selected presentations from theWINTER CLINICAL DERMATOLOGY CONFERENCE™

Held at the Ritz Carlton Kapalua Resort, Maui, Hawaii, March 14–18, 2008

wwwwww.jcadonline.com.jcadonline.com

SUPPLEMENT A TO THE 2008 NOVEMBER

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CONTENTSCONTENTS

NONSURGICAL APPROACHES

TO THE TREATMENT OF

NON-MELANOMA SKIN CANCER

by Marc D. Brown, MD,and Nana Smith, MDPAGE 2

WHAT’S NEW IN ACNE

by Guy Webster, MD, PhDPAGE 8

UPDATE ON THE MEDICAL

MANAGEMENT OF ROSACEA

by James Q. Del Rosso, DO,FAOCDPAGE 10

PRESIDENT

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MATRIX MEDICAL COMMUNICATIONS

The articles published in this sup-plement are based on selected pre-sentations from the Winter ClinicalDermatology Conference, whichwas held at the Ritz CarltonKapalua Resort, Maui, Hawaii,March 14–18, 2008.

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[ N o v e m b e r 2 0 0 8 • V o l u m e 1 • N u m b e r 4 ]S u p p l e m e n t A t o2

Non-melanoma skin cancer(NMSC) is not only commonbut imparts a substantial

morbidity to the patient and cost tosociety. It is frequently quoted thatmore than one million cases of basalcell carcinoma (BCC) occur eachyear in the United States, but morerecent estimates indicate that 3 to 4million cases or higher occur eachyear. The incidence of NMSC hasbeen increasing worldwide at a rateof 3 to 8 percent per year over thelast four decades. There is also anincreasing incidence among youngeradults.

The goals of any treatment forNMSC are the same. A high curerate is desired considering the localdestruction of tissue that can becaused. Because many NMSCspresent on the head and neck, anacceptable cosmetic result is desiredand, ideally, at a reasonable cost.Finally, for many patients, thesimplicity of treatment is of great

importance. Nonsurgical treatments are

desirable for many reasons. Topicalapproaches are less invasive andmay be especially important formedically frail and elderly patients.Topical approaches also cause lessinitial pain. Improved cosmeticoutcomes are often achieved,especially in potentially complexsurgical cases or cosmeticallysensitive locations. In patients withmultiple lesions, nonsurgicalmodalities may offer a moresimplistic treatment option. Lastly,treatment of subclinical disease canbe achieved with topical approaches,in contrast to surgery.

Disadvantages to topical ormedical treatment of NMSC exist.Surgery (including Mohsmicrographic surgery) is no doubtthe “gold standard” of care andoffers higher cure rates. The mainreason for this is the lack of margincontrol with nonexcisional therapy.

For this reason, high-risk BCCs andinvasive squamous cell carcinomas(SCCs) are best treated byexcisional procedures.

This review will focus on thenonsurgical treatment of “low-risk”NMSC. These entities are defined bythe following: primary tumorslacking any prior treatment, smallersize, superficial or nodular BCCs,SCC in situ, and location outside ofthe H-zone on the face. Unlessotherwise stated, the efficacy resultsquoted are the as-treated data fromthe particular study and notintention-to-treat.

Although traditional proceduralapproaches like cryotherapy,curettage, and radiotherapy areappropriate treatments for NMSC,we did not include these to limitthe scope of the review. Discussionabout actinic keratoses is alsoexcluded. Readers are encouragedto read a recent paper by Tull et alfor a more comprehensive review.1

Nonsurgical Approachesto the Treatment of

Non-melanoma Skin Cancerby MARC D. BROWN, MD, and NANA SMITH, MD

AUTHOR AFFILIATIONS: Dr. Brown is Professor of Dermatology and Oncology, University of Rochester School of Medicine, Rochester, NewYork. Dr. Smith is Resident in Dermatology, University of Rochester, Department of Dermatology; Masters of Science in Clinical EpidemiologyCandidate, University of Pennsylvania Center for Clinical Epidemiology and Biostatistics, Philadelphia, Pennsylvania.

ADDRESS CORRESPONDENCE TO: Nana Smith, MD; e-mail: [email protected]

2

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[ N o v e m b e r 2 0 0 8 • V o l u m e 1 • N u m b e r 4 ] S u p p l e m e n t A t o 3

This paper will focus on the clinicalevidence for topical treatment ofNMSC.

PHOTODYNAMIC THERAPY Photodynamic therapy (PDT) is a

modality that combines topicalapplication of a photosensitizer withsome method of light energy. Mostcommonly, blue (417nm) or red(570–670nm) light is used. Thetopical agent available in the UnitesStates is 5-aminolevulinic acid(ALA), which is preferentially takenup by tumors and dysplastic cellsand then enzymatically converted toprotoporphyrin IX (PpIX). This isdone by leaving the ALA on the skin,with or without occlusion, forseveral hours. The initial studiesrecommended between 14 and 18hours; however, more recently,success has been seen with shortercontact (i.e., 1–3 hours). The ALA isthen washed off. Upon exposure tored or blue light or lasers (pulseddye, intense pulsed light, light-emitting diode, etc.) theintracellular PpIX induces anoxygen-dependent cytotoxicreaction. PDT is Food and DrugAdministration (FDA) approved forthe treatment of actinic keratoses(i.e., Levulan, DusaPharmaceuticals, Wilmington,Massachusetts). Studies have alsobeen done on PDT in the treatmentof Bowen’s disease and superficialand nodular BCCs.

PDT is not without disadvantages.Photosensitivity is a side effect oftreatment and can lead todiscomfort and pain. The lightenergy itself can also be painful.Multiple treatments are sometimesrequired. Also, issues arise whenreimbursement from insurancecompanies is sought. A promisingalternative to ALA, methylaminolevulinate (MAL), is notavailable in the Unites States yet,but is widely used in Europe.Advantages of MAL over ALAinclude less pain and potentiallybetter efficacy, as MAL is more

lipophilic and better absorbed intothe skin.

PDT for nodular BCCs. Rhodeset al conducted a randomized, non-blinded, controlled trial comparingPDT with MAL versus surgicalexcision for biopsy-proven nodularBCCs.2 Most tumors were less than2cm. Subjects were randomized toPDT (MAL cream 160mg/g, Metvix,Galderma and PhotoCure ASA) orsurgical excision with 5-mmmargins. Metvix was occluded forthree hours and illuminated with redlight (570–670nm, fluence 75J/cm2,fluence rate 50–200mW/cm2).Subjects in the PDT group weretreated with one or two cycles (eachone week apart), depending onclinical response.

For this follow-up study, theauthors took all patients whoachieved a complete clinicalresponse at three months post-treatment and followed them yearlyfor five years for recurrence. Theprimary endpoint was clinicalrecurrence, but suspectedrecurrences were confirmed bybiopsy. Initially 101 subjects weretreated.

Sixty-six subjects had five-yearfollow-up data. There were similarnumbers of men and women in eachgroup. Most baseline characteristicsof the groups were similar; however,subjects in the surgery group hadsignificantly more lesions on theface and scalp. Using a time-to-eventanalysis, the lesion recurrence wasfound to be 14 percent for PDT(7/49 lesions) versus four percentfor surgery (2/52 lesions). After fiveyears, “good” or “excellent”cosmetic outcomes were found in 87percent (CI 70–96%) in the PDTgroup and in 54 percent (CI37–71%) in the surgery group(p=0.007). Therefore, a trendtoward a higher cure rate withsurgery was seen; however, PDTshowed significantly better cosmeticoutcomes.

International guidelines forPDT in NMSC. Perhaps the most

comprehensivereview of treatmentfor NMSC by PDTcomes from aninternational consensus put forth bythe International Society forPhotodynamic Therapy inDermatology.3 The consensus(based on an extensive Medlineliterature review) is based on datathat tended to be heterogeneous.The included studies used differentlight sources, different number oftreatments, and various times ofapplication. The consensus alsodiscusses both ALA and MAL.Because of this, therecommendations may or may notbe generalizable to a particularpatient population.

Regarding PDT for SCC in situor Bowen’s disease, 16 open-labeland four randomized, controlledtrials were found. Recurrence rateswere between 12 and 15 percent.The conclusion was that PDT forBowen’s had similar efficacy tocryotherapy or 5-fluorouracil (5-FU), but with less side effects. PDTshould not be used for invasiveSCC, as the evidence does notsupport it. Finally, the studies warnthat patients not responsive to PDTshould be considered for surgery.

For the treatment of superficialBCCs with PDT, 12 studies werefound. Two retrospective studies;eight open-label, nonrandomizedstudies; and two randomized,controlled, open-label studies wereincluded. Initial clearance rates werebetween 80 and 97 percent with afour-year follow-up recurrence rateof 22 percent. Cosmetic outcomeswere good to excellent. Theconclusion was that PDT should beconsidered for large or multiplelesions.

Treatment of nodular BCCs withPDT was also summarized. Twelvestudies were found of which twowere randomized, placebo-controlled, and double blind. Of theremaining studies, one wasretrospective; seven were open-


[ N o v e m b e r 2 0 0 8 • V o l u m e 1 • N u m b e r 4 ]S u p p l e m e n t A t o4 44

label,nonrandomized;and the rest wererandomized but

open label. Initial response rateswere 73 to 94 percent with a five-year recurrence rate of 14 percent.Because MAL is more lipophilic, ithad better efficacy than ALA.Although PDT achieved bettercosmetic outcomes, the authorsbelieve that surgery remains the“gold standard” for treatment ofnodular BCCs.

5-FLUOROURACIL 5-FU is an antimetabolite that

exerts its cytotoxic effects byinhibiting DNA synthesis andprovoking cell death. Althoughmostly used for actinic keratoses, 5-FU has been studied in both BCCand SCC. Disadvantages to 5-FUinclude local side effects, which canbe quite uncomfortable. Therefore,patient compliance is unpredictable.Common local side effects includeerythema, erosions, and dermatitis.

5-FU for BCC. Although 5-FU isFDA approved for the treatment ofsuperficial BCCs, there are fewpublished studies to cite. In a studyconducted by ValeantPharmaceuticals (Aliso Viejo,California), the success rate of 5-FU(cream and solution combined) forsuperficial BCCs was 93 percentbased on 113 lesions in 54 subjects.The company states that 5-FUshould be used after a confirmatorybiopsy as efficacy has not beenestablished for other types of BCCs.Valeant also states that with“isolated, easily accessible BCCs,”surgery is the recommended methodof treatment. In other words, 5-FUshould be reserved for patients withmultiple BCCs or lesions in “difficulttreatment sites.” The recommendeddosage is twice daily for 3 to 6weeks or as long as 12 weeks, ifnecessary.4

Gross et al conducted an open-label, single-arm study in twocenters.5 Twenty-nine subjects with

31 biopsy-proven, superficial BCCson the trunk or limbs received 5-FUtwice daily for a maximum of 12weeks. Treatment was curtailed ifresponse was noted earlier. At threeweeks post-treatment, the initiallesion was excised. Beginning tumorsize was 0.5cm to 2cm in diameter.The histologic cure rate was 90percent (28/31); mean time toclinical cure was 10.5 weeks. Mostsubjects had only mild or moderateerythema and/or erosions. Sixteenpercent of subjects had mild scarringat 15 weeks, but most had goodcosmetic outcomes.

5-FU for Bowen’s disease.Salim et al conducted a randomizedtrial comparing PDT versus 5-FU forthe treatment of Bowen’s disease.6

Forty-two subjects from two centerswere initially enrolled who hadpreviously untreated, biopsy-provenBowen’s disease, measuring 0.5 to4.0cm in largest diameter. The PDTgroup was treated with 20 percentALA applied four hours beforeillumination with 100J/cm2

narrowband red light (630nm). 5-FUwas applied to lesions once daily forone week and then twice daily for upto four weeks. Two subjectswithdrew. After 12 months, completeclinical clearance rates were 82percent and 48 percent in the PDTand 5-FU groups, respectively. Moreadverse reactions were found in the5-FU group. No histologicconfirmation of recurrence wasperformed.

IMIQUIMODImiquimod is FDA approved for

the treatment of actinic keratosesand superficial BCC. It is used in anoff-label fashion for a number ofother dermatologic conditions. Itworks through toll-like receptor 7 toinduce local cytokine and chemokinerelease, activate dendritic cells, andthen enhance innate and cell-mediated immunity.

Imiquimod for BCC. Geisse etal studied treatment of superficialBCCs in two randomized, controlled,

double-blind Phase 3 trials.7 Thesestudies were the basis for FDAapproval of imiquimod for thisindication. Subjects were treatedwith imiquimod or vehicle once dailyfor five or seven days per week forsix weeks. The lesions wereexamined at 12 weeks post-treatment and were then excisedwith 3 to 4-mm margins. Data fromboth studies were pooled to finallyrepresent 55 centers in the UnitedStates. Lesions were 0.5 to 2.0cm2 indiameter. Of the 724 subjectsrandomized, 663 applied at least 80percent of the required doses andwere included in the final analysis.More subjects in the seven-day-per-week group had to take rest periodsthan in the other groups. In theintention-to-treat analysis, histologiccure rates were 82 percent (CI76–87%) for the five-days-per-weekgroup and 79 percent (CI 73–85%)for the seven-day-per-week group.The differences between each activegroup and the corresponding vehiclewere significant (p<0.001). Therewas no significant differencebetween active groups in histologiccure. More local skin reactions(erythema, crusting, edema, itching,etc.) were found in the seven-day-per-week group than in the five-day-per-week group (p=0.002) and theseverity of reaction correspondedsignificantly with both clinical andhistologic clearance. The negativepredictive value for clinicalassessments (if the clinicalassessment was negative, what is thelikelihood that the histologic findingwas negative) was greater than 90percent.

Gollnick et al present results froman interim two-year results from afive-year study using imiquimod totreat superficial BCCs.8 This is anongoing, Phase 3, open-label studyusing imiquimod five times per weekfor six weeks. Twenty-five Europeancenters enrolled 182 subjects. BCCshad to be 1cm from the hairline,eyes, ears, nose, and mouth.Diameter was between 0.5cm and



2.0cm2. Tumors with aggressivehistology were excluded as weretumors deeper than 1mm. Subjectswere seen at Weeks 2, 4, and 6 oftreatment. Follow-up was at 12weeks post-treatment and at Months3, 6, and 12 post-treatment. Subjectswere then followed annually. Initialclinical clearance rate (intention-to-treat) was 89.6 percent at 12 weekspost-treatment. The clinicalresponse rates increased as local sitereaction severity increased.Nineteen percent of subjects had totake rest periods because of localsite reactions.

Preliminary five-year data forsustained clearance rates arepromising. The two-year clinicalclearance rate is 91 percent, whichis higher than the 79.4 percent theinitial study predicted. Five-yearsustained clearance rates areapproaching 87 percent. Mostsubjects who had clinicalrecurrences did so within the firsttwo years.

Shumack et al used imiquimod totreat biopsy-proven nodular BCCsin two different studies.9 The firstwas a six-week, open-label trial at10 sites in Australia and NewZealand. Ninety-nine subjects weretreated with imiquimod once daily,three or seven days per week ortwice daily three days per week. Ina 12-week randomized, controlled,double-blind trial in the UnitedStates, 92 subjects at 12 sites weretreated with imiquimod or acorresponding vehicle for three,five, or seven days per week. Bothgroups initially had a twice-daily,seven-days-per-week arm, but thiswas eliminated because of thefrequency of local skin reactions.Tumors were between 0.5cm and1.5cm2, and were >1cm from theeyes, nose, mouth, ear, or hairline.The entire tumor area was excisedsix weeks after treatment with 3 to4-mm margins. Both studiesreported data from an intention-to-treat analysis.

In the 12-week study, 88 of 92

subjects had complete follow-up.Complete histologic cure was foundin 13 percent (3/24), 60 percent(12/20), 70 percent (16/23), and 76percent (16/21) of subjects in thevehicle, three-days-per-week, five-days-per-week, and seven-days-per-week groups, respectively.Compared to vehicle, all activetreatment groups showedstatistically significantly betterresponse rates. Significantcorrelations were found between theintensity of local side effects andresponse rate in the five-day-per-week group (p=0.003) only. Thenegative predictive value forcomplete response was 91 percentand the positive predictive value forrecurrence was 54 percent. Localskin reactions were mostly mild ormoderate.

In the six-week study, 95 subjects(mostly men) had complete follow-up. A significant correlation betweenintense erosion and response ratewas found in the once daily, seven-days-per-week group (p=0.046), butnot in other groups. Similar sideeffects were seen as in the 12-weekstudy. Complete histologic responserates were seen in 59 percent(19/32), 42 percent (13/31), and 71percent (25/35) of subjects in theonce daily, three-days-per-week;twice daily, three-days-per week;and once daily, seven-days-per-weekgroups, respectively.

Eigentler et al conducted a Phase3, randomized, open-label studyusing imiquimod for biopsy-provennodular BCCs three times weeklyfor eight or 12 weeks.10 Tumors hada maximum diameter of 1.5cm. Ateight-weeks post-treatment,excision was performed with 3-mmmargins. Ninety subjects completedthe study. The clinical response ratewas 78 percent and the histologiccure rate was 64 percent. Notsurprisingly, smaller (<1cm atrandomization) tumors had highercure rates (both clinically andhistologically). Local site reactionswere seen in 92 percent of subjects

and includederythema, edema,vesicles, erosions,ulcers,desquamation, and drainage andpigmentary problems. Most sideeffects were moderate, as per thephysician’s judgment. Almost onethird of the lesions were found tohave residual tumor by histology.

Imiquimod for Bowen’sdisease. Mackenzie-Wood et altreated 16 subjects with Bowen’sdisease in a Phase 2, open-labelstudy.11 Imiquimod was applied dailyfor 16 weeks. Six weeks post-treatment, a biopsy was performed.Tumors ranged from 1 to 5.4 cm(median diameter >3cm2) indiameter and most were on legs.Previously treated lesions, lesions onthe face, and subjects onimmunosuppressive orimmunomodulating drugs wereexcluded. At the six-week post-treatment visit, 93 percent ofspecimens were clear. Local sitereactions were seen in 15 of 16subjects. In five subjects, satellitereactions occurred, whichmanifested as skin irritationinvolving an area up to double thesize of the initial tumor. Six subjectshad to discontinue treatment at fourweeks secondary to local sitereactions, and four subjectseventually needed oral antibiotics.

In a retrospective study, Rosen etal treated subjects with imiquimodfor Bowen’s disease.12 Subjects usedimiquimod daily for six weeks.Almost all subjects were male andlesions were mostly on theextremities. Lesions on the genitaliawere treated every other day. Forty-nine subjects had a clinical responserate of 86 percent. The remainingsubjects required additionaltreatment.

There are several disadvantagesto the use of imiquimod. Local skinreactions are common. Erythema isthe most common side effect.Edema, ulceration, burning, erosionpruritus, scabbing, and



dyspigmentationare also common.Althoughuncommon, flu-like

symptoms can occur. The extent ofreaction by a particular patient isdifficult to predict. The cream is alsoexpensive and packagedinconveniently. The regimen of sixweeks of treatment may also becumbersome to some patients.Finally, the histologic cure rate isabout 80 percent, which is arguablyimpressive for a topical cream.Imiquimod is indicated forsuperficial BCCs, which are <2cmand not on the face. The advantagesof imiquimod in the treatment ofsuperficial BCCs include thefollowing: it is patient administered,leads to excellent cosmesis, isusually well tolerated, can treatsubclinical disease, and has goodcure rates.

Imiquimod as adjuvanttreatment. Another use forimiquimod is as adjuvant treatmentfollowing curettage. Imiquimod canbe useful when superficial marginsare positive after excision. It canalso be used to clean-upbackground actinic damage prior toMohs surgery. Additionally, severalstudies have investigated theadjuvant use of imiquimod aftercurettage (with or withoutelectrodessication).

Spencer conducted a double-blind, vehicle-controlled, pilot studyusing imiquimod afterelectrodessication and curettage(ED&C) in patients with nodularBCC, compared to ED&C alone.13

Tumors were 4 to 17mm in diameter.Twenty-two subjects received threecycles of ED&C, followed by eitherimiquimod or vehicle daily for onemonth. Twenty subjects completedthe trial. At eight weeks (four weekspost-treatment), residual tumor wasidentified histologically in 10 percentand 40 percent in imiquimod andvehicle groups, respectively. All siteswere well healed by eight weeks,although the vehicle group healed

more quickly. More subjects in thevehicle group had atrophic and/orhypopigmented areas by grossinspection. Imiquimod was welltolerated in most subjects. Inconclusion, imiquimod plus ED&Chad a much higher histologic curerate but the treated areas tooklonger to heal.

In an open-label, pilot study,Neville et al treated 15 subjects with17 nodular BCCs with 5% imiquimodafter initial treatment withcurettage.14 Curettage wasperformed on the lesion as well as3mm of surrounding normal skin.One week later, imiquimod wasapplied once daily, five times perweek for six weeks. Six weeks afterthis, patients returned to have thearea excised with 3-mm margins.There was a 100-percent histologicclearance rate. Local site reactionsoccurred in 67 percent (10) ofsubjects, and nine subjects requiredrest periods.

Rigel et al conducted an open-label, pilot study in 57 subjects withboth nodular and superficial BCCsusing 5% imiquimod followingcurettage.15 One week post-curettage, imiquimod cream wasapplied once daily, five times perweek for six weeks. At one-yearpost-treatment, zero percent ofsubjects had clinical recurrences.Cosmetic results were good toexcellent. No hypertrophic scarswere noted, which is importantbecause one of the most commonadverse cosmetic outcomes withcurettage is hypertrophic scarring.

Tillman and Carroll enrolled 90subjects in an open-label study usingimiquimod 5% cream after curettagefor biopsy-confirmed BCCs (61%nodular, 13% infiltrative, 13% mixed,7% superficial, and 7% recurrent).16

Sixty-six percent were in high-riskanatomical areas. Of 101-treatedtumors, a 96-percent clinicalclearance rate was found at anaverage of 36 months follow-up.Although no histologic cure rate wasreported, the clinical cure rate is

very high for such a largepercentage of high-risk tumors.

Advantages to adjuvant therapy ofBCCs with imiquimod followingcurettage include higher cure rates(than ED&C alone) and improvedcosmesis. Disadvantages include ahigher cost, slower healing, andincreased work by the patient.

CONCLUSIONImiquimod, topical 5-FU, and PDT

all show effectiveness in the treat-ment of superficial, low-risk tumors.Imiquimod has especially good effi-cacy for superficial BCCs with clini-cal cure rates approaching 90 per-cent. The results are not as good fornodular BCCs. In general, imiquimodis well tolerated and results in agood cosmetic outcome. 5-FU is notwell studied for BCCs and Bowen’sdisease although it is FDA approvedfor the treatment of superficialBCCs. The major use for 5-FU is stillfor actinic keratoses. PDT is widelyused in Europe for Bowen’s diseaseand BCCs. It is likely to be morewidely accepted in the United Stateswhen MAL is available and withshorter contact time employed.

Cosmesis is consistently good toexcellent with all topical therapies dis-cussed. The combination of curettagewith imiquimod, topical 5-FU, or PDTmay improve the cure rate.

Surgery, particularly Mohs sur-gery, continues to show the highestcure rates and remains the treat-ment of choice for high-risk BCC andinvasive SCC.

REFERENCES1. Tull S, Nunley K, Sengelmann R.

Nonsurgical treatment modalities for

primary cutaneous malignancies.

Dermatol Surg. 2008;34:859–872.

2. Rhodes LE, deRie MA, Leifsdottir R, et

al. Five-year follow-up of a randomized,

prospective trial of topical methyl

aminolevulinate photodynamic therapy

vs surgery for nodular basal cell carci-

noma. Arch Dermatol.

2007;143(9):1131–1136.

3. Braathen LR, Szeimies R, Basset-Seguin

N, et al. Guidelines on the use of photo-



dynamic therapy for nonmelanoma skin

cancer: an international consensus. J

Am Acad Dermatol. 2007;56:125–143.

4. http://www.fda.gov/medwatch/safe-

ty/2005/Oct_PI/Efudex_PI.pdf.

Accessed September 29, 2008.

5. Gross K, Kircik L, Kricorian G. 5% 5-

fluorouracil cream for the treatment of

small superficial basal cell carcinoma:

efficacy, tolerability, cosmetic outcome,

and patient satistfaction. Dermatol

Surg. 2007;33:433–440.

6. Salim A, Leman JA, McColl JH, et al.

Randomized comparison of photody-

namic therapy with topical 5-fluo-

rouracil in Bowen’s disease. Br J

Dermatol. 2003;148:539–543.

7. Geisse J, Caro I, Lindholm J, et al.

Imiquimod 5% cream for the treatment

of superficial basal cell carcinoma:

results from two phase III, randomized,

vehicle-controlled studies. J Am Acad

Dermatol. 2004;50:722–733.

8. Gollnick H, Barona CG, Frank R, et al.

Recurrence rate of superficial basal cell

carcinoma following successful treat-

ment with imiquimod 5% cream: inter-

im 2-year results from an ongoing 5-

year follow-up study in Europe. Eur J

Dermatol. 2005;15(5):374–381.

9. Shumack S, Robinson J, Kossard S, et

al. Efficacy of topical 5% imiquimod

cream for the treatment of nodular

basal cell carcinoma. Arch Dermatol.

2002;138:1165–1171.

10. Eigentler TK, Kamin A, Weide BM, et

al. A phase III, randomized, open-label

study to evaluate the safety and effica-

cy of imiquimod 5% cream applied

thrice weekly for 8 and 12 weeks in the

treatment of low-risk nodular basal cell

carcinoma. J Am Acad Dermatol.

2007;57:616–621.

11. Mackenzie-Wood A, Kossard S,

deLauney J, et al. Imiquimod 5% cream

in the treatment of Bowen’s disease. J

Am Acad Dermatol. 2001;44:462–470.

12. Rosen T, Harting M, Gibson M.

Treatment of Bowen’s disease with topi-

cal 5% imiquimod cream: retrospective

study. Dermatol Surg. 2007;33:

427–432.

13. Spencer JM. Pilot

study of imiquimod

5% cream as

adjunctive therapy

to curettage and

electrodesiccation for nodular basal cell

carcinoma. Dermatol Surg.

2006;32:63–69.

14. Neville JA, Williford PM, Jorizzo JL.

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cream in the treatment of nodular basal

cell carcinoma after initial treatment

with curettage. J Drugs Dermatol.

2007;6(9):910–914.

15. Rigel DS, Torres AM, Ely H.

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16. Tillman DK, Carroll MT. A 36-month

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Limiting antibiotic usage intreating acne is becoming atopic of great interest as the

problem of antibiotic resistanceincreases in both importance and inpublic awareness. The antibioticsthat we use most, the tetracyclines,have recently assumed a greater rolein treating infections since they areone of the few inexpensive drugs towhich methicillin-resistantStaphylococcus aureus strainsrespond. Situations that promoteresistance such as long-termtreatment occur routinely indermatology. For example, manyacne patients require antibiotics foran extended period, but for manyothers there are methods to limitantibiotic use and still obtain anexcellent clinical response.1,2

LIMITING THE DURATION OFANTIBIOTIC TREATMENT

One technique to limit theduration of antibiotic treatment is tooptimize topical retinoid use. Usedas monotherapy, topical retinoids area slow way to treat acne. Patientsneed to use topical retinoids forabout 12 weeks for optimalresponse. However, few acnepatients persevere long enough forretinoids to be effective. Typically,

dermatologists add retinoids later intherapy, but this is not optimal.Several studies document that if apatient with inflammatory acnebegins topical retinoid therapy at thesame time as an oral antibiotic, theoral antibiotic can be discontinuedafter three months and the patientcan be maintained on topicalretinoid alone from that pointforward.2,3 The patients in whom thisworks are those who had a goodresponse at three months (i.e., abouta 75% improvement). It must also beemphasized that the topical retinoidmust be faithfully used from thestart. If it is started late or usedsporadically, results will be lessrewarding. About 70 percent of acnepatients in my practice are treatedin this manner.

Another technique to limitantibiotic use is to usesubantimicrobial dosages ofdoxycycline. At very low doses,beneath the minimal inhibitorydosage, the drug still has significantanti-inflammatory activity. Althoughapproved for rosacea usage, anti-inflammatory-dose doxycycline alsohas some benefits in acne, especiallyin those patients with an overlap ofacne and rosacea. A logical questionarises as to whether antimicrobial

dosages of doxycycline are as anti-inflammatory as higher doses, and itseems this is true. An analysis of theeffects of weight, dosage, andclinical response in rosacea showthat a nearly four-fold difference inweight has no effect on outcome,suggesting that 40mg of doxycyclineis as effective as 160mg in thetreatment of rosacea.4 A secondrecent study compared lesion countsin rosacea patients treated withtopical metronidazole and either 40or 100-mg doxycycline and foundthe regimens to be equivalent (datanot yet published).

The possibility of subantimicrobialminocycline arises frequently.However, minocycline isconcentrated in certain tissues (e.g.,the sebaceous glands), and althoughblood levels might be subinhibitory,tissue levels may not be so.

THE EMERGENCE OF TOPICALDAPSONE

Topical dapsone is soon to be anaddition to the acne arsenal.Although approved two years ago, itsrelease was delayed until it could beshown that the drug was safe forpatients with G6PD deficiency. Thosestudies have been performed and thedrug was shown to have no effect on

What’s New in Acne

by GUY WEBSTER, MD, PHD

AUTHOR AFFILIATIONS: Dr. Webster is Clinical Professor, Department of Dermatology, Jefferson Medical College, Philadelphia, Pennsylvaniaand in private practice.

ADDRESS CORRESPONDENCE TO: Guy Webster, MD, PhD; 720 Yorklyn Road, Suite 10, Hockessin, DE 19707

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[ N o v e m b e r 2 0 0 8 • V o l u m e 1 • N u m b e r 4 ] S u p p l e m e n t t o 9

hemoglobin levels. No blood test isneeded to prescribe topical dapsoneand it may be safely given to patientswith G6PD deficiency. In Phase 3studies, topical dapsone showed goodactivity against both inflammatoryand noninflammatory acne lesions(Figure 1).5 As yet, there are nocomparisons available with othertopical or oral acne medications, butthese will certainly be forthcomingafter the drug becomes available laterthis year.

THE iPLEDGE PROGRAMThe results of the first year of the

iPledge program show no decrease inreported pregnancies compared tothe preceding year, but it can besafely assumed that the iPledgenumber is an accurate one and isprobably lower than the number ofpregnancies in earlier years. Nothingis known regarding the illicit use ofisotretinoin outside of the iPledgeprogram. There are legitimateconcerns that some patients may beacquiring the drug in other countriesor via internet pharmacies.

ANTIMICROBIAL PEPTIDESAntimicrobial peptides, part of the

innate immune system, have received

a lot of attention as potential acnemedications, but, to date, have failedin clinical trials, perhaps because ofinactivity in the lipid environment ofthe follicle. Early trials suggest thatthese medications may have someactivity in rosacea. Research isongoing in this area.

LIGHT AND LASER THERAPYLight and laser therapy of acne

continues to be a promising area ofinvestigation. There are manytargets for phototherapy in acne;the follicle wall, P. acnes, thesebaceous gland, and theinflammatory response itself.Numerous case reports andcollections of cases suggest thatvarious light-based treatments havesome activity in acne, but becauseof numerous variations betweenpatients’ regimens and co-treatment with other agents, it isimpossible to say how effectivelight-based treatments truly are andwhat role they should play intreating the disease.

One proof-of-concept study hasshown what might be possible withphototherapy in acne. Anderson et al6

sensitized patients with aminolevulinicacid and then delivered a large

amount of light. Afterhealing they found adramatic suppressionin sebaceous activity. Although thisregimen is too unpleasant for routineuse, it does demonstrate that a topicalagent can reach the sebaceous glandand cause its destruction when photo-activated. An isotretinoin-like effectwould seem possible.

A photo-active drug currentlyunder development may make sucha promise real. Lemuteporfin is amolecule that is photoactive andwill target sebaceous glands only,sparing the rest of the skin. Inanimal studies the drug was shownto selectively destroy sebaceousglands when activated by light.Human trials are set to begin soon.

REFERENCES1. Webster GF. The pathophysiology of

acne. Cutis. 2005;76(2 Suppl):4–7.

2. Leyden JJ, Del Rosso JQ, Webster GF.

Clinical considerations in the treatment

of acne vulgaris and other inflammato-

ry skin disorders: focus on antibiotic

resistance. Cutis. 2007;79(6

Suppl):9–25. Review.

3. Leyden J, Thiboutot DM, Shalita AR, et

al. Comparison of tazarotene and

minocycline maintenance therapies in

acne vulgaris: a multicenter, double-

blind, randomized, parallel-group study.

Arch Dermatol. 2006;142(5):605–612.

4. Theobald K, Bradshaw M, Leyden J.

Anti-inflammatory-dose doxycycline

(40mg controlled-release) confers

maximum anti-inflammatory efficacy

in rosacea. Skinmed. 2007;6(5):

221–226.

5. Draelos ZD, Carter E, Maloney JM,

Elewski B, Poulin Y, Lynde C, Garrett S;

United States/Canada Dapsone Gel

Study Group. Two randomized studies

demonstrate the efficacy and safety of

dapsone gel, 5% for the treatment of

acne vulgaris. J Am Acad Dermatol.

2007;56(3):439.e1–10.

6. Hongcharu W, Taylor CR, Chang Y, et al.

Topical ALA-photodynamic therapy for

the treatment of acne vulgaris. J Invest

Dermatol. 2000;115(2):183–192.

Figure 1. Effect of dapsone gel on inflammatory and noninflammatory acne lesions

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The pathogenesis of rosacearemains poorly understoodand as a result, there is a

conspicuous absence in thedevelopment of new active agents totreat rosacea. Importantly, rosacea isbest viewed as a spectrum of clinicalpresentations with multiple features,which may or may not be present ina given patient.1 This perspective ledto the definition of distinctive rosaceasubtypes, the most common of whichinclude erythematotelangiectatic(subtype 1) and inflammatory(subtype 2). The latter is alsoreferred to as papulopustularrosacea.2 Multiple pathophysiologicmechanisms have been reported tobe associated with rosacea, such asdegradation of dermal matrix bysome matrix metalloproteinaseenzymes (MMPs), increasedcutaneous oxidative stress due toexhaustion of the inherentprotective effect of superoxidedismutase, and innate epidermalbarrier dysfunction of the centralface leading to increasedtransepidermal water loss (TEWL)and “sensitive skin”.3,4 However, howthese specific mechanisms may ormay not be involved with individualsubtypes of rosacea has not been

clearly defined. Additional researchis needed to further define thepathogenesis of rosacea and itssubtypes as such information assistsin the development of therapies thattarget defined pathophysiologicmechanisms.

While we await new research onthe pathogenesis of rosacea, clinicaltrials have been performed morerecently evaluating therapeuticresults for patients with theinflammatory (papulopustular)subtype. In addition, multiplestudies evaluating subantimicrobialdosing of doxycycline have definedits efficacy more completely andhave established lack of antibioticselection pressure. These trials aresummarized next.

ROLE OF SKIN CARE IN THEMANAGEMENT OF ROSACEA

With additional research, itbecomes increasingly apparent thatsymptoms of “sensitive skin”observed in patients with botherythematotelangiectatic andinflammatory rosacea relate toinherent epidermal barrierdysfunction.5,6 The importance ofproper skin care as a component ofthe management program for rosacea

is well recognized, as use of a gentlecleanser and moisturizer serves todecrease signs and symptoms ofsensitive skin that are common inrosacea patients and can improve thetolerability of topical medication.6–8

Recently published RosaceaManagement Guidelines from theAmerican Acne and Rosacea Society(AARS) support the importance ofappropriate skin care and rationalproduct selection as importantcomponents of optimal rosaceamanagement.9

A question often asked byclinicians and their support staffwho are involved with educatingpatients about rosacea is, “Whatgets applied first, the moisturizer orthe medication?” This question hasbeen addressed in a recentlyperformed percutaneous absorptionkinetics study using human skin.10 Inthis study, the percutaneousabsorption kinetics of azelaic acidformulated as the commerciallyavailable 15% gel (Finacea, Intendis,Berlin, Germany) were documentedutilizing an established in-vitrohuman skin model. These resultswere compared to the percutaneousabsorption profiles of azelaic acidwhen the 15% gel was applied

Update on the Medical Management

of Rosaceaby JAMES Q. DEL ROSSO, DO, FAOCD

AUTHOR AFFILIATIONS: Dr. Del Rosso is Clinical Associate Professor (Dermatology), University of Nevada School of Medicine and TouroUniversity College of Osteopathic Medicine; Dermatology Residency Director, Valley Hospital Medical Center and Las Vegas Skin and CancerClinics, Las Vegas and Henderson, Nevada.

ADDRESS CORRESPONDENCE TO: James Q. Del Rosso, DO, FAOCD; e-mail: [email protected]

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before or after application of one ofthree brand moisturizer lotions(CeraVe Lotion, Coria Laboratories,Fort Worth, Texas; Cetaphil Lotion,Galderma Laboratories, Fort Worth,Texas; Dove Lotion, EnglewoodCliffs, New Jersey). The resultsdemonstrated that the applicationof any of the three brandmoisturizer lotions did not impairthe percutaneous penetration ofazelaic acid if applied first.

METRONIDAZOLEMultiple studies have confirmed

the efficacy of topical metronidazolein the treatment of rosacea, including0.75% gel, lotion, and creamformulations applied twice daily and1% gel and cream formulationsapplied once daily.1,5,11 Metronidazolegel 1% (MetroGel 1%, GaldermaLaboratories, Fort Worth, Texas) isincorporated into a new water-basedgel technology called HSA-3, whichutilizes betadex (cyclodextrin) tosolubilize metronidazole, a very lowconcentration of propylene glycolwhich serves as a humectant, and alow concentration of niacinamidewhich is proposed to assist inmaintaining epidermal barrierintegrity.6 The HSA-3 vehicletechnology is not associated withincreased TEWL and may producesome hydrating effect based oncorneometry. Metronidazole gel 1%has been shown to be therapeuticallyequivalent to metronidazole cream1%, and to azelaic acid gel 15% incontrolled noninferiority studies.6,7

AZELAIC ACIDAzelaic acid 15% gel applied twice

daily has been shown in multiplestudies to be effective for thetreatment of inflammatoryrosacea.1,11–13 A recent, controlled, 12-week study has demonstrated thatazelaic acid 15% once daily istherapeutically equivalent to twicedaily application based onquantitative assessment(inflammatory lesion reduction) andboth static and qualitative

investigator assessments.14 Theimportance of these findings areclinically relevant as once dailyapplication is anticipated to correlatewith improved compliance and lowercost of therapy per unit time.

ANTI-INFLAMMATORY-DOSEDOXYCYCLINE

Anti-inflammatory-dosedoxycycline refers specifically todoxycycline 40-mg delayed release,formulated as a 30-mg immediate-release and 10-mg delayed-releasecapsule (Oracea, CollaGenexPharmaceuticals, Inc., Newtown,Pennsylvania) administered oncedaily. Therefore, the term anti-inflammatory-dose doxycycline isused interchangeably withdoxycycline 40-mg delayed-releasecapsule once daily. Anti-inflammatory-dose doxycycline isapproved by the US Food and DrugAdministration (FDA) for treatmentof inflammatory rosacea.15

Importantly, anti-inflammatory-dosedoxycycline is devoid of antibioticactivity, even with prolongedadministration, based onpharmacokinetic and long-termmicrobiologic studies.15,16 Theapproved labeling for anti-inflammatory-dose doxycyclineincludes nine-month microbiologicand safety data, supporting both thelack of antibiotic activity and afavorable safety profile withprolonged administration.16,17

A recent, double-blind, 16-weektrial compared the efficacy and safetyin patients randomized to receivemetronidazole gel 1% once daily andeither doxycycline 100mg daily ordoxycycline 40-mg delayed-releasecapsule once daily. Efficacy asmeasured by inflammatory lesionreduction, investigator globalassessment, and erythema reductionwas confirmed and was essentiallyequivalent in both study arms. Inaddition, the speed of onset and timecourse of clinical efficacy were thesame in both groups, based onassessment of all three efficacy

parameters. In thissame trial, adversereactions (especiallygastrointestinal sideeffects such as nausea and abdominalpain) were markedly higher in thegroup of subjects receivingdoxycycline 100mg once daily.

What is the clinical significance ofthe findings from the studycomparing anti-inflammatory-dosedoxycycline versus doxycycline100mg once daily in subjects alsotreated with metronidazole gel 1%once daily? Several observations canbe made from the study results.

First, it is important to recognizethat clinical studies evaluatingconventional antibiotic dosing oftetracyclines and other antibioticsused to treat rosacea are limited, andthat no dose-response studies havebeen performed.1,11,15,19 As such, thefinding that doxycycline 40-mgdelayed-release capsules once daily istherapeutically equivalent todoxycycline 100mg once dailysuggests that “more” is notnecessarily synonymous with “better”for rosacea, as sufficient andpotentially optimal anti-inflammatoryactivity is achieved using anti-inflammatory-dose doxycycline.

The observation that anti-inflammatory-dose doxycycline anddoxycycline 100mg once dailyexhibited the same onset and timecourse of clinical efficacy suggeststhat anti-inflammatory effects, and notantibiotic activity, are responsible fortherapeutic benefit when atetracycline derivative is used to treatinflammatory rosacea. Third, thegreater incidence of adverse reactions,especially gastrointestinal side effects,supports a more favorable safetyprofile with anti-inflammatory-dosedoxycycline as compared todoxycycline 100mg once daily.

ROSACEA MEDICALMANAGEMENT GUIDELINES

The AARS has independentlydeveloped and published RosaceaManagement Guidelines, which



discuss availablemedical therapyoptions, includingtopical therapies,

systemic therapies, and skincare.9,20 These guidelines weredeveloped solely by the AARS andapproved by its leadership, not tocreate a structured treatmentalgorithm, but rather to provide anoverview of the various options andtypes of evidence which supporttheir use. The AARS RosaceaManagement Guidelines are easilyaccessible, succinct, referenced,and reflective of a consensusamong several dermatologists whoare very interested andknowledgeable regarding rosacea.It is also hopeful that theseguidelines may prove to be ahelpful reference to thoseevaluating formulary access andthird-party coverage in order toassure that an adequate menu oftherapeutic choices is available forclinicians treating rosacea patients.

SUMMARYAlthough much more fundamental

research needs to be performed tofurther elucidate thepathophysiologic pathways involvedin rosacea, clinical trials serve tofurther the development oftreatment advances despite theconspicuous absence of new activecompounds. In addition, suchresearch defines potentially betterways to apply therapeutic optionsthat are already present in ourarmamentarium. Examples of morerecent advances and/or observationsin rosacea include vehicletechnology employed withmetronidazole gel 1%, therapeuticequivalence of azelaic acid gel 15%applied once daily as compared totwice daily, information onmoisturizer use and order of

application, and confirmation thatanti-inflammatory-dose doxycyclineis therapeutically equivalent todoxycycline 100mg daily.

REFERENCES1. Del Rosso JQ. Medical treatment of

rosacea with emphasis on topical thera-

pies. Expert Opin Pharmacother.

2004;5:5–13.

2. Wilkin J, Dahl M, Detmar M, et al.

Standard classification of rosacea:

report of the National Rosacea Society

Expert Committee on classification and

staging of rosacea. J Am Acad

Dermatol. 2002;46:584–587.

3. Dahl MV. Pathogenesis of rosacea. Adv

Dermatol. 2001;17:29–45.

4. Del Rosso JQ. Update on rosacea

pathogenesis and correlation with med-

ical therapeutic agents. Cutis.

2006;78:97–100.

5. Dirschka T, Tronnier H, Folster-Holst R.

Epithelial barrier function and atopic

diathesis in rosacea and perioral der-

matitis. Br J Dermatol.

2004;150:1136–1141.

6. Del Rosso JQ. The role of skin care and

maintaining proper barrier function in

the management of rosacea. Cosmet

Dermatol. 2007;8:485–490.

7. Del Rosso JQ, Baum EW.

Comprehensive medical management of

rosacea: an interim study report and lit-

erature review. J Clin Aesthet

Dermatol. 2008;1:20–25.

8. Subramanyan K. Role of mild cleansing

in the management of patient skin.

Dermatol Ther. 2004;17(suppl

1):26–34.

9. Del Rosso JQ, Baldwin H, Webster G.

Rosacea medical management guide-

lines (American Acne and Rosacea

Society). J Drugs Dermatol. 2008. In

press.

10. Del Rosso JQ. Percutaneous absorption

kinetics of azelaic acid 15% gel. Cutis.

2008 (submitted for publication).

11. Pelle MT, Crawford GH, James WD.

Rosacea II. Therapy. J Am Acad

Dermatol. 2004;51:499–512.

12. Thibotout D, Thieroff-Ekerdt R, Graupe

K. Efficacy and safety of azelaic acid

(15%) gel as a new treatment for papu-

lopustular rosacea: results from two

vehicle-controlled, randomized phase

III studies. J Am Acad Dermatol.

2003;48:836–845.

13. Elewski BE, Fleischer AB, Pariser DM.

A comparison of 15% azelaic acid gel

and 0.75% metronidazole gel in the top-

ical treatment of papulopustular

rosacea. Arch Dermatol.

2003;139:1444–1450.

14. Thiboutot DM, Fleischer AB, Del Rosso

JQ, et al. Azelaic acid 15% gel once

daily vs. twice daily in papulopustular

rosacea: a multicenter, double-blind,

clinical trial. J Drugs Dermatol. 2008.

In press.

15. Del Rosso JQ, Webster GW, Jackson M,

et al. Two randomized phase III clinical

trials evaluating anti-inflammatory-dose

doxycycline (40mg doxycycline, USP

capsules) administered once daily for

treatment of rosacea. J Am Acad

Dermatol. 2007;56:791–802.

16. Oracea [product monograph].

Newtown, PA: CollaGenex

Pharmaceuticals; 2006.

17. Preshaw PM, Novak MJ, Mellonig J, et

al. Modified-release subantimicrobial

dose doxycycline enhances scaling and

root planing in subjects with periodon-

tal disease. J Periodontol.

2008;79:440–452.

18. Del Rosso JQ, Schlessinger J, Werschler

P. Comparison of anti-inflammatory

dose doxycycline versus doxycycline

100mg in the treatment of rosacea. J

Drugs Dermatol. 2008 (accepted for

publication).

19. Bikowski JB. Subantimicrobial dose

doxycycline for acne and rosacea. Skin

Med. 2003;2:234–245.

20. American Acne and Rosacea Society.

Rosacea medical management guide-

lines. Poster presented at: 2007 Fall

Clinical Dermatology Conference;

October 2007; Las Vegas, NV.


Project1 9/9/08 11:42 AM Page 1

Answer irritation with hydration—Duac® Care System (CS)

One less battle in the fight against acne

Irritating acne treatments can

discourage compliance1

• Increasing irritation correlates with increasing transepidermal water loss (TEWL)2

• Poor compliance has been reported to be the most common cause of nonresponse to acne medication3

DUAC Topical Gel is indicated for the topical treatment of inflammatory acne vulgaris.

Important Safety Information

DUAC Topical Gel is contraindicated in patients who have shown hypersensitivity to any of its components or lincomycin, and in those with a history of regional enteritis,ulcerative colitis, or antibiotic-associated colitis.Diarrhea, bloody diarrhea, and colitis have been reported with the use of topical clindamycin.Discontinuation is recommended if significant diarrhea develops.

Side effects may include erythema, peeling, burning, and dryness.

Please see brief summary of prescribing information on the following page.

References: 1. Tanghetti EA. The building blocks to better acne treatment. Skin Aging.2005;13(8):74-77. http://www.skinandaging.com/article/4494. Accessed September 27,2007. 2. Wu Y, Wang X, Zhou Y, et al. Correlation between stinging, TEWL and capacitance.Skin Res Technol. 2003;9(2):90-93. 3. Zaghloul SS, Cunliffe WJ, Goodfield MJD. Objective assessment of compliance with treatments in acne. Br J Dermatol. 2005;152(5):1015-1021.4. Del Rosso JQ. The role of the vehicle in combination acne therapy. Cutis. 2005;76(suppl 2):15-18. 5. Fagundes DS, Fraser JM, Klauda HC. Difference in the irritation potential and cosmetic acceptability of two combination topical acne gels—combined results of two comparative studies. Todays Ther Trends. 2003;21:269-275. 6. Data on file, Stiefel Laboratories, Inc. 7. Langner A, Chu A, Goulden V, Ambroziak M. A randomized, single-blind comparison of topical clindamycin + benzoyl peroxide and adapalene in the treatment of mild to moderate facial acne vulgaris. Br J Dermatol. 2008;158(1):122-129.

© 2008 Stiefel Laboratories, Inc. DTG-28-2008-USA

US Patent No. 5466446. Patents Pending.

DUAC, STIEFEL, and STIEFEL and the “S” logo are

registered trademarks of Stiefel Laboratories, Inc. www.stiefel.com

Duac® CS is designed to

minimize irritation4,5

• DUAC® Topical Gel is unique acne medication because it contains 1% dimethicone and 4% glycerin

• With its unique hydrating vehicle, DUAC Topical Gel significantly reduces TEWL (P=.0193)6

Patients agree, DUAC Topical Gel

delivers impressive results7

• Significant improvement in acne grade began as early as week 1 (P=.013) and continued throughout the study (P .038)

• At 12 weeks, ~90% of patients using DUAC Topical Gel (n=65) agreed with physician assessment that their acne was improved

C4_jcad_0908_Stiefel.qxp 9/3/08 4:20 PM Page 1

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