Supplement to the January 2010 issue of
Proceedings from the
2009 Alabama Dermatology Society Meeting
www.jcadonline.com
Dermatology on the Beach
Matrix Medical Communications
The Alabama Dermatology Society’s “Dermatology
on the Beach” meeting has rapidly grown into one of President
the highest attended dermatology meetings in the Robert L. Dougherty
country. Over the last two years, attendance has rdougherty@matrixmedcom.com
exceeded 323 registrants each year, and the geo- Partner
graphical distribution has encompassed participants Patrick D. Scullin
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quality program offered by this medical event. Executive Editor
Kimberly B. Chesky
The first presentation discussed will be from Dr. kchesky@matrixmedcom.com
George Martin, the program director of Maui Derm,
who shares his extensive experience treating actinic Assistant Editor
keratoses with both topical and physical modalities. Angela M. Hayes
Actinic keratosis is perhaps the most common treat- ahayes@matrixmedcom.com
ment diagnosis in the world of dermatology besides
acne. Classified Sales Manager
Melanie A. Wolfrom
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Proceedings from The 2009 Alabama Dermatology Society Meeting
Contents George Martin, MD
Director
Changing Paradigms and Emerging Dermatology and Laser Center
of Maui
Therapies in the Treatment of Maui, Hawaii
Actinic Keratoses
4 by George Martin, MD
New Dermatology Treatment
Regimens and Clinical James Q. Del Rosso, DO, FAOCD
Dermatology Residency Director
Applications Relevant Valley Hospital Medical Center
Las Vegas, Nevada
to Daily Patient Care
11 by James Q. Del Rosso, DO, FAOCD
Carlos Ricotti, MD
Optimizing Management of Instructor
Department of Dermatology,
Nonmelanoma Skin Cancers Division of Dermatopathology
University of Texas
Actinic Keratosis and Squamous Cell Southwestern Medical Center
Dallas, Texas
Carcinoma: The Debate Over Classification
and What it Means for Patients
14 by Carlos Ricotti, MD, and Clay J. Cockerell, MD
The Current Standards of Care in Darrel S. Rigel, MD
Clinical Professor,
Basal Cell Carcinoma NYU Medical Center
Attending Physician,
17 by Darrel Rigel, MD NYU Tisch Hospital
New York, New York
The Current Standards of Care in Actinic
Keratosis and Squamous Cell Carcinoma
19 by Theodore Rosen, MD
Recent Advances and Practice Trends in the
Treatment of Basal Cell Carcinoma, Actinic Theodore Rosen, MD
Professor of Dermatology
Keratosis, and Squamous Cell Carcinoma Baylor College of Medicine
Houston, Texas
23 by Eggert Stockfleth, MD, PhD
Eggert Stockfleth, MD, PhD
Professor of Dermatology
This supplement features selected presentations from Head of Skin Cancer Center
The Alabama Dermatology Society Meeting, which was held in Charité
Department of Dermatology,
Sandestin, Florida from June 25 to June 28, 2009. This sup- Venereology and Allergology
plement was supported by Graceway Pharmaceuticals, LLC. Charité—University Medical
Center
Berlin, Germany
Changing Paradigms and Emerging Therapies
in the Treatment of Actinic Keratoses
by George Martin, MD
Dermatology and Laser Center of Maui, Hawaii
ctinic keratoses (AKs) have long been considered the AKs were graded as KIN I, II, or III, depending on the degree
A earliest part of a biological continuum, ending in inva-
sive squamous cell carcinoma (SCC).1 Recently, based
on clinical, histopathology, cytopathology, and molecular
of epidermal involvement of dyskeratotic cells (Figure 2). In
2006, Ackerman2 proposed unifying a group of keratinocytic
neoplasms, including AKs, beneath one heading. Because of
findings, there has been a paradigm shift away from consid- their noninvasive biological behavior, he recommended that
ering AKs as “pre-cancers” and instead defining them as solar keratosis (AKs), arsenical keratosis, radiation ker-
superficial SCCs.2 Clinical support for this conceptual change atoses, Bowen’s disease, bowenoid papulosis, actinic cheili-
comes from the observation that there has never been a pub- tis, leukoplakia, and keratoacanthoma be referred to as SCC,
lished set of guidelines defining a logical clinical boundary superficial type. Despite their relative merits, neither classifi-
between an AK and a superficial SCC. Histology sections from cation system has yet to receive widespread acceptance
an AK are indistinguishable from those taken from a SCC in among the dermatopathology and pathology community.
situ (Bowen’s disease).3 The cytological atypia found in ker-
atinocytes from an AK are indistinguishable from that found
in cells from an invasive SCC.2,3 At a molecular level, the same Field Therapy
mutation profile found in AKs is found in SCC, particularly in
the p53 gene.4,5,6 However, despite the mounting evidence in The photograph in Figure 3 shows a patient with wide-
favor of equating AKs to SCC superficial type, most dermatol- spread actinic damage. The term “field cancerizaton”11 has
ogists and dermatopathologists do not consider AKs and often been applied to this type of clinical presentation. The
superficial SCC to be one and the same. use of liquid nitrogen (LN2) as “field therapy” in this clinical
Research in the area of toponomics7,8,9,10 may provide crit- setting is impractical. The US Food and Drug Administration
ical information regarding cellular similarities and differ- (FDA)-approved field therapies include diclofenac gel, 5-fluo-
ences between cells from AKs, tumors regarded as superficial rouracil, imiquimod, and both aminolevulinic acid (ALA) and
SCC, and invasive SCC. Considered by scientists as the next methyl aminolevulinate (MAL) photodynamic therapy (PDT).
step beyond mapping the human genome, toponomics However, each modality, when performed according to the
involves identifying the approximately 10,000 proteins in the package insert, is associated with a significant number of side
human cell that form spatially determined molecular net- effects, patient downtime, adherence issues, and physician
works. These networks perform the myriads of cell functions. reticence to prescribe the therapy. For these reasons, AK ther-
The entire map of this functional cellular network is referred apies have been modified from their FDA-approved protocols
to as the toponome. Figure 1 represents the cell surface in an effort to increase patient adherence while maintaining
toponome of a CD4 cell. Future studies involving mapping the therapeutic efficacy.
toponomes of AKs and invasive SCCs will likely provide a bet-
ter understanding of the specific changes involved in the
transformation of AKs into invasive SCC and potentially could Diclofenac Gel
help to identify therapeutic targets.
Diclofenac gel, a topical nonsteroidal anti-inflammatory
drug (NSAID) preparation, is an effective therapy for AKs.12 Its
Actinic Keratoses Under The Microscope reported mechanism of action is attributed to its ability to
block the enzyme COX-2, which is overproduced in epithelial
In 2000, Cockerell et al published a histological classifi- tumors.13 This blockade allows apoptosis (controlled cell
cation system for grading AKs.3 They used the cervical death) to occur in AKs.14 Phase 3 clinical studies showed that
intraepithelial neoplasia (CIN) classification system as a the efficacy of a 90-day treatment course with diclofenac was
model for AKs. The term developed for a classification system limited to the face and forehead.12
for AKs was keratinocytic intraepidermal neoplasia (KIN). Until recently, data on long-term, sustained AK clearance
S4 S U P P L E M E N T T O T H E J O U R N A L O F C L I N I C A L A N D A E ST H E T I C D E R M ATO LO GY [ J A N U A R Y 2 0 1 0 • VO LU M E 3 • N U M B E R 1 ]
Proceedings from The 2009 Alabama Dermatology Society Meeting
following diclofenac therapy was lacking. The long-term effi-
cacy of diclofenac in maintaining clearance following a 90-
day treatment was reported in a one-year extension15 of a
Phase 4 study.16 In the study, 81 percent (52/64) of the Phase
4 clinical study patients reported no additional treatment for
AK lesions during the one-year extension. Of the 52 patients,
47 were studied and demonstrated a 75-percent clearance
rate of 91 percent (95% CI, 84–99%) for target lesions; 70
percent (95% CI, 57–83%) for cumulative lesions, and 100-
percent clearance rate of 79 percent (95% CI, 67–90%) for
target lesions; 30 percent (95% CI, 17–43%) for cumulative
lesions. Based on a severity index, the majority (96%)
reported improvement over baseline.
5-Fluorouracil
5-fluorouracil (5-FU) therapy has a predictable pattern of Figure 1. Toponome colocalization map of a CD4 T-lymphocyte
side effects that limit patient adherence. Significant irritation
usually begins by the fourth to fifth day of daily therapy. This
is followed by frank erosions associated with significant dis-
comfort between the seventh and tenth days, lasting for the
duration of therapy and for a period of a week or longer post-
therapy. Investigators have sought a more tolerable regimen
while attempting to maintain efficacy. This led to the evalua-
tion of interval or short-duration (1- and 2-week) therapies.
The largest controlled study of 0.5% 5-FU used once
daily for one, two, and four weeks was performed in two par-
allel studies. In a study17 of 207 patients, the percentage
reduction in the number of individual AK lesions from base-
line was 69.5 percent following one week of therapy, 86.1
percent after two weeks, and 91.7 percent after four weeks
compared to 21.6 percent for the control group. A parallel
study18 of 177 patients demonstrated similar clearance rates.
These studies demonstrated that significant clearance rates
could be achieved following one week of therapy without Figure 2. Histological features of keratinocytic intraepidermal
enduring the associated side effects associated with longer neoplasia (KIN).
(4-week) therapies. Figure reprinted from Yantsos VA, et al. Semin Cutan Med Surg.
The concept that 5-FU could be applied one or two days 1999;18:3–14. Photo courtesy of Clay Cockerell, MD
per week for prolonged periods and achieve therapeutic effi-
cacy was introduced by Pearlman19 in 1991. The study
included 10 patients using twice-daily, once-weekly 5% 5-FU
for nine weeks or until smooth. He reported that “weekly
pulse dosing” resulted in a 98-percent lesion clearance rate.
Epstein (1998),20 in a small patient study using photographic
analysis, failed to reproduce similar efficacy. Robbins
(2002),21 in a small study (5 patients in each group), evalu-
ated 5-FU used (1) every other night for one month; (2) two
days on, one day off for one month; (3) one week on, one
week off, one week on for a total of three weeks; or (4) two
weeks on, two weeks off, two weeks on for a total of six
weeks. He reported that 95 percent of patients experienced
complete clearance of AKs on the face and 70 to 95 percent
of patients experienced clearance for scalp lesions.
Labandeira et al22 studied the efficacy of intermittent dosing
of 5% 5-FU on 53 patients with a total of 85 AKs. Using 2 to 4 Figure 3. This patient has widespread actinic damage.
applications per week of 5-FU (BID dosing), they reported an
[ J A N U A R Y 2 0 1 0 • VO LU M E 3 • N U M B E R 1 ] S U P P L E M E N T T O T H E J O U R N A L O F C L I N I C A L A N D A E ST H E T I C D E R M ATO LO GY S5
receptor (TLR) 7 agonist.23,24 It is an immune modulator that
TABLE 1. Imiquimod: Anti-tumor effects stimulates both the innate and cell-mediated immune system.
Table 1 provides a summary of many of the immune-mediated
Clusters of related genes activated effects of imiquimod.25 Phase 3 clinical studies using
imiquimod twice weekly for 16 weeks resulted in an 83-percent
MyD88, TLR7; also TLR3, TLR8, IRF7 median reduction in AKs.26 However, the impracticality of a 16-
week dosing regimen26,27 led to studies that examined the
Proapoptotic (MX1, TRAIL) cyclic use of thrice-weekly applications for one month.28 In
Cell growth inhibitory (IFI16, IFIH1, AIM2) Europe, the thrice-weekly dosing regimen is standard protocol.
Krawtchenko et al29 compared the efficacy of 5%
Chemokine/receptors (MIP1a, 1b, CCR1, CCR5) imiquimod cream, 5% 5-FU ointment, and cryotherapy (Table
2). In the first group, imiquimod was applied thrice weekly
Cytokines (CXCL10,11,12 among others)
over four weeks with a rest period of four weeks followed by
Death receptor signaling an evaluation at eight weeks. If lesions remained after a rest
period, the four-week treatment was repeated once followed
NK recognition and cytolytic response by four weeks rest period and re-evaluation. The second
group received 5% 5-FU BID for four weeks. The third group
Macrophage/monocyte (CD14, CD163) received LN2 cryospray (20–40 secs). If lesions remained
after two weeks following the first cryotherapy, a second ses-
T-cell activation; CD8 T-cells; sion was performed. Histology was performed to assess
T-cell memory (SELL, LAIR1) clearance after the initial treatment and again at 12 months.
Sustained clearance of individual AKs at 12 months was
Adapted from: Torres A, Storey L, Anders M, et al.
Microarray analysis of aberrant gene expression in actinic
28 percent for LN2, 54 percent for 5-FU, and 73 percent for
keratosis: effect of the Toll-like receptor-7 agonist imiquimod. Total field clearance was four percent for LN2, 33
imiquimod. Br J Dermatol. 2007;157(6):1132–1147.25 percent for 5-FU, and 73 percent for imiquimod. The superior-
ity of imiquimod
compared to 5-FU for
field therapy was
TABLE 2. Efficacy of cryosurgery vs 5-fluorouracil vs imiquimod against actinic clearly demonstrated.
keratoses LN2 is ineffective as
a field therapy.
CRYOSURGERY TOPICAL 5-FUa IMIQUIMODb Imiquimod required
PARAMETER P VALUE
(n=25) (n=24) (n=26) at least two four-
Initial clinical clearance rate 68% 96% 85% 0.03 week cycles to
achieve significant
Histologic clearance rate 32% 67% 73% 0.03 efficacy. There was
Sustained clearance rate of initially only a 22-percent
28% 54% 73% 1 year) suggested that a sig- as a light source. This small study reported significant sus-
nificant percentage of patients failed to achieve the thera- tained efficacy at one year.
peutic efficacy levels reported with short ALA incubation peri- In a series of individual case studies,40 0.5% 5-FU was
ods.38–41 Additionally, the fluorokinetics of PpIX accumulation used daily for 7 to 10 days prior to short contact (1 hour) ALA
in AKs would not have predicted these results because one- PDT using blue light (BLU-U) at 10J/cm2. The blue light was
hour ALA incubation produces less than one-third the chosen to maximize the PDT effect as it is a more efficient light
amount of PpIX present after 12 hours of incubation. The use source for performing ALA PDT.36 Figure 7 demonstrates a split-
of 14- to 18-hour incubation times during Phase 3 clinical tri- face comparison of 5-FU pretreatment followed by ALA PDT
als was predicated upon maximizing tissue level of PpIX in versus ALA PDT alone. The patient, three months post- ther-
AKs. apy, applied 0.5% 5-FU for one week to both sides of the face
To detect residual AKs following short-incubation (1 to highlight any residual AKs. The enhanced efficacy resulting
hour) ALA PDT, an improved system for AK identification from the 5-FU pretreatment is readily visible. Optimal 5-FU
needed to be developed. Counting AKs has been demon- pretreatment times were determined to be one week for the
strated to be unreliable and is fraught with intraobserver vari- face and 10 days for the scalp, trunk, and extremities.
ations.42 Photographic assessments by experienced blinded There are a few possible mechanisms by which using 5-
observers provide only a qualitative assessment. 43 To FU as a pretreatment prior to ALA PDT can enhance therapeu-
enhance both clinical and photographic detection of AKs, tic efficacy. 5-FU may increase epidermal penetration of ALA
0.5% 5-FU was applied for seven days to the measurement into actinically damaged skin. Future fluorokinetic studies
areas. This was done following a waiting period of at least measuring the effect of 5-FU pretreatment on PpIX levels in
three months after completion of therapy to allow inflamma- AKs are needed. Additionally, 5-FU as monotherapy has a
tion to subside. 5-FU is reasonably specific for AKs and the direct cytotoxic effect on AKs. Controlled studies using 0.5%
response to 5-FU is predictable. By Day 7 of exposure to 5-FU, 5-FU alone demonstrate a nearly 70-percent reduction in
AKs take on a red, crusty, eroded appearance, allowing for individual AKs after one week of therapy.17,18
easier detection and identification.
Figure 6 demonstrates the patient three months after
one-hour incubation ALA PDT. The right cheek is shown Why Some AKs Resist Treatment
before (left panel) and after seven days of 0.5% 5-FU (right
panel). Residual lesions are readily visible clinically and pho- In well-controlled studies employing aggressive therapy,
tographically. The significant number of residual lesions a significant percentage of AKs resist treatment. One mecha-
S8 S U P P L E M E N T T O T H E J O U R N A L O F C L I N I C A L A N D A E ST H E T I C D E R M ATO LO GY [ J A N U A R Y 2 0 1 0 • VO LU M E 3 • N U M B E R 1 ]
Proceedings from The 2009 Alabama Dermatology Society Meeting
nism that allows atypical keratinocytes to avoid destructive
therapy was reported by Goldberg et al.50 They examined
lesions from three separate patients who failed a variety of
modalities, including LN2, 5-FU, and trichloroacetic acid
(TCA) peels. Histology of these lesions obtained by Mohs
micrographic surgery and processed by standard H&E
demonstrated deep migration of atypical keratinizing cells
along the hair follicles and sweat ducts (Figure 8). The
authors used the term “proliferative AKs” (PAK) to describe
these lesions. They suggested an algorithm for evaluating
and treating PAKs, which included a more aggressive treat-
ment with LN2 followed by biopsy and excision if aggressive
Figure 6. These photos demonstrate the patient three months
LN2 treatment failed. after one-hour incubation ALA PDT to the right cheek before and
after seven days of 5-FU.
Conclusion
There are a number of factors that ultimately determine
a physician’s treatment plan for patients with significant
actinic damage. These factors include the patients’ overall
health, tolerability and duration of the treatment, availability
of the treatment, patient finances, physician and patient
treatment preferences, and likelihood for adherence.
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study of topical 5% imiquimod vs. topical 5-fluorouracil vs. 47. Jorizzo J, Weiss J, Vamvakias G. One-week treatment with 0.5% flu-
cryosurgery in immunocompetent patients with actinic keratoses: orouracil cream prior to cryosurgery in patients with actinic ker-
a comparison of clinical and histological outcomes including 1- atoses: a double-blind, vehicle-controlled, long-term study. J
year follow-up. Br J Dermatol. 2007;157 (Suppl. 2), 34–40. Drugs Dermatol. 2006;5(2):133–139.
30. Zeichner JA, Stern DW, Uliasz A, Itenberg S, Lebwohl M. Placebo- 48. Katz BE. The fluor-hydroxy pulse peel: a pilot evaluation of a new
controlled, double-blind, randomized pilot study of imiquimod superficial chemical peel. Cosmet Dermatol. 1995;8:24–30.
5% cream applied once per week for 6 months for the treatment 49. Marrero GM, Katz BE. The new fluor-hydroxy pulse peel. A combi-
of actinic keratoses. J Am Acad Dermatol. 2009;60(1):59–62. nation of 5-fluorouracil and glycolic acid. Dermatol Surg.
31. Levulan® Kerastick® [package insert]. Wilmington, MA: Dusa 1998;24(9):973–978.
Pharmaceuticals. 50. Goldberg LH, Chang JR, Baer SC, Schmidt JD. Proliferative actinic
32. Niedre MJ, Yu CS, Patterson MS, Wilson BC. Singlet oxygen lumi- keratosis: three representative cases. Dermatol Surg.
nescence as an in-vivo photodynamic therapy dose metric: vali- 2000;26(1):65–69.
S10 S U P P L E M E N T T O T H E J O U R N A L O F C L I N I C A L A N D A E ST H E T I C D E R M ATO LO GY [ J A N U A R Y 2 0 1 0 • VO LU M E 3 • N U M B E R 1 ]
Proceedings from The 2009 Alabama Dermatology Society Meeting
New Dermatology Treatment Regimens
and Clinical Applications
Relevant to Daily Patient Care
by James Q. Del Rosso, DO, FAOCD
Dermatology Residency Director, Valley Hospital Medical Center, Las Vegas, Nevada;
Clinical Associate Professor (Dermatology), Touro University College of Osteopathic Medicine,
Henderson, Nevada, and University of Nevada School of Medicine, Las Vegas, Nevada;
Las Vegas Skin & Cancer Clinics, Las Vegas and Henderson, Nevada
retinoid dermatitis, such as peeling and redness, were
Order of Moisturizer Application and Topical Medications for reduced in the group that regularly used the moisturizer first,
Acne and Rosacea without affecting efficacy. Diseases such as acne vulgaris and
rosacea benefit from regular use of moisturizers in order to
Patients treated for acne vulgaris often ask whether they maintain the integrity of the epidermal barrier.
should be using a moisturizer before or after applying their top- In another study, the percutaneous penetration of azelaic
ical medications. Questions regarding whether the medication acid 15% gel applied either before or after moisturizer appli-
will still be effective if a moisturizer is also applied often arise. cation was measured in vitro. A membrane of human skin in
A common question is whether applying the moisturizer before vitro, utilizing a recognized methodology (modified Frantz
a topical retinoid has any affect on the efficacy of the topical cell chamber assay), evaluated active ingredient penetration
retinoid. Also, does it impact the tolerability profile? into skin.
In a multicenter, investigator-blinded, 16-week study Azelaic acid 15% gel (Finacea®, Intendis, Pine Brook, New
among patients with mild-to-moderate acne vulgaris Jersey) was independently tested along with three different
(N=119), investigators evaluated one group that applied moisturizers, Cetaphil Moisturizing Lotion ® (Galderma
moisturizer in addition to using tazarotene 0.1% cream Laboratories, Fort Worth, Texas), CeraVe lotion, and Dove®
(Tazorac®, Allergan, Inc., Irvine, California). The moisturizer in lotion. Each was tested separately with azelaic acid 15% gel.
the study was CeraVe™ cream (Coria Laboratories, Fort Worth, The results showed that after a single application of azelaic
Texas) applied twice daily. The moisturizer was applied in the acid 15% gel is applied to the skin, there is initial rapid
morning and then at night before the tazarotene 0.1% cream, uptake of active drug penetration, with the cutaneous drug
which was used only once a day. In the second study group, level slowly dissipating over time.
patients applied only tazarotene 0.1% cream at night; how- When Cetaphil Moisturizing Lotion is added, the skin pen-
ever, if on a given night they perceived some dryness or flak- etration is the same whether the moisturizer is applied
ing, they could use CeraVe lotion on an as-needed basis. All before or after azelaic acid 15% gel. It did not make any dif-
patients in the study were instructed to use the CeraVe ference which was applied first. There was no decrease in the
cleanser. Patients were not allowed to use any other thera- penetration of the azelaic acid by applying the Cetaphil lotion
peutic agents or cosmeceuticals for their condition, and cos- before or after. In the case of CeraVe lotion, if applied first
metic use was limited and controlled when applicable. before azelaic acid 15% gel, there was slightly better pene-
With regard to efficacy, which was based primarily on tration of the azelaic acid. Even if applied in the opposite
measuring inflammatory and noninflammatory lesion reduc- order, there was still good penetration of azelaic acid into the
tions, there was no difference between the two groups. It was skin. The same percutaneous penetration profile occurred
concluded that applying the CeraVe cream before the with Dove lotion. Thus, the data suggest that there is no
tazarotene cream did not reduce the efficacy of the retinoid. reduction in penetration of active ingredient by applying a
Importantly, as a part of the protocol, patients were told to moisturizer first.
wait 20 minutes between moisturizer application and Potentially, with some moisturizers, there may actually be
tazarotene cream use. Importantly, the visible signs of better penetration of the active ingredient by applying the
[ J A N U A R Y 2 0 1 0 • VO LU M E 3 • N U M B E R 1 ] S U P P L E M E N T T O T H E J O U R N A L O F C L I N I C A L A N D A E ST H E T I C D E R M ATO LO GY S11
moisturizer first. The potential clinical relevance of this scien- Tetrix cream as compared to nontreated sites, Tetrix-treated
tific data is that tolerability may be improved by applying the areas improved at all time points. Patients who had chronic
moisturizer first. hand dermatitis on the Tetrix-treated sides reported markedly
better improvement with both itching and burning.
Additionally, a study measuring substantivity with Tetrix
Skin Barrier Care cream was performed to see if the product persists on the
skin after hand washing. Vaseline® Intensive Care cream and
Epidermal barrier dysfunction seen in atopic dermatitis Tetrix cream were mixed along with a brown iron oxide pig-
has been a major topic of interest over the past few years. ment foundation. Patients washed their hands in a standard-
Many topical treatments have been developed to help repair ized fashion, and after 15 minutes, rated whether there was
components of the epidermal barrier and the intercellular residual pigmentation reflective of substantivity. Tetrix cream
lipid membrane, including barrier repair creams, such as proved to exhibit markedly greater substantivity than the
MimyX® (Stiefel Laboratories, Inc., Coral Gables, Florida), active control. Hand washing did not remove Tetrix cream;
Atopiclair® (Graceway Pharmaceuticals LLC, Bristol, however, it did remove nearly the entire product of Vaseline
Tennessee), Eletone® (Ferndale Laboratories Inc., Ferndale, Intensive Care cream.
Michigan), and EpiCeram® (Promius™ Pharma, LLC). Unlike
traditional topical treatments for atopic dermatitis, such as
corticosteroids and calcineurin inhibitors, which target inflam- Oral Therapy for Papulopustular Rosacea
matory pathways, these formulations work by restoring the
lipid components and barrier function of the stratum A multicenter, randomized, double-blind study compared
corneum. These agents add lipid back into the interstices of the efficacy and safety of 40mg delayed-release doxycycline
the stratum corneum, allowing for decrease in transepidermal (Oracea®, Galderma Laboratories, Fort Worth, Texas) and
water loss. These products are involved in barrier repair while immediate-release doxycycline (Vibramycin®, Pfizer, New York,
the innate repair mechanisms of the skin work to actively New York) in adult subjects with inflammatory (papulopustu-
restore the function of the epidermal barrier on its own. lar) rosacea. One group received doxycycline 40mg delayed-
In addition to barrier repair, there is also barrier protec- release capsules once daily, which is an anti-inflammatory
tion, which is not necessarily replacing lipid, but rather, pro- agent with no antibiotic effect. This agent is approved by the
tecting the barrier from initial breakdown. Barrier repair is a US Food and Drug Administration for papulopustular rosacea.
component of active treatment after the stratum corneum has The other group received nonenteric-coated, immediate-
been compromised, while barrier protection incorporates the release doxycycline 100mg once daily. All patients were also
component of prevention. An aluminum magnesium hydrox- treated once daily with metronidazole 1% gel (Metrogel® 1%,
ide stearate-based, nonsteroidal cream called Tetrix™ (Coria Galderma Laboratories). The study lasted 16 weeks, and the
Laboratories, Ltd., Fort Worth, Texas) provides skin barrier results showed that both formulations of doxycycline had the
protection. It is an aqueous emulsion that is primarily same onset of effect and the same degree of efficacy at all
designed for prevention and treatment of hand eczema, is study time points. The major difference between study arms
water-impermeable, and also contains silicates (dime- was with adverse events, especially gastrointestinal side
thicone, cetyl dimethicone, and cyclomethicone), which pro- effects. All cases of nausea, vomiting, and abdominal discom-
vide protectant activity. The indication for this formulation is fort were reported only in subjects treated with 100mg/day
to manage and relieve burning associated with contact der- doxycycline.
matitis, atopic dermatitis, and irritant or allergic contact der- Maintenance data from a study of initial management of an
matitis. It can be used with other topical medications during active flare with azelaic acid 15% gel (Finacea) and doxycy-
active flares of eczematous dermatitis (preferably applied cline 100mg twice daily for up to 12 weeks has been reported.
last in sequence) or used alone to protect against commonly In the initial 12-week phase of the trial, if patients demon-
encountered irritants and allergens that may cause repeat strated at least 75-percent inflammatory lesion reduction
flare-ups. between four and 12 weeks, they then went into a double-
Tetrix cream has demonstrated the ability to protect blind, randomized, maintenance phase for six months using
against common allergens in patients with contact dermatitis either azelaic acid 15% gel or vehicle gel twice daily.
induced by allergy to nickel, neomycin, or fragrance by acting Approximately 82 percent of the patients achieved at least 75-
as a barrier against skin penetration. Using bilateral compar- percent inflammatory-lesion reduction by 12 weeks, some as
ison patch testing, the study showed that Tetrix was able to early as four weeks. Almost 71 percent of patients had at least
decrease the number of positive tests at 24 and 48 hours, 50-percent lesion reduction by Week 4 and more than 90-per-
which was statistically significant. In real life, these patients cent reduction by Week 12.
would be applying the product 2 to 3 times a day, especially Over this six-month maintenance phase, the investigators
if they often work with their hands or if their hands are always were able to show that 75 percent of the patients that contin-
in contact with water and other irritants. ued utilizing the azelaic acid 15% gel did not have a flare,
In a trial using a visual analog scale (VAS) to rate itching with a 33-percent lower relative risk of flaring as compared to
and burning at affected areas of hand dermatitis treated with vehicle.
S12 S U P P L E M E N T T O T H E J O U R N A L O F C L I N I C A L A N D A E ST H E T I C D E R M ATO LO GY [ J A N U A R Y 2 0 1 0 • VO LU M E 3 • N U M B E R 1 ]
Proceedings from The 2009 Alabama Dermatology Society Meeting
cryotherapy. Cryotherapy is an important modality, but one
Demodex and Rosacea must be cognizant of the actual cure rates and hopefully
choose to also manage the entire field with a medical therapy
A recent study looked at the possibility of Demodex der- to optimize both short-term and long-term treatment results.
matitis (demodicidosis) in 60 subjects with “rosacea” (unre- One study looked at cycle therapy with imiquimod 5%
solved facial eruption with erythema) refractory to conven- cream (Aldara), three times a week for four weeks on, fol-
tional therapies. The average age of the patients was 50 lowed by four weeks off representing a single cycle of ther-
years, with even distribution between males and females. apy. If patients had residual lesions, they could receive a sec-
Several subjects presented with erythema, scaling, dryness, ond cycle. A second group in the study received 5-FU 5%
and inflammatory lesions. Approximately half exhibited a cream (Efudex) twice daily for four weeks. These patients
positive potassium hydroxide (KOH) preparation for Demodex were allowed to take a one-week rest period if the inflamma-
mites. The rest either were not tested or were negative. All tory reaction was too severe. A third group received cryother-
were treated with topical crotamiton 10% (Eurax®, Ranbaxy) apy for 20 to 40 seconds for the individual lesions. At two
cream or lotion twice daily as monotherapy. weeks later, if any lesions were still present, cryotherapy
The results showed that 91 percent of the patients had at could be repeated. Clinical and histological clearance were
least a 50-percent improvement within the first follow-up reported at the end of the initial treatment, which was
visit (usually Week 2). Surprisingly, 98 percent had at least approximately at one month after patients finished the
50-percent improvement by the second follow up (usually course of therapy. Imiquimod cleared about 85 percent of the
Week 4). Even patients who were negative on KOH for lesions, 5-FU cleared 96 percent, and cryotherapy cleared
Demodex mites, or were not tested, showed a similar about 70 percent of the lesions. One year later, patients
response to topical crotamiton. Thus, if rosacea patients are returned for clinical evaluation. The sustained clearance of
not responding to conventional therapy as anticipated, top- the lesions that were treated initially was about 70 percent
ical crotamiton may be a safe and well-tolerated alternate with imiquimod, 50 percent with 5-FU, and about 30 percent
treatment to try. with cryotherapy.
Another study included patients with AKs involving both
the cutaneous and mucosal lip (vermillion region). These
Management of Actinic Keratoses patients were treated with diclofenac 3% gel (Solaraze) twice
daily for three months, then followed one month later to
There are many topical treatments for actinic keratosis assess lesion clearance. Most patients had complete or
(AK), including topical 5-fluorouracil (5-FU) 5% cream marked clearance with very little irritation. At study endpoint,
(Efudex®, Valeant Pharmaceuticals, Aliso Viejo, California) or 80 percent of the total lesions (including the subclinical AKs)
0.5% microsphere cream (Carac®, Dermik, Bridgewater, New cleared and 90 percent of the initial lesions cleared.
Jersey), imiquimod 5% cream (Aldara®, Graceway Tolerability was very favorable.
Pharmaceuticals, LLC), and diclofenac 3% gel (Solaraze®,
PharmaDerm, Florham Park, New Jersey). However, with AK,
initial versus long-term therapy should be considered. Many Summary
dermatologists make the assumption that when they “freeze”
an AK lesion with liquid nitrogen, the lesion clears almost 100 This article includes results from studies that are relevant
percent of the time. Certainly, a lot of the lesions resolve, but to clinical practice. As new information comes forward, clini-
not 100 percent of them. Additionally, the adjacent field of cians may modify their management approaches in order to
actinic damage with subclinical AKs is not being treated with achieve successful therapeutic results.
[ J A N U A R Y 2 0 1 0 • VO LU M E 3 • N U M B E R 1 ] S U P P L E M E N T T O T H E J O U R N A L O F C L I N I C A L A N D A E ST H E T I C D E R M ATO LO GY S13
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Optimizing Management of
Nonmelanoma Skin Cancers
by aCarlos Ricotti, MD; bDarrel Rigel, MD; cTheodore Rosen, MD; dEggert Stockfleth, MD, PhD
a
University of Texas Southwestern Medical Center, Dallas, Texas; bNYU Medical Center and NYU Tisch
Hospital, New York, New York; cBaylor College of Medicine, Houston, Texas;
d
Charité—University Medical Center, Berlin, Germany
Actinic Keratosis and Squamous Cell Carcinoma: and well studied are p53 mutations, which are present in 69
The Debate Over Classification and What it Means percent of SCCs and 53 percent of AKs.5 The tumor-suppressor
for Patients protein, p53, regularly arrests the cell after DNA damage in
order to allow for DNA repair. If there is a mutation in p53, DNA
by aCarlos Ricotti, MD and bClay J. Cockerell, MD is allowed to replicate in a damaged fashion, leading to an
a
Instructor, Department of Dermatology abnormal keratinocyte DNA phenotype that may result in an AK
Division of Dermatopathology or SCC.
University of Texas Southwestern Medical Center UV radiation suppresses the immune system in multiple ways
Dallas, Texas including inhibition of antigen presentation and induction of
b
Clinical Professor of Dermatology and Pathology suppressive cytokine production and suppressor T cell activity.
Director, Division of Dermatopathology Although it may have therapeutic implications in inflammatory
University of Texas Southwestern Medical Center dermatoses, it has been suggested that these immunosuppres-
Dallas, Texas sive effects may promote skin cancer formation. By diminishing
the hosts immunosurveillance systems, keratinocytes that have
Actinic keratoses (AKs) are keratotic papules that present undergone mutations may continue to develop into AK and SCC.6
on sun-exposed skin and are primarily a result of ultraviolet It has also been shown that psoralen plus UVA (PUVA) therapy-
(UV) radiation. The histological classification of AK as an early induced immunosuppression affects the host response to
form of squamous cell carcinoma in situ (SCCIS) has been a human papillomavirus (HPV) infections of the skin that result in
subject of extensive discussion among dermatologists and the development of SCCs.7 HPV, and more recently the Merkel
dermatopathologists. More importantly, the following ques- cell polyomavirus, has been found in DNA of atypical ker-
tions arise: Are AKs simply incipient squamous cell carcinomas atinocytes of SCC.8 The role polyomavirus plays in SCC formation
(SCCs)? Should we formally classify AK as an early precursor to has yet to be completely elucidated, but the oncogenic mecha-
SCC? nisms of HPV are well established. The most common HPV types
The pathogenesis of AKs and SCCs is similar and is a result of associated with SCC formation are 5, 8, 16, 18, 31, and 34.
UV damage that induces thymidine dimer formation and other Persistent HPV infections are common and the host immune sys-
deoxyribonucleic acid (DNA) photoproducts, changing the DNA tem keeps infected cells in check. When the immune system fails
sequence, altering protein synthesis, and ultimately resulting in or the virus overwhelms the host, there is a potential for cancer
cell cycle dysregulation. The cellular transformation creates progression. Although details of the molecular mechanisms of
small foci of atypical keratinocytes that continue to proliferate HPV oncogenesis are beyond the scope of this manuscript, when
throughout the epidermis.1,2 The photocarcinogenic effects of the HPV DNA integrates at random into the host DNA, the result
UVB and UVC wavelengths are much more established than is increased expression of proteins that interfere with cell cycle
those of UVA. Both UVB and UVC rays have been directly impli- checkpoint proteins, such as p53 and pRB. The result is carcino-
cated in the production of photoproducts from DNA that result in genic progression and genetic instability of host keratinoctyes.9
the DNA mutations. In an in-vitro setting, a wavelength of As a result of their clinical similarities, distinguishing AK from
260nm (UVC range) is the most effective in photoproduct induc- SCC on clinical grounds alone may be difficult. Clinically AKs and
tion, although in the skin, a wavelength of 300nm is most harm- SCCs may both appear as thickened and scaly skin with a rough
ful to keratinocyte DNA in the basal layer of the epidermis. texture (Figure 1). Biopsies are indicated in lesions that are sus-
Furthermore, oxidation byproducts created during DNA repair, pected for malignancy; these are typically clinically broad, poorly
such as super oxygen species, can further distort and alter DNA.3 defined, indurated, erythematous, or markedly hyperkeratotic.
Although these findings are stronger for UV radiation in the UVB SCCs often fail to respond to conventional AK therapy and are
and C wavelengths, there is supporting data that UVA radiation recurrent/persistent.1,10
can also induce DNA photoproducts and induce oxidative reac- The pathological features of AK include thickening of the epi-
tions on DNA that result in mutations.4 dermis, large cells with pinkish cytoplasm, atypical hyperchro-
Multiple common genes and proteins have been implicated matic nuclei, extensive mitotic figures, and necrotic cells.
in the pathogenesis of both AKs and SCC. The most common Histological features of extensive UV exposure, such as solar
S14 S U P P L E M E N T T O T H E J O U R N A L O F C L I N I C A L A N D A E ST H E T I C D E R M ATO LO GY [ J A N U A R Y 2 0 1 0 • VO LU M E 3 • N U M B E R 1 ]
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Proceedings from The 2009 Alabama Dermatology Society Meeting
Figure 2. Cytological features of well-differentiated squamous cell
carcinoma and actinic keratosis identical irrespective of size or
Figure 1. Clinical photo of actinic level of involvement. Images courtesy of Clay Cockerell, MD.
keratosis
Figure 3. Postulated steps in the pathogenesis of keratinocytic Figure 4. Histological features of keratinocytic intraepidermal neo-
intraepidermal neoplasia (KIN). Reprinted from: Yantsos VA, Conrad N, plasia (KIN). Reprinted from: Yantsos VA, Conrad N, Zabawski E, Cockerell
Zabawski E, Cockerell CJ. Incipient intraepidermal cutaneous squamous CJ. Incipient intraepidermal cutaneous squamous cell carcinoma: a pro-
cell carcinoma: a proposal for reclassifying and grading solar (actinic) ker- posal for reclassifying and grading solar (actinic) keratoses. Semin Cutan
atoses. Semin Cutan Med Surg. 1999;18:3–14. Med Surg. 1999;18:3–14.
elastosis, is common. On cytological grounds alone it is difficult out the epidermis (Figure 4).
to differentiate SCC from advanced AK. The cytological features Therapy of KIN I, or basic low-grade AKs, should be
of well-differentiated SCC and AK are identical, irrespective of inspected and treated with topical therapy, such as 5-fluo-
size or level of involvement (Figure 2). rouracil, imiquimod, diclofenac, liquid nitrogen, trichloroacetic
As far as AK and its relationship to malignancy, most cuta- acid (TCA) peels, or other laser resurfacing methods. KIN II
neous SCCs have features of AKs within them. It has been esti- lesions are progressive AKs that spare the acrosyringium and
mated that 90 to 97 percent of SCCs have either AK adjacent to do not involve the dermis or the full thickness of the epidermis.
or within the tumors.5 The progression of AKs to SCC, in several These lesions also require topical therapy or cryotherapy.
studies, has shown 0.6 percent at one year, 2.6 percent at four However, KIN III lesions, which are full thickness and equiva-
years, and 13 to 20 percent over a 10-year period.5,10,11 AKs are lent to SCC, should be biopsied; surgical therapy may be
SCCs monitored by the immune system, which keeps them in required for these lesions.
check. When host factors deteriorate and a progression occurs, More recently, the theory of “field cancerization” has been
things change. These cells continue to proliferate involving the developed. This theory hypothesizes that the entire epidermal
full thickness of the epidermis and may result in invasive dis- surface of the skin has an increased risk for the development of
ease.10 Immunosuppressed patients are at an increased risk of malignant lesions because of multiple genetic abnormalities in
SCC transformation from AKs, up to 65-fold.12 It has not been the whole tissue region. The genetic abnormalities as described
shown that benign cutaneous proliferations in patients with above are a result of UV damage. Currently, the question has
solid organ transplants have malignant transformation poten- been raised whether multiple lesions develop independently
tial. These findings support the concept that AKs represent from each other or from migrated malignant or progenitor cells.
early or incipient SCCs. Furthermore, does cytokine signaling from atypical keratinocytes
The progression of AK to SCC has been described as directly in AKs promote cancer progression to SCC? The understanding of
analogous to that of the cervical intraepithelial neoplasia to inva- this phenomenon will likely improve our therapeutic approach to
sive cervical carcinoma. Furthermore, therapy of multiple AKs more effectively prevent SCC.
decreases the incidence of SCCs.10,13 As a result, many groups There are more than one million skin cancers diagnosed in
have actually postulated a classification system of AKs into ker- the United States yearly, most developing in association with
atinocytic intraepidermal neoplasias (KIN), specifically KIN I, II, AKs. Up to 78 million people are diagnosed with AKs every year
and III, or low, intermediate, or high grade (Figure 3).14 The clas- in the United States. Prevention recommendations include
sification is based on the extent of keratinocyte atypia through- protective clothing, avoidance of sun exposure, and use of
[ J A N U A R Y 2 0 1 0 • VO LU M E 3 • N U M B E R 1 ] S U P P L E M E N T T O T H E J O U R N A L O F C L I N I C A L A N D A E ST H E T I C D E R M ATO LO GY S15
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sunscreen. Unfortunately, the United States population contin- radiation immunosuppression in non-melanoma skin cancer as
ues to overexpose themselves to UV light.14–17 Ubiquitously evidenced by gene-environment interactions. Carcinogenesis.
used products could significantly reduce the incidence of sun 2008;29(10):1950–1954.
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SPF5 starting at 10 years of age can dramatically reduce the widespread cutaneous carcinoma after PUVA photochemotherapy.
accumulative exposure to UV by 65 percent.18,19 Retinoids have Arch Dermatol. 1995;131(6):701–704.
been shown to affect apoptosis and cellular proliferation and 8. Dworkin AM, Tseng SY, Allain DC, et al. Merkel cell polyomavirus in
have been used for chemoprophylaxis in a variety of patient cutaneous squamous cell carcinoma of immunocompetent indi-
populations. Clinical studies have demonstrated that viduals. J Invest Dermatol. 2009;129(12):2868–2874.
isotretinoin can reduce the number of new skin cancers in 9. Mantovani F, Banks L. The interaction between p53 and papillo-
patients with xeroderma pigmentosum, and a high-risk maviruses. Semin Cancer Biol. 1999;9:387–395.
immunocompetent population with abnormal repair of UV- 10. Yantsos VA, Conrad N, Zabawski E, Cockerell CJ. Incipient intraepi-
induced DNA damage. There is also extensive support for sys- dermal cutaneous squamous cell carcinoma: a proposal for reclas-
temic retinoid therapy for the prevention of SCC formation in sifying and grading solar (actinic) keratoses. Semin Cutan Med
patients who have received chronic phototherapy.20,21 The best Surg. 1999;18:3–14.
studied patients are those who have received solid organ 11. Weinstock MA, Bingham SF, Cole GW, et al. Reliability of counting
transplants and concomitant systemic retinoid therapy. In the actinic keratoses before and after brief consensus discussion: the
latter group, there is up to a 13.4-percent decrease in the total VA topical tretinoin chemoprevention (VATTC) trial. Arch Dermatol.
number of keratotic lesions in the acitretin group, as compared 2001;137:1055–1058.
to a 28.2-percent increase in the placebo group. Also, trans- 12. Berg D, Otley CC. Skin cancer in organ transplant recipients:
plant patients previously treated with acitretin who have dis- Epidemiology, pathogenesis, and management. J Am Acad
continued therapy have an increase in number of skin cancers Dermatol. 2002;47:1–17.
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are not treated with systemic retinoids.22 A dosage of mous cell carcinoma of the skin and of the cervix: a critique in his-
0.3mg/kg/dL long term is well tolerated and effective as a torical perspective. Am J Dermatopathol. 2006;28:537–545.
chemoprophylaxis for skin cancer in solid organ transplant 14. Vitasa BC, Taylor HR, Strickland PT, et al. Association of non-
patients.23 melanoma skin cancer and actinic keratosis with cumulative solar
The widening acceptance of AK as an early malignant ultraviolet exposure in Maryland watermen. Cancer. 1990;65:
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tem that more accurately reflects the nature of the lesion. In our 15. Zagula-Mally ZW, Rosenberg EW, Kashgarian M. Frequency of skin
opinion, AKs are clinical manifestations of UV radiation-induced cancer and solar keratoses in a rural southern county as deter-
neoplastic transformation of keratinocytes. They represent a mined by population sampling. Cancer. 1974;34:345–349.
continuum that can progress to SCC. The term “keratinocytic 16. McGovern TW, Leffell D. Actinic keratoses and non-melanoma skin
intraepidermal neoplasia” accurately reflects the nature of the cancer. American Academy of Dermatology website. http://
early transformation process and when implemented could www.aad.org/education/students/ak_nonmelanoma.htm.
lead to improved diagnosis and appropriate early aggressive Accessed on: October 14, 2008.
treatment to prevent SCC. 17. Robinson JK, Kim J, Rosenbaum S, Ortiz S. Indoor tanning knowl-
edge, attitudes, and behavior among young adults from
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atosis. Br J Dermatol. 2003;149(suppl 66):34–36. Photochem Photobiol B. 1997;40:3–7.
2. Roewert-Huber J, Stockfleth E, Kerl H. Pathology and pathobiology 20. Nijsten TE, Stern RS. Oral retinoid use reduces cutaneous squa-
of actinic (solar) keratosis—an update. Br J Dermatol. 2007; mous cell carcinoma risk in patients with psoriasis treated with
157(suppl 2):18–20. psoralen-UVA: a nested cohort study. J Am Acad Dermatol.
3. Kvam E. Induction of oxidative DNA base damage in human skin 2003;49(4):644–650.
cells by UV and near visible radiation. Carcinogenesis. 21. Kovach BT, Murphy G, Otley CC, et al. Oral retinoids for chemopre-
1997;18:2379–2384. vention of skin cancers in organ transplant recipients: results of a
4. Young AR, et. al. Human melanocytes and keratinocytes exposed survey. Transplant Proc. 2006;38(5):1366–1368.
to UVB or UVA in vivo show comparable levels of thymine dimers. 22. Bavinck JN, Tieben LM, Van der Woude FJ, et al. Prevention of skin
J Invest Dermatol. 1998;111:936–940. cancer and reduction of keratotic skin lesions during acitretin ther-
5. Anwar J, Wrone DA, Kimyai-Asadi A, Alam M. The development of apy in renal transplant recipients: a double-blind, placebo-con-
actinic keratosis into invasive squamous cell carcinoma: evidence trolled study. J Clin Oncol. 1995;13(8):1933–1938.
and evolving classification schemes. Clin Dermatol. 2004;22: 23. McKenna DB, Murphy GM. Skin cancer chemoprophylaxis in renal
189–196. transplant recipients: 5 years of experience using low-dose
6. Welsh MM, Karagas MR, Applebaum KM, et al. A role for ultraviolet acitretin. Br J Dermatol. 1999;140(4):656–660.
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Proceedings from The 2009 Alabama Dermatology Society Meeting
The Current Standards of Care in Intralesional interferon has also been used to treat BCC. BCCs
Basal Cell Carcinoma treated with intralesional interferon alpha three times a week
for three weeks have shown an 81-percent cure rate. Side
by Darrel S. Rigel, MD effects from this treatment included flu-like symptoms.8 Thus,
Clinical Professor of Dermatology intralesional interferon should be considered only for alterna-
New York University Medical Center tive therapy due to the unacceptable side-effect profile. A more
New York, New York effective, yet longer, mode of therapy for BCC is topical
imiquimod, which has shown a cure rate of 90 percent in 18
Currently, there are more skin cancer cases in the United months with very few side effects.9
States than all other cancer cases combined. In fact, there were Meta-analysis continues to reveal that Mohs micrographic
nearly 1.25 million basal cell and squamous cell carcinoma surgery (MMS) is still the gold standard with the highest cure
cases in 2008, and one in five Americans develops skin cancer rate for BCC by treatment modality. However, a number of other
of some sort during his or her lifetime. Once a patient develops modalities have shown acceptable cure rates (Figure 1).
one basal cell carcinoma (BCC), the chance of getting a second Theoretically, there should be an advantage to combining
BCC is high; therefore, follow up is extremely important among therapies in the treatment of BCC. Combination therapy for
these patients. Data have shown that in 12 percent of patients BCC, as with other dermatological conditions, is often applica-
with BCC, recurrence occurs within one year and in six percent ble. When treating BCC with two therapies, and therapy A is 85-
of patients with BCC, recurrence occurs within two years. percent effective and therapy B is 90-percent effective, by
The first step in treating BCC is to perform a biopsy. Multiple using both therapies, the outcome should minimally be as well
other approaches are then available to treat these neoplasms. as the better of the two. Additionally, there would be hope that
When treating BCC, surgical excision is the most common there is some synergy, so that using the two therapies would
procedure. However, surgical excision has limitations, includ- be better than each of them individually. This logic holds true
ing nontissue sparing, scarring, and site pain.1 Studies have for combination therapy with clinical evidence on various com-
shown that when BCCs with 5mm margins were surgically binations. Relatively recent European data looking at basal
excised, only eight percent showed histological persistence cells treated with ALA PDT after curettage show a cure rate of
when re-excised. The recurrence rate is minimal because about 81 percent. This combination shows toleration, but not
excised BCCs with positive margins probably have an immune a tremendous gain in cure rate.10 When looking at BCC therapy
response that occurs, wiping out small, remaining basal cells.2 comparing surgical excision to a combination of curettage plus
The recurrence rate or the persistence rate has been shown to cryosurgery, surgical excision was better than curettage plus
be a function of the diameter of the lesion. For smaller, less- cryotherapy, even with the combination. Therefore, not every
than-6mm BCCs, only a three-percent recurrence rate is seen. combination is better, necessarily, but is certainly worth con-
When the excision is more than 10mm in size, a nine-percent sidering.11
recurrence rate is seen. The bigger the lesion, the greater the Using topical treatments, such as imiquimod, to pretreat
risk of recurrence.3 BCC in order to shrink the tumor before MMS, has been
Electrodessication and curettage (ED&C) is one of the most demonstrated in two-week, four-week, or six week-trials.
common ways BCCs are removed in the United States. Data on Research found that two weeks of treatment was not enough
treating BCCs with ED&C have shown that five percent of to have an effect, but those patients who were pretreated
patients have recurrence after five years. If the lesions are with imiquimod four weeks and six weeks before MMS had
smaller, less than 6mm, the recurrence rate decreases to 3.3 smaller subsequent defects.12
percent.3 Electrodessication negatively impacts the cosmetic result.
Cryosurgery can also be used. In a recent European study, a Curettage alone seems to offer a better cosmetic result along
series of 58 patients with superficial basal cells received a with an 89.5-percent cure rate at 15 years. In fact, a study has
double freeze/thaw cryotherapy cycle. The cure rate among demonstrated that BCC with curettage at five-year follow up
this sample was about 80 percent at five years. The study con-
cluded that cryosurgery was effective in treating superficial
BCC. There are also data showing that radiation is very effective
in the treatment of BCC. However, the drawback of radiation
therapy is that the cosmetic result worsens over time.4–6
Nonsurgical therapy options, such as photodynamic ther-
apy (PDT), use light to treat BCC. In a recent study using PDT
and aminolevulinic acid (ALA) on 80 BCC lesions that were
more than 2cm in diameter, there was a clearance rate of 88
percent after several treatments. However, 11 percent recurred
after 24 months. ALA PDT is an effective, tissue-sparing modal-
ity for these clinically difficult BCC lesions.7 Recent European
data have shown that red light, which requires 50 percent less
energy, has a cure rate of about 75 to 80 percent at five years.4 Figure 1. Cure rates for basal cell carcinoma for various treatments
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has shown only a nine-percent recurrence rate with better cos- therapy for basal cell carcinoma. J Am Acad Dermatol. 1990;23(4
metic results than ED&C, x-ray, and cryosurgery, and as good Pt 1):694–700.
as excision.13–15 A recent paper using curettage alone showed a 9. Warshauer E, Warshauer BL. Clearance of basal cell and superfi-
cure rate of 96 percent after a five-year follow up.16 Thus, cial squamous cell carcinomas after imiquimod therapy. J Drugs
nonaggressive curettage alone has a cure rate similar to the Dermatol. 2008;7(5):447–451.
published rates for ED&C with better cosmetic results. 10. Christensen E, Skogvoll E, Viset T, Warloe T, Sundstrøm S.
BCC treated with curettage followed by imiquimod not only Photodynamic therapy with 5-aminolaevulinic acid, dimethyl-
treats the lesion, but also lowers the risk of keloid scars. sulfoxide and curettage in basal cell carcinoma: a 6-year clini-
Imiquimod 5% cream once daily for one month as adjunctive cal and histological follow-up. J Eur Acad Dermatol Venereol.
therapy after ED&C substantially reduced the frequency of resid- 2008 Sept 18. [Epub ahead of print].
ual tumors and improved the cosmetic appearance compared 11. Kuijpers DI, Thissen MR, Berretty PJ, et al. Surgical excision ver-
with ED&C alone. Also, imiquimod improved cure and postsurgi- sus curettage plus cryosurgery in the treatment of basal cell car-
cal healing of electrodessication scars. Curettage followed by cinoma. Dermatol Surg. 2007;33(5):579–587.
imiquimod has a very effective cure rate of 94 percent for the 12. Torres A, et al. Poster presented at the World Congress on
treatment of primary nodular BCC on the trunk and limbs with Cancers of the Skin; 2003.
pleasing cosmetic results and very mild hypopigmentation.17–22 13. Reymann F. 15 years’ experience with treatment of basal cell
A treatment regimen where BCCs are curetted, then after carcinomas of the skin with curettage. Acta Derm Venereol
one week are treated with imiquimod five times a week for six Suppl (Stockh). 1985;120:56–59.
weeks, offers a cure rate with a lower limit of 97 percent, with 14. Johnson TM, Tromovitch TA, Swanson NA. Combined curettage
excellent cosmetic results and very few, if any, recurrences at and excision: a treatment method for primary basal cell carci-
one, two, and three years. There may be some mild hypopig- noma. J Am Acad Dermatol. 1991;24(4):613–617.
mentation, but certainly superior cosmetic results are seen 15. McDaniel WE. Therapy for basal cell epitheliomas by curettage
with sequential therapy.22 only. Further study. Arch Dermatol. 1983;119(11):901–903.
In summary, although MMS is usually thought of initially for 16. Barlow JO, Zalla MJ, Kyle A, et al. Treatment of basal cell carci-
the treatment of BCCs, there are other options when cosmesis noma with curettage alone. J Am Acad Dermatol. 2006;54(6):
is an issue. Curettage followed by topical therapy, such as 1039–1045.
imiquimod, may be the therapy of choice. The treatment of BCC 17. Spencer JM. Pilot study of imiquimod 5% cream as adjunctive
is dynamically evolving. Advances in combination approaches therapy to curettage and electrodesiccation for nodular basal
to BCC treatment will significantly impact dermatology in the cell carcinoma. Dermatol Surg. 2006;32(1):63–69.
next 5 to 10 years. 18. Wu JK, Oh C, Strutton G, Siller G. Australas J Dermatol.
2006;47(1):46–48.
19. Tillman DK Jr, Carroll MT. A 36-month clinical experience of the
References effectiveness of curettage and imiquimod 5% cream in the
treatment of basal cell carcinoma. J Drugs Dermatol. 2008;7(1
1. McLoone NM, et al. J Eur Acad Dermatol Venereol. Suppl 1):s7–s14.
2006;20:698–701. 20. Neville JA, Williford PM, Jorizzo JL. Pilot study using topical
2. Hussain M, Earley MJ. The incidence of incomplete excision in imiquimod 5% cream in the treatment of nodular basal cell car-
surgically treated basal cell carcinoma: a retrospective clinical cinoma after initial treatment with curettage. J Drugs Dermatol.
audit. Ir Med J. 2003;96(1):18–20. 2007;6(9):910–914.
3. Silverman MK, Kopf AW, Bart RS, Grin CM, Levenstein MS. 21. Rigel D, et al. J Am Acad Dermatol. 2006;54:AB174. [Poster 2420]
Recurrence rates of treated basal cell carcinomas. Part 3: surgi- 22. Rigel DS, Torres AM, Ely H. Imiquimod 5% cream following curet-
cal excision. J Dermatol Surg Oncol. 1992;18(6):471–476. tage without electrodesiccation for basal cell carcinoma: prelim-
4. Basset-Seguin N, Ibbotson SH, Emtestam L, et al. Topical methyl inary report. J Drugs Dermatol. 2008;7(1 Suppl 1):s15–s16.
aminolaevulinate photodynamic therapy versus cryotherapy for
superficial basal cell carcinoma: a 5 year randomized trial. Eur J
Dermatol. 2008;18(5):547–553.
5. Silverman MK, Kopf AW, Gladstein AH, et al. Recurrence rates of
treated basal cell carcinomas. Part 4: x-ray therapy. J Dermatol
Surg Oncol. 1992;18(7):549–554.
6. Locke J, Karimpour S, Young G, Lockett MA, Perez CA.
Radiotherapy for epithelial skin cancer. Int J Radiat Oncol Bio
Phys. 2001;51(3):748–755.
7. Morton CA, Whitehurst C, McColl JH, Moore JV, MacKie RM.
Photodynamic therapy for large or multiple patches of Bowen
disease and basal cell carcinoma. Arch Dermatol. 2001;137(3):
319–324.
8. Cornell RC, Greenway HT, Tucker SB, et al. Intralesional interferon
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Proceedings from The 2009 Alabama Dermatology Society Meeting
treatment may be warranted (Figure 3).7
The Current Standards of Care in Actinic Keratosis In the algorithm shown in Figure 3, the primary decision
and Squamous Cell Carcinoma point, assuming histological confirmation of AK, is a single
lesion versus multiple lesions. Lesion-directed treatment
may be considered for a single lesion. Although, if there is
by Theodore Rosen, MD evidence of extensive photodamage, field therapy should
Professor of Dermatology, Baylor College of Medicine also be considered, given the likelihood of additional sub-
Houston, Texas clinical foci. In patients with multiple lesions, field therapy
should be a strong consideration. The presence of additional
Actinic keratosis (AK) has a very high prevalence in the subclinical foci can be regarded as nearly certain, and field
United States, with about 27 percent of men and 13 percent therapy is the only modality capable of addressing these foci.
of women diagnosed with AK each year. In organ transplant In addition, field therapy using imiquimod has shown evi-
and immunocompromised patients, the prevalence dence of sustained clearance for up to 18 months following
increases to 40 percent within five years post-transplant. treatment cessation.7 Lesion-targeted therapy includes
Since 1999, AK is the second most common dermatology cryosurgery, curettage, electrosurgery, and PDT. Field-
diagnosis after acne (Figure 1).1–3 For this reason, AKs are a directed pharmacological treatment includes 5FU,
target for managed care, and changes in guidelines are most imiquimod, and diclofenac, with additional options, such as
likely on the horizon. The National Comprehensive Cancer retinoids, trichloroacetic acid, PDT adopted for this goal, and
Network emphasizes that AK be aggressively treated at first chemical peels.
development.4 Accepted treatment modalities include Curettage and electrodessication are not usually consid-
cryosurgery, topical 5-fluorouracil (5FU), imiquimod, ered part of the standard of care for AK. Cryosurgery is the
diclofenac, photodynamic therapy (PDT), and curettage and preferred treatment for individual lesions. However, there is
electrodessication. Chemical peels and ablative skin resur- no standardization for freeze times. Cryosurgery is meant for
facing may also be considered. Therefore, the optimum ther- lesions with small, well-demarcated borders. Initial AK clear-
apy is difficult to ascertain. Moreover, the most appropriate ance rates may vary widely depending upon the duration of
outcome standard is uncertain: Should it be short-term clini- cryofreeze (39 to 83 percent). Hypopigmentation is a risk in
cal clearance? Long-term clearance? Should we count only 29 to 88 percent of patients. Lesions may recur and clearance
apparent lesions or also include subclinical, unmasked of the total treatment field remains low at one year.8–12
lesions? The ultimate final outcome standard, a goal not yet Cryosurgery is not intended for treating a large number of
definitively reachable, should be to reverse major genotypic lesions occupying an extensive field.
abnormalities characterizing both AK and squamous cell car- The patient seen in Figure 4 has had repeated
cinoma (e.g., p53, p14, p16, ras). cryosurgery and there is evidence of hypopigmentation
Field cancerization means that ultraviolet (UV)-induced where freezing occurred. This patient likely should have
damage occurs at different stages at multiple sites through- received field treatment with a topical product at the outset.
out the sun-exposed skin (Figure 2).5,6 Field cancerization As you can see, despite repeated cryosurgery, the patient still
characteristics include cancer initiation (separate, individual has multiple AKs.
foci of UV-induced cellular transformation caused by direct Combination, sequential therapy may be the most thor-
damage to DNA), cancer promotion (broad UV-induced ough means of approaching severely solar-damaged skin.
immunosuppression and reduced immunosurveillance), and There are three basic topical therapies for AK, one of which is
cancer progression (the potential for additional UV-induced 5FU—an antineoplastic that is converted and manages to
mutations, leading to the development of invasive and keep cells from multiplying. 5FU interferes with deoxyribonu-
potentially metastatic tumors).5,6 cleic acid (DNA) synthesis and ribonucleic acid (RNA) forma-
The typical treatment algorithm for AK is to employ tion as well as causes the death of rapidly growing cancer
“lesion-directed” therapy, such as cryosurgery, for individual cells. It has multiple strengths and multiple formulations with
lesions. However, when multiple lesions are evident, sequen- complete clearance in about 50 percent of patients. Although
tial therapy using lesion-targeted therapy along with topical 5FU is efficacious and convenient (bid dosing for 2–4 weeks),
Figure 1. Examples of actinic keratosis of the hand, ear and temple
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bid for 90 days, is about 50 percent. Thus, the three topical
treatments are nearly equal in reported efficacy based upon
published trials. However, the difference between the three
topical treatments is tolerability, which may determine
adherence. Diclofenac is twice daily dosage for 60 to 90 days
with minimal irritation and high tolerability (Figure 5).22–25
To accomplish PDT, the skin is exposed to appropriate
wavelengths of light following exposure to a photosensitizer,
such as 5-aminolevulinic acid or methylaminolevulinic acid.
The activated photosensitizer, which has been selectively
taken up by abnormal cells, induces cell death. While PDT is
designed to treat individual lesions, it can certainly be
adapted to treat larger areas or entire cutaneous cosmetic
Figure 2. Field cancerization animation illustrating subclinical units. There is a high response rate to PDT, but the biggest
actinic keratosis, actinic keratosis, and squamous cell drawback is pain. Patients usually tend to choose a different
carcinoma. Illustration courtesy of Eggert Stockfleth, MD, PhD. therapy the second time around.26–28
Dermatologists treat AK because they are concerned that
such lesions will evolve into squamous cell carcinoma (SCC).
Most view AK and SCC to be the same disease, with a trans-
formation from pre-invasive to invasive biology. Even though
the risk of an individual AK turning into a squamous cell is
very small, over time, the risk for developing SCC is about 10
percent for patients who have large numbers of visible or
subclinical AK. Since it is never evident which AK lesions are
going to become SCC, the best option is to attempt to treat all
such lesions.29,30
The standard of care for AK is moving toward field ther-
apy along with lesion-directed therapy as follow up.
Conversely, lesion-directed therapy may be followed by a
Figure 3. Actinic keratosis treatment algorithm
field therapy. Two field-directed therapeutic interventions
may even be used sequentially or concurrently (e.g., 5FU and
imiquimod). Most importantly, whatever treatment option is
selected, the goal in AK treatment is to prevent transforma-
tion into SCC.
When assessing nodes and metastases and looking for
involvement of SCC, the positron emission tomography (PET)
scan (Table 1) is more sensitive and specific than magnetic
resonance imaging (MRI) and computed tomography (CT).31
The data shown in Figure 6 are from a prospective compari-
son with conventional imaging modalities in lymph node
staging of head and neck cancer. It has been found that PET
scan is the best test for extracutaneous SCC.32
Figure 4. Patient with numerous hypopigmentation marks from
High-risk SCC includes the following lesion types:
cryosurgery • Located in the ear, nose, lip, or genitalia
• Size = >2cm or >1.0cm (lip)
• Thickness = 4 to 6mm
the downside is pain and a risk of patient intolerance and • Depth = 4 to 6mm
dissatisfaction.11,13–17 Imiquimod works as a cytokine genera- • Undifferentiated
tor with a directed cytotoxic response. Imiquimod is • Histological type (desmoplastic, acantholytic,
approved for use twice a day for 16 weeks, which often com- spindle cell, arising in Bowen’s disease, perineural
promises adherence. With imiquimod, shorter therapy might invasion)
be better, but complete clearance is about 50 percent utiliz- • Recurrent or from SCC in situ
ing the US Food and Drug Administration (FDA)-approved reg- • Secondary to or associated with immune defect.
imen.18–21 Diclofenac has a mode of action that inhibits the Low-risk SCC may be treated with cryosurgery, excision,
production of prostaglandins, which is important in terms of curettage and electrodessication, or radiotherapy.11,33–36
immunosuppression, proliferation of cells, and angiogene- However, the gold standard for high-risk SCC is Mohs micro-
sis. The reported AK clearance with diclofenac, when dosed graphic surgery (MMS), which certainly can be adaptable to
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Proceedings from The 2009 Alabama Dermatology Society Meeting
TABLE 1. Assessment: Nodes and Metastases
STUDY CHOSEN SENSITIVTY SPECIFICITY
90%
PET scan 94%
Down to 0.6cm
82%
CT scan 85%
Down to 1.0cm
80%
MRI 79%
Down to 1.0cm
PDF/nmsc.pdf. Published 2008. Accessed September 18, 2008.
5. Slaughter DP, Southwick HW, Smejkal W. Field cancerization in
oral stratified squamous epithelium; clinical implications of mul-
ticentric origin. Cancer. 1953; 6(5):963–968.
Figure 5. Topical treatments for actinic keratosis. Illustration courtesy 6. Tabor MP, Brakenhoff RH, van Houten VM, et al. Persistence of
of James Q. Del Rosso, DO. genetically altered fields in head and neck cancer patients: bio-
logical and clinical implications. Clin Cancer Res. 2001;7(6):
any lesion of any size at any location with a 97- to 98-percent 1523–1532.
cure rate.37 7. Lee PK, Harwell WB, Loven KH, et al. Long-term clinical outcomes
In summary, both medical and surgical treatment options following treatment of actinic keratosis with imiquimod 5%
should be utilized in the treatment of AK and SCC. As with AK, cream. Dermatol Surg. 2005; 31(6):659–664.
SCC can be treated with combination or sequential therapy. If 8. Bath-Hextall F, Bong J, Perkins W, Williams H. Interventions for
cryosurgery or curettage is out of the question for a specific basal cell carcinoma of the skin: systematic review. BMJ.
patient, adjunctive treatment that works well includes 5FU 329(7468):705. Epub 2004 Sep 13.
and imiquimod, each dosed once daily for one week out of the 9. Nguyen TH, Ho DQ. Nonmelanoma skin cancer. Curr Treat Options
month for three consecutive months. Other innovative thera- Oncol. 2002;3(3):193–203.
peutic combinations for AK and SCC include the following: 10. Zouboulis CC, Röhrs H. [Cryosurgical treatment of actinic keratoses
Combination therapy: and evidence-based review] Hautarzt. 2005;56(4):353–358.
• Imiquimod plus 5FU 11. Thai KE, Fergin P, Freeman M, et al. A prospective study of the use
• Curettage followed by imiquimod of cryosurgery for the treatment of actinic keratoses. Int J
Sequential therapy: Dermatol. 2004;43(9):687–692.
• Cryosurgery followed by diclofenac 12. Krawtchenko N, Roewert-Huber J, Ulrich M, et al. A randomised
• Diclofenac followed by cryosurgery study of topical 5% imiquimod vs. topical 5-fluorouracil vs.
• Cryosurgery followed by imiquimod cryosurgery in immunocompetent patients with actinic keratoses:
• Imiquimod followed by cryosurgery a comparison of clinical and histological outcomes including 1-
• Microdermabrasion followed by PDT year follow-up. Br J Dermatol. 2007;157(Suppl 2):34–40.
• 5FU followed by PDT 13. Efudex® [package insert]. Aliso Viejo, CA: Valeant Pharma-
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23. Gebauer K, Brown P, Varigos G. Topical diclofenac in hyaluronan assessment of cancer therapy. N Engl J Med. 2006;354(5):
gel for the treatment of solar keratoses. Australas J Dermatol. 496–507.
2003;44(1):40–43. 33. Graham GF, Clark LC. Statistical analysis in cryosurgery of skin
24. Wolf JE Jr, Taylor JR, Tschen E, Kang S. Topical 3.0% diclofenac in cancer. Clin Dermatol. 1990;8(1):101–107.
2.5% hyaluronan gel in the treatment of actinic keratoses. Int J 34. Honeycutt WM, Jansen GT. Treatment of squamous cell carcinoma
Dermatol. 2001;40(11):709–713. of the skin. Arch Dermatol. 1973;108(5):670–672.
25. Rivers JK, Arlette J, Shear N, et al. Topical treatment of actinic ker- 35. Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recur-
atoses with 3.0% diclofenac in 2.5% hyaluronan gel. Br J rence, metastasis, and survival rates in squamous cell carcinoma
Dermatol. 2002;146(1):94–100. of the skin, ear, and lip. Implications for treatment modality selec-
26. Goldman M, Atkin D. ALA/PDT in the treatment of actinic kerato- tion. J Am Acad Dermatol. 1992;26(6):976–990.
sis: spot versus confluent therapy. J Cosmet Laser Ther. 36. Johnson TM, Rowe DE, Nelson BR, Swanson NA. Squamous cell
2003;5(2):107–110. carcinoma of the skin (excluding lip and oral mucosa). J Am Acad
27. Sandberg C, Stenquist B, Rosdahl I, et al. Important factors for Dermatol. 1992;26(3 Pt 2):467–484.
pain during photodynamic therapy for actinic keratosis. Acta 37. Robins P, Dzubow LM, Rigel DS. Squamous-cell carcinoma treated
Derm Venereol. 2006;86(5):404–408. by Mohs surgery: an experience with 414 cases in a period of 15
28. Holmes MV, Dawe RS, Ferguson J, Ibbotson SH. A randomized, years. J Dermatol Surg Oncol. 1981;7(10):800–801.
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Recent Advances and Practice Trends in the treatment, 80 percent of the subjects showed partial clear-
Treatment of Basal Cell Carcinoma, Actinic ance. Thus, after two courses of treatment, 69 percent of
Keratosis, and Squamous Cell Carcinoma subjects showed total clearance and 80 percent of subjects
showed partial clearance. The study concluded that
by Eggert Stockfleth, MD, PhD, Program Chair imiquimod is an effective topical treatment option for AK
Professor of Dermatology with a high clearance rate as well as a partial clearance rate.
Head of Skin Cancer Center Charité, Department of This study had no limitation of treatment area and included
Dermatology, Venereology and Allergology hyperkeratotic and hypertrophic AKs. Up to two sachets of
Charité—University Medical Center, Berlin, Germany imiquimod were used per application. No safety issues were
seen in the study. Only two out of 829 patients dropped out
Field cancerization refers to the entire skin scenario of the study due to side effects.1
including invasive squamous cell carcinoma (SCC) and sub- In Europe, 5FU 5% is approved for twice-daily use over
clinical actinic keratosis (AK). It is the cascade that occurs at four weeks. Despite the success with topical therapy, many
different stages at multiple sites throughout the sun- dermatologists are still using cryotherapy for a varying num-
exposed skin. Imiquimod is a topical treatment option for AK ber of seconds with no real guidelines as to freeze time. In a
and may be used alone or in combination with other medical comparative, randomized study, subjects received either
or surgical options. The mode of action of imiquimod incor- 5FU, cryotherapy, or imiquimod. All subjects were immuno-
porates an immune-response modifier that actually acti- sufficient patients with AK. In this study, cryotherapy was
vates the innate immunity, or very early immune response, used for 20 to 40 seconds. If lesions remained after two
through Toll-like receptor activation (TLR). This very early weeks, a second session of cryotherapy for another 20 to 40
immune response generates anticancer and antiviral activ- seconds was performed. The outcome of the study showed
ity. For this reason, imiquimod may be used to treat viral dis- that 5FU was most efficacious, followed by imiquimod, then
eases, such as genital warts and human papillomavirus 6 cryotherapy (Figure 2).2
and 11, and cancer. Imiquimod can also be used for basal The evidence-based histology analysis compared all
cell carcinoma (BCC) and lentigo maligna. treatment groups. Imiquimod showed 73-percent histologic
A recent, open-label study to access efficacy and safety of clearance, 5FU showed 67-percent histologic clearance, and
imiquimod 5% cream for treatment of AK on the head was cryotherapy showed only 32-percent histologic clearance.
conducted in 100 private offices, having limited or no expe- The best clinical outcome four weeks after treatment was
rience with immune-response modifiers.1 The objective of with 5FU. However, imiquimod provided the best histologi-
this noncontrolled interventional clinical study was to evalu- cal clearance rate at 85 percent. Cryotherapy was the worst
ate the efficacy of imiquimod in the treatment of fields with choice for clinical and histological clearance. Sustained
multiple, multiform AK. One hundred eighty office-based clearance data in all patients, for initially cleared lesions, 12
dermatological practices in Germany participated. Patients months after treatment, showed that imiquimod maintained
with clinically typical, visible AK lesions on the head were 73-percent clearance, with 5FU and cryotherapy at 54 and
treated with 5% imiquimod cream three times per week for 28 percent, respectively (Figure 3).2
four weeks followed by a four-week treatment pause. If This is the same in daily practice, with a higher recurrence
lesions were still present, a second course of treatment rate with cryosurgery than with topical therapy. Interestingly,
(COT) was given. Complete clearance rate (i.e., no clinically the sustained field clearance rates 12 months after end of
visible AK lesions in the treatment area) was the main out- treatment showed imiquimod at 73 percent, 5FU at 33 per-
come measure. Eight hundred twenty-nine patients were cent, and cryosurgery at a mere four percent (Figure 4).
enrolled. The complete clearance rate was 40.5 percent after Cosmetic results showed a high statistically significant
the first COT and 68.9 percent overall (Figure 1). Altogether, difference between the groups with imiquimod providing
85.4 percent of the 7,427 baseline lesions were cleared. better results than 5FU and cryosurgery.
Patients with hyperkeratotic/hypertrophic lesions showed Treating AK in organ transplant patients can be difficult.
comparable responses. Local skin reactions were the most These patients have chronic infections, malignancies, and a
commonly reported adverse effects, causing discontinua- relative risk of skin tumors (Table 1) compared to nontrans-
tion in only four patients. Severity of the local skin reactions plant patients. They are also at high risk for developing AK
was a strong predictor of the outcome. Patients with multi- and invasive SCC. In these patents, the relative risk of AK is
ple, multiform AK on the head can be successfully and safely greater than 250 to 1, the risk of SCC is greater than 100 to
treated with topical imiquimod in daily practice. Assurance 1, and the risk of BCC is 10 to 1.
of patient understanding that treatment success is closely In a similar study of organ transplant recipients,
correlated to proper drug administration is important. imiquimod showed complete clearance in 65 percent of kid-
In the same study, imiquimod demonstrated partial clear- ney transplant patients and partial clearance (>75% clear-
ance rates of 80 percent of the whole area, which is very well ance) in 80 percent of kidney transplant patients, which is
accepted in Europe. With only one course of treatment after exactly the same data seen with nonimmunosuppressed
four weeks on and four weeks off, 47 percent of subjects patients. Thus, imiquimod works well in the chronic,
showed partial clearance and with the second course of immunosuppressed patient.
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Figure 1. Complete response rate (%) of AK with imiquimod. Figure 2. Clinical evaluation: Clearance comparison of all treatment
Reprinted from: Meyer T, Stockfleth E, Christophers E. Immune response groups.
profiles in human skin. Br J Dermatol. 2007;157(suppl 2):41–46. Reprinted from: Krawtchenko N, Roewert-Huber J, Ulrich M, et al. A randomised
study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immuno-
competent patients with actinic keratoses: a comparison of clinical and histologi-
cal outcomes including 1-year follow-up. Br J Dermatol. 2007;157(suppl 2):34–40.
Figure 3. Sustained clearance of initially cleared lesions in all Figure 4. Sustained field clearance rates in all patients.
patients. Reprinted from: Krawtchenko N, Roewert-Huber J, Ulrich M, et al. A ran-
Reprinted from: Krawtchenko N, Roewert-Huber J, Ulrich M, et al. A randomised domised study of topical 5% imiquimod vs. topical 5-fluorouracil vs.
study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immuno- cryosurgery in immunocompetent patients with actinic keratoses: a com-
competent patients with actinic keratoses: a comparison of clinical and histologi- parison of clinical and histological outcomes including 1-year follow-up. Br
cal outcomes including 1-year follow-up. Br J Dermatol. 2007;157(suppl 2):34–40. J Dermatol. 2007;157(suppl 2):34–40.
Three placebo-controlled studies in renal transplant nonresponders or whether this nonresponse was related to
recipients and one large multicenter study in kidney, heart, the level of systemic immunosuppression is not known.
and liver transplant recipients found imiquimod to be safe A recent multicenter, placebo-controlled, safety and effi-
when treating areas of field cancerization not exceeding cacy study performed by the Skin Care in Organ-transplant
100cm2 and two sachets per application. For all studies pub- Patients (SCOPE) research network enrolled 43 patients in
lished so far on the use of imiquimod in organ transplant six European transplant centers. Among patients random-
recipients, the drug was applied three times per week for 16 ized to imiquimod, the histologically confirmed complete
weeks. clearance rate was 62 percent compared to a complete clear-
A randomized, blinded, placebo-controlled study evalu- ance rate of zero percent in the vehicle group.4 In order to
ated imiquimod or placebo in 21 high-risk renal transplant exclude graft rejections induced through the Th1 immune
recipients with skin dysplasia. Of the 14 patients receiving response of the immune-response modifier imiquimod, all
imiquimod, seven patients (1 taking placebo) had reduced patients were monitored for changes in hematology and
skin atypia, seven (none taking placebo) had reduced viral serum chemistry. In all studies published to date with
warts, and five (1 taking placebo) showed less dysplasia his- imiquimod in organ transplant recipients, no adverse effect
tologically. Over a 12-month period, fewer invasive SCCs of the immune-response modifier on the function of the graft
arose in the imiquimod-treated skin areas than in control has been observed.
areas. The authors concluded that topical 5% imiquimod To summarize, when dealing with field cancerization
cream was effective in reducing cutaneous dysplasia in a (Figure 5), the future is in treating the field with topical ther-
proportion of renal transplant recipients and may reduce the apy. What is left should be treated with cryotherapy, laser
frequency of invasive SCC developing subsequently in surgery, or another form of therapy. The most important
treated areas of skin. A proportion of renal transplant recip- point is to treat the field first.
ients in this study did not react to imiquimod and did not
show benefit from treatment. Whether these were genuine
S24 S U P P L E M E N T T O T H E J O U R N A L O F C L I N I C A L A N D A E ST H E T I C D E R M ATO LO GY [ J A N U A R Y 2 0 1 0 • VO LU M E 3 • N U M B E R 1 ]
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Proceedings from The 2009 Alabama Dermatology Society Meeting
TABLE 1. Relative risk (RR) of skin tumors
in organ transplant patients
TUMOR TYPE RELATIVE RISK
Actinic keratoses >250
Squamous cell carcinoma >100
Basal cell carcinoma 10
Kaposi’s sarcoma 500
Figure 5. Field of cancerization: Treat the field first with topical Anogenital tumors 100
therapy
Melanoma 5
References
1. Meyer T, Stockfleth E, Christophers E. Immune response pro- plant recipients: clinicopathological features and outcome in
files in human skin. Br J Dermatol. 2007;157(suppl 2):41–46. 100 cases. Am J Transplant. 2008;Sept 8. [Epub ahead of
2. Krawtchenko N, Roewert-Huber J, Ulrich M, et al. A randomised print].
study of topical 5% imiquimod vs. topical 5-fluorouracil vs. 4. Ulrich C, Bichel J, Euvrard S, et al. Topical immunomodulation
cryosurgery in immunocompetent patients with actinic ker- under systemic immunosuppression: results of a multicentre,
atoses: a comparison of clinical and histological outcomes randomized, placebo-controlled safety and efficacy study of
including 1-year follow-up. Br J Dermatol. 2007;157(suppl imiquimod 5% cream for the treatment of actinic keratoses in
2):34–40. kidney, heart, and liver transplant patients. Br J Dermatol.
3. Matin RN, Mesher D, Proby CM, et al. Melanoma in organ trans- 2007;157(suppl 2):25–31.
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