Supplement to the June 2009 issue of
Selected presentations from the
Society of Dermatology Physician Assistants 6th Annual Fall Conference
Support provided by Stiefel Laboratories
www.jcadonline.com
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Contents
Topical and Systemic Corticosteroids: Clinical S3 Implications and Exit Strategies
James Q. Del Rosso, DO, FAOCD
MATRIX MEDICAL COMMUNICATIONS
PRESIDENT Robert L. Dougherty rdougherty@matrixmedcom.com PARTNER Patrick D. Scullin pscullin@matrixmedcom.com VICE PRESIDENT, PUBLISHER Joseph J. Morris jmorris@matrixmedcom.com VICE PRESIDENT, EDITORIAL DIRECTOR Elizabeth A. Klumpp eklumpp@matrixmedcom.com EXECUTIVE EDITOR Kimberly B. Chesky kchesky@matrixmedcom.com ASSOCIATE EDITOR Colleen M. Hutchinson chutchinson@matrixmedcom.com ASSISTANT EDITOR Angela M. Hayes ahayes@matrixmedcom.com CLASSIFIED SALES MANAGER Melanie A. Wolfrom mwolfrom@matrixmedcom.com
A Review of Current Treatment Options for Acne S6 and Rosacea
Rana M. Hassan, PA-C
Therapeutic Decisionmaking for Basal Cell S11 Carcinoma: A Practitioner’s Point of View
James Spencer, MD
New Dermatology S16 Treatment Regimens: A Therapeutic Update
James Q. Del Rosso, DO, FAOCD
MATRIX MEDICAL COMMUNICATIONS
1595 Paoli Pike, Suite 103 West Chester, PA 19380 Toll-free: (866) 325-9907 Fax: (484) 266-0726
This supplement features selected presentations from the Society of Dermatology Physician Assistants 6th Annual Fall Conference, which was held in Tampa, Florida, from November 5–8, 2008. This supplement was supported by Stiefel Laboratories.
Copyright © 2009 Matrix Medical Communications. All rights reserved. Opinions expressed by authors, contributors, and advertisers are their own and not necessarily those of Matrix Medical Communications, the editorial staff, or any member of the editorial advisory board. Matrix Medical Communications is not responsible for accuracy of dosages given in the articles printed herein. The appearance of advertisements in this journal is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality, or safety. Matrix Medical Communications disclaims responsibility for any injury to persons or property resulting from any ideas or products referred to in the articles or advertisements.
TOPICAL AND SYSTEMIC CORTICOSTEROIDS: CLINICAL I M P L I C AT I O N S A N D E X I T S T R AT E G I E S
James Q. Del Rosso, DO, FAOCD
T
opical corticosteroids are used to suppress a variety of inflammatory mechanisms involved in the pathogenesis of several cutaneous disorders.1,2 These agents are not curative, but are used to control eruptions and relieve associated symptoms and erythema. Exogenously administered corticosteroids are derivatives of natural corticosteroid hormones that are produced by the adrenal glands. Corticosteroids exhibit a wide variety of anti-inflammatory effects and therefore are commonly used to exert rapid control of a variety of inflammatory disorders, including eczematous, autoimmune, and many bullous dermatoses. However, their long-term use is limited by the potential risk of adverse events, with either systemic or topical administration. TOPICAL CORTICOSTEROIDS A wide variety of topical corticosteroids are available. The potency of a corticosteroid is, to some degree, inherent to the compound itself and the concentration of that compound in the formulation.3 Potency is also dictated significantly by the vehicle, as formulation characteristics can directly affect percutaneous penetration.4 In the past, the vehicle that tended to give the greatest potency was usually an ointment. Compounds, such as betamethasone valerate or mometasone, demonstrated a higher potency in an ointment formulation than a cream. Lotions tended to be even less potent. These days, the rules have changed. Even though this trend is still true with some compounds, there are many new vehicle formulations that are
exceptions.5 Lotions and foams have been improved to allow for superpotent (Class 1) topical corticosteroid delivery. Probably the most important factor, when choosing a topical corticosteroid, is the disease and the anticipated responsiveness of that disease to a corticosteroid. For example, clobetasol propionate is usually overkill for seborrheic dermatitis, which typically responds to a low-to-medium potency topical corticosteroid. Disease states, such as plaque psoriasis or lichen planus, may be harder to get under control with medium and lower-potency agents, unless the plaques are very thin or located in intertriginous areas. A thick plaque of psoriasis on the elbow or knee is going to do a lot better, at least early on, with a higher-potency or super-potency agent. Obviously, the anatomic location makes a big difference. A topical corticosteroid applied to the axilla or groin, even a lowerpotency agent, will achieve greater cutaneous penetration due to natural anatomic occlusion.4 Although lotions have usually tended to be of lower potency than some of the more advanced creams or ointments, dermatology practitioners now have available a clobetasol propionate lotion (Clobex®, Galderma, Fort Worth, Texas), which exhibits superpotent activity due to its formulation characteristics, including the incorporation of propylene glycol.5 The same holds true for formulations such as fluocinonide 0.1% cream (Vanos®, Medicis Pharmaceutical Corporation, Scottsdale, Arizona).6 Other examples are hydroethanolic and emollient foams of clobetasol propionate (Olux,
Olux-E, Stiefel Laboratories, Coral Gables, Florida), which allow for very rapid penetration.7 Thus, the practitioner should learn each compound individually, rather than rely on speculative generalizations that may no longer be true. When a super-potent topical corticosteroid is needed for the scalp, foam formulations and sprays are amenable. Clobetasol propionate spray (Clobex®, Galderma, Fort Worth, Texas) may be used on glabrous skin or on the scalp. Triamcinolone spray (Kenalog®, Ranbaxy Laboratories, Inc., Princeton, New Jersey), a medium-potency corticosteroid with a nozzle applicator designed for scalp application, may help with seborrheic dermatitis, eczematous dermatitis, or psoriasis affecting the scalp or glabrous skin. Many practitioners start with a superpotency product with foam or spray. Then, later on, they step down to a mid-potency agent, if warranted clinically, depending on the status of disease progress. The newer formulation advances of foams and sprays allow for better treatment of the scalp, which is a difficult area to medicate, especially if the patient has a lot of scalp hair. There are potential adverse effects, such as cutaneous atrophy, which can become concerning when corticosteroids are prescribed over a prolonged period of time.8,9 Also, unauthorized refills can pose a problem. It is very important to have some type of control on how much corticosteroid a patient is receiving. Dermatology practitioners should be aware of the problem and counsel their staff not to continue to refill prescriptions for topical
DISCLOSURE: Dr. Del Rosso is a consultant and speaker for Allergan, Coria, Galderma, Intendis, Medicis, Ortho Dermatology, Ranbaxy, Stiefel, Triax, and Warner Chilcott. ADDRESS CORRESPONDENCE TO: James Q. Del Rosso, DO, FAOCD; e-mail: jqdelrosso@yahoo.com
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corticosteroids without approval. Even with the best of intentions, patients who may be treated outside of a dermatology practice may be given a medication, probably appropriately at that initial visit, and then continue to receive the medication from their primary clinician for too long a period. They keep applying it to the groin, axilla, or face and suddenly have a problem with atrophic skin, telangiectasias, and striae. Tinea incognito occurs when a topical corticosteroid is applied to a cutaneous dermatophyte infection.10 The corticosteroid essentially masks the clinical appearance of the eruption until the dermatophyte proliferates and extends more deeply into the skin (tinea profunda). Tinea profunda is a deeper cutaneous infection, often with follicular involvement, frequently requiring a systemic antifungal agent for eradication. A rosacea-like eruption or perioral dermatitis may appear with prolonged application of a topical corticosteroid to facial skin.11 Atrophy caused by prolonged application of topical corticosteroids can be reduced to some extent by controlling application frequency. Despite product labeling recommendations, the majority of medium-to-super potent topical corticosteroids work equally well when applied once daily, especially for eczematous dermatoses and seborrheic dermatitis.12 Twice-daily dosing does not always achieve additional benefits. This is helpful to know when using an ointment formulation, since they are very messy to apply during the day but not as much of a problem when applied at bedtime. Thus, if a patient is utilizing a topical corticosteroid that is high-to-super potency, it is likely to be effective if applied once daily. At other times during the day, another “steroid-sparing” topical agent may be added topically if needed, especially for chronic disorders such as atopic dermatitis and plaque psoriasis. An example would be application of a super-potent topical cortiS4
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costeroid, such as clobetasol propionate, or halobetasol propionate (Ultravate®, Bristol-Myers Squibb, Princeton, New Jersey) and ammonium lactate 12% (Lac-Hydrin®, BristolMyers Squibb). Concomitant application of ammonium lactate has been shown to reduce the atrophogenic effects of a topical corticosteroid, including a potent agent. Ammonium lactate 12% (Lac-Hydrin®) and halobetasol propionate (Ultravate®) are available together in a packaged prescription “kit” called Ultravate PAC®. SYSTEMIC CORTICOSTEROIDS Systemic corticosteroid therapy is an extremely valuable therapeutic tool in dermatology. It is often used to rapidly clear an acute allergic eruption, such as Rhus dermatitis (poison ivy), in which case the eruption resolves if the allergenic contactant is avoided. Often corticosteroid therapy is used to ameliorate an exacerbation of a disease that may become chronic, such as a severe eczematous eruption, a marked flare of an autoimmune disease, or pyoderma gangrenosum. However, as such disorders are typically chronic and often recurrent, attention must be given to how to taper systemic corticosteroid therapy appropriately. A potential adverse effect with prolonged use of systemic corticosteroid therapy is hypothalamic-pituitary axis (HPA) suppression.14 Once the daily dose exceeds 5 to 7mg/day of prednisone, HPA axis suppression occurs, usually after one month or longer. Untoward metabolic effects of excessive systemic corticosteroid therapy include osteoporosis, increase in blood pressure, hyperglycemia, and cataracts.14–16 Patients with hypertension and diabetes should be monitored carefully. Osteoporosis is a slow degradation of the trabecular bones, which will begin to develop after one month of systemic corticosteroid use.14–16 Osteonecrosis is a vascular necrosis, usually of the hip, which is
more of an acute, painful problem that tends to develop with more chronic treatment.14–16 Gastrointestinal side effects are common.14–16 That is why it is important to administer an oral corticosteroid (i.e., prednisone) with food in the morning. Regardless of the length of systemic corticosteroid therapy, the dose is best administered in the morning, as this simulates the natural, physiologic state of what normally happens with endogenous cortisone. Corticosteroid-induced myopathy can take place if patients are on higher doses of systemic corticosteroids for 2 to 4 weeks and then tapered too quickly.14–16 Cataracts can occur with chronic treatment of systemic corticosteroids. However, as with osteonecrosis, this does not occur after only 3 or 4 weeks of systemic corticosteroid therapy. Chronic corticosteroid therapy will be more of a risk if the patient is on another immunosuppressive agent, such as azathioprine, an immunosuppressant used in organ transplantation and autoimmune diseases, such as rheumatoid arthritis, pemphigus, or inflammatory bowel disease. Chronic immunosuppression with systemic agents in patients with solid organ transplants (i.e., kidney), for example, can increase the risk of lymphoma, and also increases the potential for development of cutaneous squamous cell carcinoma.14–16 When it is necessary for a patient to be on systemic corticosteroid therapy for more than a month, dermatology practitioners should work with the patient’s primary clinician toward prevention of osteoporosis.14–16 Supplementing vitamin D and calcium along with administration of an agent used to treat osteoporosis are to be considered. A bisphosphonate, or some of the newer agents to prevent osteoporosis in males and females, should be discussed. Long-term use of systemic corticosteroids creates osteoporosis in any gender.
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As stated earlier, the prevention of glucocorticoid-induced osteoporosis is important. The relative risk during oral corticosteroid therapy is close to two-fold for the hip and about threefold for the vertebrae, compared to matched controls for age, sex, and disease state.17 If the patient is getting more than 10mg of prednisone equivalent a day, and is receiving continuous treatment for more than 90 days, concern regarding osteoporosis is warranted. A staggering seven-fold increase in hip fractures, and a 17-fold increase in vertebral fractures, over time, has been found in these patients.17 When treating an acute contact dermatitis, 10 days to 2 weeks of systemic corticosteroid therapy is usually sufficient. Treatment may be initiated using 40 to 60mg per day of prednisone for 5 to 7 days, and then dropping the dose down to 30mg per day for 5 to 7 days, then to 20mg per day for 5 to 7 days. If therapy starts to go beyond four weeks, the potential risks of HPA axis suppression and osteoporosis must be considered.14–17 When tapering systemic corticosteroid therapy after using supraphysiologic doses beyond one month of treatment, lower the daily dose by 20 to 30 percent every 1 to 2 weeks.14-16 Alternate-day use of oral corticosteroid therapy is another option when long-term therapy is needed to control a more difficult dermatologic disorder, such as pyoderma gangrenosum or bullous pemphigoid.14–16 A bullous pemphigoid patient that has slowly been tapered down to 20mg per day to control his or her disease cannot be continued on this dosage indefinitely. An attempt should be made to control
the disorder with 40mg every other day. Sometimes an additional dose is needed on the alternate day. This is the classic method used to change a patient from daily therapy to alternate day therapy, that is, double the dose and give it on alternate days. Alternate-day dosing protects the patient against HPA axis suppression over time. However, it does not reduce the risk of cataracts, osteoporosis, or osteonecrosis. Thus, if the patient is still going to be on long-term alternate day therapy, consider osteoporosis prevention and monitor for other potential adverse events, such as hypertension, hyperglycemia, onset of hip pain, and cataracts. REFERENCES
1. Feldman SR. The biology and clinical application of systemic glucocorticosteroids. Curr Probl Dermatol. 1992;4:211–234. Barnes PJ. Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci (London). 1998;7: 1–40. Cornell RC, Stoughton RB. Correlation of the vasoconstriction assay and clinical activity in psoriasis. Arch Dermatol. 1985;121: 63–67. Yohn JJ, Weston WL. Topical glucocorticosteroids. Curr Probl Dermatol. 1990;2:38–63. Warino L, Balkrishnan R, Feldman SR. Clobetasol propionate for psoriasis: are ointments really more potent? J Drugs Dermatol. 2006;5: 527–532. Uliasz A, Zeichner J, Suong J, et al. A single-center, double-blind, randomized trial of the atrophogenic effects of fluocinonide cream 0.1% versus
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clobetasol propionate cream 0.05% in participants with corticosteroidresponsive dermatoses. Cutis. 2008; 81:517–519. Purdon CH, Haigh JM, Surber C, et al. Foam drug delivery in dermatology: beyond the scalp. Am J Drug Deliv. 2003;1:71–75. Akers WA. Risks of unoccluded topical steroids in clinical trials. Arch Dermatol. 1980;116:786–788. Kirby JD, Munro DD. Steroidinduced atrophy in an animal and human model. Br J Dermatol. 1976;94 (Suppl 12):111–119. Ive FA, Marks R. Tinea incognito. BMJ. 1968;3:149–152. Leyden JJ, Tew M, Kligman AM. Steroid rosacea. Arch Dermatol. 1974;110:619–622. Lagos BR, Maibach HI. Frequency of application of topical corticosteroids: an overview. Br J Dermatol. 1998;139:763–766. Lavker RM, Kaidbey K, Leyden JJ. Effects of topical ammonium lactate on cutaneous atrophy from a topical corticosteroid. J Am Acad Dermatol. 1992;26:535–544. Wolverton SE. Major adverse effects from systemic drugs: defining the risks. Curr Probl Dermatol. 1995;7: 1–40. Nesbitt LT. Minimizing complications from systemic glucocorticosteroid use. Dermatol Clin. 1995;13: 925–937. Lester RS, Knowles SR, Shear NH. The risks of systemic corticosteroid use. Dermatol Clin. 1998;16:277–288. Vermaat H, Kirtschig G. Prevention and treatment of glucocorticoidinduced osteoporosis in daily dermatologic practice. Int J Dermatol. 2008;47:737–742.
Dr. Del Rosso is Dermatology Residency Director, Valley Hospital Medical Center, Las Vegas, Nevada, Touro University College of Osteopathic Medicine, Henderson, Nevada; Clinical Associate Professor, Dermatology, University of Nevada School of Medicine, Las Vegas, Nevada; Las Vegas Skin & Cancer Clinics, Las Vegas and Henderson, Nevada.
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A R E V I E W O F C U R R E N T T R E AT M E N T OPTIONS FOR ACNE AND ROSACEA
Rana M. Hassan, PA-C
linical dermatology practitioners see patients suffering from acne or rosacea every day. For many dermatology practitioners, acne and rosacea patients are still the bread and butter of daily patient visits. Although there are many treatment options for both entities, practitioners still face countless decisions and complications when it comes to prescribing treatment regimens for patients suffering from acne or rosacea. Although prescription therapy is still the mainstay of treatment for acne and rosacea, it is refreshing to know that there are many other alternative, yet successful, treatment options available to patients. The social impact of acne is significant, with 85 percent of 12- to 24year-olds affected by acne.1 Women are significantly more affected in age groups over 20.2 The emotional impact acne has on individuals is profound and results in decreased self-esteem, anxiety, anger, depression, altered body image, and even suicidal ideation in up to seven percent of patients.1 Practitioners cannot ignore the social and emotional impact acne has on their patient population. However, practitioners are faced with some treatment limitations and challenges. Therefore, it is imperative that they develop treatment regimens that are individualized and tailored toward their patients’ personal needs. Traditional Acne Therapy Traditional acne treatment is readily available and still very successful for most acne patients. Traditional therapies address the major causative factors of acne, including hormonal contri-
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butions, the presence of Propionibacterium acnes (P. acnes), increased sebum production, comedone formation, and inflammation. Spironolactone and oral contraceptives. For female patients suffering from acne with noted hormonal influences, spironolactone or oral contraceptives are reasonable options. These agents help to decrease levels of free testosterone, therefore reducing sebum production. Oral contraceptives should not be used as monotherapy and risk factors must be considered when prescribing these medications.3 Retinoids. The largest category of topical therapies for acne include the comedolytic agents, or retinoids, that target the prevention of the microcomedone. The retinoids include tretinoin, adapalene, tazarotene, azelaic acid, and additional combination formulations. The retinoids are available in varying strengths and vehicles for specific patient needs. Benzoyl peroxide. Benzoyl peroxide (BPO) is a fast-acting antimicrobial agent with mild comedolytic and anti-inflammatory effects. BPO is available in various strengths ranging from 2.5- to 10-percent preparations. BPO has been proven efficacious in many different vehicles, including washes, lotions, creams, gels, and combination products. BPO, if well tolerated, should always be incorporated in an acne regimen as studies have shown no increase in antibiotic resistance with its use.3 Topical antimicrobial medications. The topical antimicrobial medications available inhibit P. acnes, in turn decreasing inflammatory acne
lesions. The topical antimicrobial agents available are erythromycin, clindamycin, metronidazole, and sodium sulfacetamide (with or without sulfur). Oral antimicrobial agents include amoxicillin, cephalexin, doxycycline, minocycline, erythromycin, tetracycline, and sulfamethoxazole/ trimethoprim. With continued increase in antibiotic resistance, it is important to limit the extended use of oral antimicrobial agents. Oral isotretinoin. Oral isotretinoin addresses multiple contributing factors of acne, including inflammation, increased sebum production, comedone formation, and increased production of P. acnes.3 Oral isotretinoin must be prescribed with caution due to its significant potential side-effect profile, and all females of childbearing potential must be compliant with the appropriate forms of contraception while on oral isotretinoin. Dapsone. The new, US Food and Drug Administration-approved topical acne therapy, dapsone, is now available. The mechanism of action of topical dapsone has not been fully established, but the clinical research seems to suggest that the anti-inflammatory properties of dapsone lead to successful treatment of acne. Topical dapsone is most efficacious when used in conjunction with other acne products, such as retinoids.4 Limitations and Challenges of Traditional Acne Therapy Antibiotic resistance. Although many of the traditional acne therapies are very successful in managing acne in most patients, there are some limitations and challenges. One of the
DISCLOSURE: Dr. Hassan acknowledges the following conflicts: Warner Chilcott, Medicis, PharmaDerm, Galderma, and Triax Pharmaceuticals. ADDRESS CORRESPONDENCE TO: Rana M. Hassan, PA-C; e-mail: ranaleichliter@msn.com
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most common challenges practitioners face is the limitation of antibiotics. Of utmost concern is the continued emergence of antibiotic resistance. In order to minimize antibiotic resistance when treating acne, practitioners must limit their use to the recommended indication and dosing time frame. Antibiotics should never be used as monotherapy and should always be an addition to a regimen that includes a topical BPO and/or topical antibiotic.5 Another option for minimizing antibiotic resistance is the subantimicrobial dosing of doxycycline. Used as first-line oral therapy along with appropriate topical treatment, this 40mg subantimicrobial dose of doxycycline is adequate therapy to reduce overall inflammatory lesions of acne.6 Oral antibiotic side effects. In addition to the concerns of antibiotic resistance, practitioners are faced with other limitations of oral antibiotics, such as common side effects, rebound flare-ups when the antibiotics are discontinued, and treatment failure. Side effects from antibiotics are both common and bothersome to patients. To minimize gastrointestinal upset in patients, practitioners should prescribe second-generation tetracyclines, such as doxycycline and minocycline. Practitioners should also consider doxycycline, enteric-coated, delayed-release tablets, in 75mg, 100mg, and 150mg dosages.7 Practitioners can also substitute minocycline hydrochloride (HCL) extended-release tablets for generic minocycline to reduce the central nervous system (CNS) side effects common with minocycline. Extended-release minocycline at a dosage of 1mg/kg reduces acute vestibular events while maintaining comparable efficacy.8 Both the delayed-release doxycycline tablets and the extended-release minocycline HCL tablets are available in once-daily dosing, which significantly increases
patient compliance. Rebound flareups are a common complaint among patients who discontinue oral antibiotic therapy. To reduce these flareups, practitioners can start oral antibiotic therapy at the highest dose based on the severity of the acne and then discontinue therapy once the acne has sufficiently cleared. Again, initiating oral antibiotic therapy in conjunction with a topical BPO and/or retinoid will reduce rebound flares once the antibiotic is discontinued.6 Oral antibiotics are not the only medications that have their prescribing limitations. The most notorious and probably most controversial oral therapy for the treatment of acne is oral isotretinoin. Oral isotretinoin, although an extremely efficacious therapy, continues to haunt practitioners—whether it is due to the logistical nightmares of the iPledge program or the media hype that causes fear among patients for the potential psychiatric side effects. Although numerous studies have discounted the idea that oral isotretinoin is linked to suicide and self injury, many patients wish to avoid this treatment completely.9 Many practitioners are faced with treating acne patients who are hesitant about oral therapy altogether, including antibiotics, isotretinoin, and oral contraceptives. In these instances, practitioners must be prepared to offer patients other alternatives. Of utmost importance is making sure that patients have sufficient therapy with topical medications. Using combination therapies, such as clindamycin phosphate 1%/BPO 5%, clindamycin phosphate 1.2%/tretinoin 0.025%, and the newest combination adapalene 0.1%/BPO 2.5%, ensures thorough coverage and adequate therapy for the patient. Other alternatives include some nontraditional, but efficacious, options. For patients who suffer from come-
donal acne, practitioners should recommend facials or deep pore cleansings by a well-trained, medically accurate aesthetician. Alternative Acne Therapies Photodynamic therapy. Photodynamic therapy (PDT) is a proven, efficacious, alternative therapy to oral antibiotics for the treatment of acne. Multiple laser and light source systems are available. These systems either aim to target and destroy P. acnes or destroy sebaceous glands. The addition of aminolevulinic acid (ALA) to PDT has enhanced the efficacy of PDT and offers practitioners another option for the treatment of moderate-to-severe inflammatory acne.10 PDT treatments are safe and tolerable and can serve as solo or adjunctive therapy to topical or oral acne treatments. Some downfalls to PDT therapy include limitations for use in patients with Fitzpatrick skin types I to IV and cost. Many insurance companies will not reimburse for these somewhat costly procedures. However, if patients have insurance coverage with flexible medical spending options, they can often get reimbursed for the procedures. Chemical peels. Chemical peels are also valuable treatment options for acne. There are many effective forms of chemical peels in varying strengths. Alpha-hydroxy peels such as glycolic acid peels, beta-hydroxy peels such as salicylic acid peels, amino acid peels, Jessner’s peels, and combination peels with retinoic acid are all suitable options for therapy. Combination peels offer the benefits of alpha-hydroxy acid, beta-hydroxy acid, resorcinol, and retinoic acid.11 These peels are safe and tolerable for skin types I to VI and provide noticeable results in as few as one treatment with a minimal downtime of up to 72 hours for slight active peeling. In addition to effectively treating
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active acne lesions and preventing additional breakouts, chemical peels have the added benefit of reducing the appearance of postinflammatory hyperpigmentation, which is often associated with acne, especially in Fitzpatrick skin types IV to VI. Although many chemical peels are not considered safe in pregnancy, glycolic acid peels are safe during pregnancy and are a good adjunctive therapy option for pregnant women with acne. Chemical peels are considered to be cosmetic procedures and are typically not covered by insurance. Chemical peels range in cost from $100 to $300 per session and most offices offer discounts for packages including multiple peels. Again, flexible medical spending accounts will often reimburse for these procedures with a letter from the physician’s office. Microdermabrasion. Microdermabrasion offers practitioners a myriad of options for the treatment of acne, postinflammatory hyperpigmentation, and associated acne scarring. There are countless microdermabrasion systems. Therefore, it is important for practitioners to research the most appropriate and effective system for their patient populations. This author recommends a medicalgrade microdermabrasion system that uses a particle-free, brush-tip bristle system to safely and effectively exfoliate the skin to prevent hyperkeratinization and follicular plugging—the precursors to acne. Epiinfusions incorporate ingredients, such as salicylic acid and witch hazel, to further fight acne.12 The cost for microdermabrasions is comparable to the cost of chemical peels. Patient Adherence Practitioners are fortunate to have a wealth of options when treating acne. However, they must remember that successful treatment is directly dependent on patient adherence. A recent Skin Matters 2008 Survey con-
cluded that 91 percent of dermatologists note that patient adherence is a barrier to treatment success.13 When considering acne therapies, practitioners have to consider management that will increase patient adherence. Acne is multifactoral; therefore, acne treatment must be as well. Practitioners cannot suggest carbon copy regimens for every patient they see. Patients need to trust their practitioners’ recommendations, knowing that the treatment will be worth their time and effort. It is important to stress to patients that successful acne treatment takes time and diligence on their part. Practitioners should suggest a simple daily skin care regimen and write it down for the patient as a reference. Practitioners should recommend all aspects of daily skin care, including cleanser, moisturizer, and daily sunscreen. They should also consider prescription medications that are packaged with cosmeceutical agents that will enhance the medication and further combat acne. For example, topical tretinoin cream and gel in various strengths packaged under the name Tretin-X™ (Triax Pharmaceuticals, Cranford, NJ) combines a complimentary gentle cleanser and noncomedogenic moisturizer that minimizes irritation common with tretinoin. Oral minocycline HCL is available in the Minocin® PAC (Triax Pharmaceuticals) with moisturizing wipes, an anti-inflammatory serum, and a calming facial masque, again enhancing the complete approach to treating acne and minimizing irritation.14 If these prescription options are not available to the patient, practitioners should consider sending the patient home with a few complimentary samples of a gentle cleanser and moisturizer. This will increase adherence and help patients avoid confusion as they walk the product aisles of their local pharmacy looking for a suitable skin care regimen. Above all, patient education is crucial. Practitioners should show
patients how to use their medications and skin care products. Engaging patients in the decision-making process when treating their acne and allowing them to choose the therapies that are most suitable for them will increase their adherence. Increased adherence equals increased efficacy and patient satisfaction. Traditional Rosacea Therapy Rosacea is another prevalent dermatological condition dermatology practitioners are faced with on a regular basis. It is estimated that about 14 million Americans are affected by the varying symptoms of rosacea. In a similar respect to patients suffering from acne, rosacea sufferers also experience decreased self esteem and social restraints, including avoidance of public appearances and missed work.15 Rosacea is classified into five subtypes—erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea, ocular rosacea, and granulomatous rosacea. Erythematotelangiectatic rosacea and papulopustular rosacea are the most common types. While examining a patient for rosacea, always take a thorough history to determine if the patient has any “trigger factors” that may be exacerbating their symptoms. The most common trigger factors identified in a recent survey by the National Rosacea Society are sun exposure, emotional stress, hot weather, and wind. However, countless other trigger factors, such as alcohol and caffeine, can cause a flare of symptoms, so it is important to keep others in mind.16 Because of the chronic nature of rosacea, treatment must be based on long-term use and permanent changes in skin care. The traditional topical therapies for rosacea include metronidazole, azelaic acid, sodium sulfacetamide/sulfur combinations, clindamycin, erythromycin, and tacrolimus and pimecrolimus.
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Sodium sulfacetamide/sulfur combinations. Sodium sulfacetamide/sulfur combinations are thought to have an anti-inflammatory effect and are therefore beneficial to patients suffering from papulopustular rosacea and any patient with the generalized erythema of rosacea. These combinations are available in washes, lotions, gels, creams, and combinations with and without sunscreen.17 Metronidazole. Metronidazole also has anti-inflammatory properties as well as antioxidant properties, which reduce the reactive oxygen species in the skin, therefore reducing inflammatory lesions and erythema in rosacea. Metronidazole is available in gels, lotions, and creams and in various strengths.19 Azelaic acid. Azelaic acid is another anti-inflammatory and antioxidant therapy for rosacea and can be used for all stages of rosacea. Azelaic acid is classified as pregnancy category B and benefits patients suffering from melasma and/or acne.19 Short-term topical therapy. Shortterm topical therapy options include the nonfluorinated corticosteroids and tacrolimus and pimecrolimus, which are especially effective for patients with erythematotelangiectatic rosacea who have considerable inflammation or an overlying seborrheic dermatitis. Oral therapies. The most commonly used oral therapies for rosacea include first- and second-generation tetracyclines, subantimicrobial dosages of doxycycline, erythromycin and clarithromycin, beta blockers, clonidine, nonsteroidal anti-inflammatory drugs (NSAIDS), and oral isotretinoin. Beta blockers, clonidine, and NSAIDS are useful for the treatment of the flushing and blushing symptoms of rosacea. However, the benefits must outweigh the risks for patients when considering prescribing these medications.18 Although not always used
as first-line therapy for rosacea, there are some nontraditional yet effective options. Retinoids. Previously, retinoids were not considered therapeutic due to the risk of irritation to the fragile rosacea skin. However, recent studies have proven them to not only be efficacious, but tolerable as well. Practitioners should consider prescribing retinoids for long-term maintenance, especially for patients who also have photodamage. Often, the clinical response may be delayed when using retinoids for rosacea. Certain retinoids, such as adapalene, lower strength tretinoin in elegant vehicles, and the combination clindamycin phosphate 1.2%/tretinoin 0.025%, have proven to be gentler and better tolerated.19 Procedures that Enhance Traditional Rosacea Therapy Additional procedures enhance the efficacy of traditional rosacea therapy and address components of rosacea not treated by the topical and oral medications. Light-based therapy is effective in treating the flushing, erythema, and telangiectasia of rosacea. Pulsed dye laser is most commonly used to treat telangiectasia, while intense pulsed light improves erythema, flushing, and skin texture. Ablative lasers, such as the CO2 or fractional lasers, improve the textural changes of rhinophyma and sebaceous hyperplasia. Surgical ablation and electrosurgery are still options for rhinophyma as well.18 Unfortunately, many of these procedures are not covered by insurance and could be costly for patients. Challenges of Traditional Rosacea Therapy As with any chronic condition and treatment regimen, there are pitfalls to consider as well. Antibiotic resistance is a concern with rosacea patients due to the chronic nature and need for longer-term therapy. In
place of choosing traditional therapies, such as tetracyclines that are both antimicrobial and anti-inflammatory, practitioners should consider subantimicrobial anti-inflammatory doxycycline as first-line therapy. Options that are currently available by prescription are doxycycline hyclate 20mg twice daily and delayedrelease doxycycline 40mg. Longerterm studies support the safety and efficacy of delayed-release doxycycline 40mg once-daily dosing.5 Increasing compliance in patients with rosacea will benefit patients tremendously and minimize flare-ups and exacerbations. Appropriate and consistent skin care is also essential for rosacea patients. Practitioners should recommend a nonirritating skin care regimen that helps to restore the compromised skin barrier. Prescription therapies packaged with cosmeceuticals, such as metronidazole packaged with a gentle skin cleanser also can be prescribed. Daily ultraviolet (UV) A and B sun protection is crucial. There are countless over-the-counter and cosmeceutical products available for adequate UVA/UVB protection. Some of the sulfacetamide/sulfur preparations are combined with a sunscreen. Another product available that helps to reduce erythema while providing adequate sunscreen is a mineralbased powder SPF 30 with titanium dioxide. Additionally, practitioners should consider adding antioxidant therapy to the daily skin care regimen with ingredients such as green tea, vitamin C, coffee berry, or oatmeal. Antioxidants are proven to reduce free radicals in the skin and add increased photoprotection to sunscreens.20 Practitioners should always recommend options for patients to help conceal their erythema. Tinted moisturizers or sunscreens are readily available as well as full-coverage mineral makeup. Green tints in moisturizers and makeup are additional
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Conclusion Acne and rosacea are multifactoral conditions that require multifactoral treatment regimens. Adherence is of utmost importance when treating acne and rosacea. Practitioners need to remember adherence equals success, and education will maximize that treatment success. Do not hesitate to use some of the nontraditional therapies that have proven to be safe and efficacious. There are a myriad of treatment options available to us as practitioners and it is our responsibility to make the best therapeutic decisions for our patients.
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REFERENCES
1. Cook-Bolden F. Clinical presentation and diagnosis of acne: patient-centric considerations. Cutis. 2008;82(2):5–7. Collier CN, Harper JC, Cafardi JA, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol. 2008;58(1):56–59. Tsche E. Addressing patient variability: clinical challenges in the initiation of acne treatment. Cutis. 2008;82(suppl)2S[i]:9–13. Draelos Z, Carter E, Maloney J, et al. Two randomized studies demonstrate the efficacy and safety of dapsone gel, 5% for the 8.
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treatment of acne vulgaris. J Am Acad Dermatol. 2007;56(3):439.e8. Del Rosso J, Leyden J, Thiboutol D, et al. Antibiotic use in acne vulgaris and rosacea: clinical considerations and resistance issues of significance to dermatologists. Cutis. 2008;82(suppl)2S[ii]:8–10. Yan A, Treat J. Beyond first-line treatment: management strategies for maintaining acne improvement and compliance. Cutis. 2008;82(suppl)2S[i]:20–22. Berger RS. A double-blind, multiple dose, placebo controlled, cross-over study to compare the incidence of gastrointestinal complaints in healthy subjects given Doryx and Vibramycin. J Clin Pharmacol. 1988;28:367–370. Fleischer A, Dinehar S, Stough D, et al. Safety and efficacy of a new extended-release formulation of minocycline. Cutis. 2006;78(suppl)4S:21–22,30. Meyer E. Acne and rosacea update. Skin and Aging. August 2008:54. Gold M. Therapeutic and aesthetic uses of photodynamic therapy: part two of a five-part series. Lasers and Light Treatments for Acne Vulgaris. J Clin Aesthetic Dermatol. 2008;1(3):28–33. www.skinmedicaaesthetics.com. Accessed on December 15, 2008.
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www.dermasweep.com. Accessed on December 15, 2008. Kean C. New survey highlights emotional toll of adult acne. Skin and Aging. August 2008:48–50. Draelos Z. The tolerability of topical tretinoin and oral minocycline hydrochloride with and without anti-inflammatory skin care products. Cosmet Dermatol. 2008;21:134–136. National Rosacea Society. What is rosacea? 2008. http://www.rosacea.org/patients/ma terials/understanding/what isrosacea.php. National Rosacea Society. Rosacea Triggers Survey. http://www.rosacea.org/patients/ materials/triggersgraph.php. Rosso J, Baum M. Comprehensive medical management of rosacea: an interim study and literature review. J Clin Aesthetic Dermatol. 2008;1(1):21. Arnold T, Brunton S, Knudtson M, et al. The many faces of rosacea: topical treatment of rosacea. a clinical update. Skin and Aging. 2008(supp):9–13. Bhatia N. Rosacea basics. Skin and Aging. 2008:60–63. Ditre C, Wu J, Baumann L, et al. Innovations in natural antioxidants and their role in dermatology. Cutis. 2008;82(supp)6s:12–13.
Ms. Hassan is from the Northern Virginia Dermatology, Vein and Surgery Center, Ashburn, Virginia.
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THERAPEUTIC DECISION-MAKING FOR BASAL CELL CARCINOMA: A PRACTITIONER’S POINT OF VIEW
James Spencer, MD
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ith more than 1.3 million cases diagnosed in the United States each year, skin cancer alone exceeds the incidence of all other cancers combined, including breast, colon, and prostate cancer. Of the three common types of skin cancer—basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma—nearly 75 percent is diagnosed as basal cell carcinoma. There are about one million BCC cases, 300,000 SCC cases, and 60,000 melanoma cases diagnosed per year. BCC is most often treated in doctors’ offices, not hospitals, and may or may not be documented in tumor registries; therefore, it is difficult to get an exact number of diagnosed cases. Although BCC is common, it is poorly understood and difficult to study in the laboratory. Because mice and rats get SCC, but not BCC, there are few laboratory models of BCC.
ETIOLOGY OF BCC
Because BCC only occurs in places that have hair follicles, it almost never occurs on the hands or mouth, unlike SCC or melanoma. Skin tumors that arise in chronic wounds or scars are SCC, but can be BCC. BCC is a slow-growing tumor that arises in the epidermis. The cell of origin is unclear, but this type of tumor is called “basal cell carcinoma” because it resembles the basal layer of keratinocytes in the epidermis. Therefore, the name does not indicate that it comes from basal cells; rather, it is just a descriptive term. Under the microscope, basal cells
are monomorphic, round cells that do not usually look very cancerous. They have mitotic figures and nuclear morphorism. Cancers are usually graded as mild, moderate, and severe atypia. Regarding BCC, the architectural pattern of cells under the microscope is important. In BCC, nodular is, by far, the most common pattern. In this pattern, cells are arranged in round, cohesive clusters that enable clinical appreciation of the size of the tumor. This architecture makes the extent of BCC easy to identify and, therefore, therapy is much more straightforward. The diffuse growth patterns include morpheaform, superficial, infiltrating, and micronodular. Both morpheaform and superficial tend to spread subclinically horizontally. Infiltrating and micronodular are the more serious lesions that tend to be deep and, thus, more difficult to treat. Although rare genetic syndromes, such as basal cell nevus syndrome and xeroderma pigmentosa, exist and may be the cause of BCC development, exposure to ultraviolet (UV) light is likely the cause of BCC most of the time. BCC has a p53 mutation (a tumor-suppressor gene) more than 50 percent of the time. This is interesting and may be evidence that UV light causes BCC, since UV light causes pyrimidine dimers and the 6-4 photoproduct, which are signature mutations. When observing these changes in the p53 gene, one can deduct the mutation was caused by UV light. Most likely, different patterns of exposure lead to the two different
kinds of skin tumors. Interestingly, people are either “basal cell makers” or “squamous cell makers.” People who develop multiple skin cancers tend to develop only one type. Those who develop SCC, develop more SCC, while those who develop BCC, develop more BCC. This is somewhat surprising in that both SCC and BCC are thought to result from excessive UV exposure, so one might expect those with multiple tumors would develop a mixture of BCC and SCC. The observed segregation suggests a difference in the causes or susceptibility of skin tumors. BCC is slow growing and takes about six months to double in size. It is locally destructive and will invade cartilage and bone. More often, BCC hits hard structures, skates along the surface horizontally, and very rarely metastasizes. Once BCC has formed, a patient has a 50-percent chance of forming another BCC within three years. About 80 percent of BCC occurs on the head and neck, 35 percent of which occurs on the nose—one of the observations leading investigators to believe that UV light triggers basal cell formation. Similar to SCC, BCC occurs on chronically sunexposed areas, such as the head. However, the pattern is a little different with BCC. In some ways, BCC is similar to melanoma and in some ways, it is similar to SCC. For example, BCC correlates with recreational sun exposure before the age of 20, similar to melanoma. BCC is overwhelmingly seen in fair-skinned, sun-sensitive people. The correla-
DISCLOSURE: Dr. Spencer reports no relevant conflicts of interest. ADDRESS CORRESPONDENCE TO: James Spencer, MD; email: jgspencer@tampabay.rr.com
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especially before the age of 20, is crucial in the preBasal cell carcinoma vention of BCC. A Pearly papule with a rolled, waxy border and overlying telangiectasia number of drugs that play a role in Slow growing chemoprevention Low risk of metastasis of BCC are becoming available. Can cause severe disfigurement There is evidence Common sites: head and neck that the COX-2 Squamous cell carcinoma inhibitors, particularly celecoxib Pink, scaly papule or plaque (Celebrex®, Pfizer Often preceded by actinic keratosis—a rough, scaly papule or Inc., New York, plaque that may be easier to diagnose by touch than by sight New York), may have a chemoLow risk of metastasis preventive effect Common sites: head, neck, hands, forearms, upper trunk, lower legs on BCC. Many topicals seem to Melanoma have some chemoVaries in color (red, white, blue, brown, or black) preventive effect High risk of metastasis as well, including green tea and Aggressive local growth genistein, which Common sites: backs of men and lower legs of women have found their way into cosmetion with chronic sun exposure, ceuticals. However, effective concenhowever, is not perfect. BCC often trations are unknown. arises in the relatively shaded area behind the ear and on the inner can- BCC PRESENTATION thus (either of the angles formed by BCC most commonly presents as a the meeting of the upper and lower smooth, somewhat translucent eyelids) (Table 1). (pearly) papule arising on sunSkin cancers are immunogenic, exposed areas. It often contains and there is always an inflammatory telangiectasias, which, as they slowly infiltrate around basal cells. The enlarge, outgrow their own blood theory of immune surveillance is supply, necrosing the center of the that the immune system continually formation. At first, a little cell is recognizes and eliminates tumor formed. Later, there is frank ulceracells. When a tumor escapes immune tion. In some cases, the diffused surveillance and grows too large for growth patterns can have atypical the immune system to kill, cancer is appearance. Superficial growths are the result. UV light induces toler- usually seen on the torso and resemance, and acts as an immunosup- ble small patches of eczema. When pressor. It is the perfect carcinogen. topicals do not improve the situation, In addition to causing cancer, UV a biopsy should be performed. light immunosuppresses, fostering Morpheaform BCC resembles a scar, skin cancer tumor persistence and while infiltrating and micro- nodular growth. BCC look more nodular. A biopsy is the gold standard. However, each biopsy PREVENTION OF BCC should contain enough of a sample to Sunscreen and sun avoidance, sense the architectural pattern.
TABLE 1. Characteristics of common skin cancers
TREATMENT OF BCC
The goal of therapy for BCC is to completely eradicate the tumor while limiting damage to surrounding normal structures. Failing to eradicate the tumor can result in local recurrence, which presents consequences. The first consequence of local recurrence is that what started out as low-risk BCC, often recurs as infiltrating or micronodular. These types of tumors become more aggressive when they recur. Secondly, recurrences are often larger in structure and multifocal, growing down into the fat. Dermatologists do not often use chemotherapy (topical chemotherapy or photodynamic therapy [PDT]), for skin cancer. Rather, they use surgery and, sometimes, radiation therapy. The four surgical procedures include curettage and electrodesiccation, cryosurgery, surgical excision, and Mohs surgery. Radiation therapy is also used, but less frequently. There are two strategies for surgery. One is blind destruction, which encompasses scraping and burning or freezing. The other is excision with some kind of histological examination—either frozen sections or permanent sections. Blind destruction is cryotherapy with liquid nitrogen or curettage and electrodesiccation, while excision comprises conventional margins or Mohs surgery. Cryosurgery. There are many cryogens, but liquid nitrogen (about -196°C) is most often used. Keratinocytes will die at about -40°C. Cryosurgery is not a completely random treatment. Freezing, actually, has some degree of selectivity. Nerves, collagen, and blood vessels are more resistant to cold than keratinocytes. Unfortunately, as seen when treating actinic keratosis (AK), melanocytes are the most sensitive. Freezing often leaves white spots or hypopigmentation. Freezing AKs takes 5 or 10 seconds. Tumors are usually frozen for about 1 to 2 minutes.
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Two freeze/thaw cycles are recommended. Studies have shown that cryoprobes placed under the skin to measure the degree of freeze do not demonstrate improved outcomes. Curettage and electrodesiccation. Curettage followed by electrodesiccation is another destructive treatment. Basal cells have lost some of their hemidesmosomes, which hold the cells together. With this treatment, a sharp loop is used to scoop out the tumor. Then, the base is burned with an electrosurgery unit to seal blood vessels and to stop bleeding. Advocates of this technique support three cycles of curettage followed by electrodesiccation. A small, nodular basal cell on a forearm will offer nearly a 95-percent cure rate with curettage. This is not true with more difficult-to-treat tumors, such as high-risk histological types (i.e., morpheaform), high-risk anatomic locations such as the nose, and any recurrent tumor. It all depends on size, location, and histology. Mohs surgery. It is well known that tumors have subclinical extensions. When dermatologists remove the visible tumor with a scalpel and send it to the pathologist, they are looking to see if they cut deep enough or far enough around the lesion. Generally, for most basal cells, 4 or 5mm of normal-appearing, marginal skin in all directions is the proper span. For tumors with a high risk of recurrence, dermatologists perform a highly specialized technique called Mohs surgery. The Mohs technique is fundamentally a pathology technique, not a surgical technique. This procedure removes tumor tissue, layer by layer, mapping and freezing each layer, and examining it for tumor cells under a microscope before proceeding to the next layer. It is a precise, complex, and time-consuming process. Mohs surgery ensures that the entire tumor is removed and minimizes scarring by preserving as much normal skin as possible. Mohs surgery
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has the highest cure rate of all therapies for advanced BCC and is particularly effective for large tumors, tumors that have recurred after other treatments, and tumors in areas such as the face that require preservation of as much normal skin as possible for cosmetic reasons. Radiation therapy. Radiation therapy has become so complex and sophisticated that a whole new field has emerged, known as radiation oncology. For the typical BCC case, a patient may receive 4,000rads divided in doses. With radiation therapy, the practitioner gives the same total dose in many small packets as a larger dose would be if it was performed all at once. The usual timeline for therapy is daily, five times a week, for 3 to 6 weeks. Radiation therapy with x-rays or high-energy particles can be useful for treating tumors in patients who are at higher risk for surgical complications. Radiation is sometimes used after surgery to destroy tumor cells that may have been missed or to treat tumors with a higher risk of recurrence. Radiation is usually delivered in small doses over a period of 3 to 4 weeks in order to avoid burning the skin. Radiation therapy is often reserved for older patients who cannot tolerate surgery. The cosmetic result of radiation may worsen and radiation sites may experience atrophy and hypopigmentation with telangiectasias over time. Although scars will improve over time, radiation sites, even 20 years out, will continue to worsen.
CHOOSING THE RIGHT THERAPY
Dermatology practitioners should categorize BCC as low risk or high risk, look at the context of the patient’s life, and make a treatment decision. Destructive therapies work well for low-risk tumors. A more sophisticated treatment, such as excision, Mohs surgery, or radiation, should be used for more high-risk
tumors. When determining risk, consider anatomic location, histology (architectural pattern), tumor size, and history (recurrence) (Table 2). Before choosing a therapy, the practitioner must analyze the patient’s life, including his or her age and overall health. The time required to receive radiation therapy (every day for one month), transportation, cosmetic priorities, and expectation should be taken into consideration. The practitioner must weigh these considerations when determining whether the BCC is high risk or low risk. The practitioner must also consider the patient’s financial situation when determining treatment. Two-year-old data from Medicare show that $562 million are spent each year treating nonmelanoma skin cancer. That figure can be doubled if the private sector is included. The cost of radiation versus a simple freeze is fivefold. Radiation therapy is, by far, the most expensive treatment. Another study shows office-based procedures at $492; ambulatory surgery center procedures at $1,000; and hospital-based procedures with preoperative care expenses, operating room expenses, and recovery room expenses at more than $5,000. As for destructive techniques, such as curettage and electrodesiccation and cryosurgery, not many practitioners, other than dermatologists, perform them. Over the last five years, Mohs surgery has increased 300 percent. Even with this increase, excision and Mohs surgery, as performed by dermatologists in the office without the need for a preoperative electrocardiogram, blood work, chest x-ray, recovery room, or anesthesiologist, greatly lowers the cost.
EMERGING TREATMENTS FOR BCC
Topical therapies. In addition to
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TABLE 2. Factors in determining low-risk versus high-risk BCCs
Location Retrospective analyses of recurrence have shown that the center of the face (upper lip, nose, around the eyes, extending out into the temples, on and around the ears) has a very high risk for recurrence. Basal cells, of any size, in that location, deserve a sophisticated treatment. Histology Nodular is low risk. A nodular basal cell in the lower back is low risk versus a nodular basal cell on the side of the nose, which is high risk. Any of the diffused patterns of any size (morpheaform, infiltrate, and micronodular) are high risk. Size Anything bigger than a sonometer on the face is high risk. Anything bigger than two sonometers on the body is high risk. History Recurrent tumors are always high risk. They are usually multifocal, bigger, and deeper than expected.
radiation and surgical procedures, effective topical therapies are emerging. 5-fluorouracil. In the 1960s, 5-fluorouracil (5-FU) was originally used in a topical form for BCC. The investigators did not know what concentration to use, so they tried 20% 5-FU with petrolatum, under occlusion, for three weeks, with a 21-percent, fiveyear recurrence rate, but scarring and other problems would occur. In the late 1970s, another study used 5% 5FU with a 10-year follow up showing a 21-percent recurrence rate. Again, in a recent BCC study, investigators used 5% 5-FU, twice daily, for 12 weeks, with a 90-percent histological clearance rate. Topical 5-aminolevulinic acid (ALA). ALA preferentially accumulates in dysplastic and malignant cells, where it is converted to protoporphyrin IX, a potent photosensitizer. In response to light from 400 to 730nm, reactive oxygen species are generated, resulting in oxidative damage and cell death. The topical product is rubbed on the face, allowed to accumulate in the dysplastic cells, and then exposed to a
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proprietary blue light. This process is US Food and Drug Administration (FDA)-approved for the treatment of AK, but not yet approved for skin cancer in the United States. Imiquimod. Imiquimod is a cream that upregulates cytokines, including interferon alpha, beta, tumor necrosis factor, and interleukin 12. Imiquimod stimulates a nonspecific immune response for formation of cytotoxic T-cells. It is FDA approved for the treatment of genital warts, AK, and superficial BCC. Two recent superficial basal cell pivotal trials were performed for imiquimod FDA submission. One was a six-week, open-label trial with 99 patients and the other was a 12-week, vehiclecontrolled trial with 128 patients. In the six-week trial, superficial basal cell patients were divided into four groups, with four different dosing regimens, once daily (3 or 7 days per week) or twice daily (3 or 7 days per week). Six weeks after the trial was complete, the site of the BCC was excised with 3mm margins using excisional specimen-stepped sectioning. The 12-week trial worked
the same way, only longer. The outcome data from the six-week and 12week trials were virtually identical. Thus, the drug plateaus at six weeks. Twice-daily dosing offered 100-percent cure rate, but none of the patients could tolerate it. Oncedaily imiquimod cream for six weeks gave patients nearly an 88-percent cure rate. In a much larger follow-up study of close to 700 BCC patients, imiquimod was compared with vehicle control either five times per week or seven times per week for six weeks. At 12 weeks following therapy, clinical inspection and excision were performed. The histological clearance rate was 82 percent—not quite as good as the first study, which demonstrated an 88-percent clearance rate. Imiquimod may not work quite as well as surgery, but it does not leave a scar. In another six-week, open-label trial with 99 nodular basal cell patients, as well as a 12-week, vehicle-control trial with 92 nodular basal cell patients, the histological clearance rate was 71 percent and 76 percent, respectively. Many clinicians would view these results as unacceptable and not recommend imiquimod for nodular basal cell treatment. Mixed therapies. Finally, practitioners should consider mixing therapies, by following curettage and electrodesiccation with imiquimod topical therapy for BCC. Topical imiquimod applied nightly immediately following curettage and electrodesiccation can result in a significantly decreased frequency of residual tumors. There will be a slightly longer healing time, but an improved cosmetic appearance. Photodynamic therapy. Derivatives of porphyrins preferentially accumulate in malignant cells. Porphyrins are in the biosynthetic pathway to make hemoglobin. Once inside the target cell, these porphyrins
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can be activated by light to produce cell death via oxidative damage. Systemic, intravenous PDT has photosensitive side effects that can sequester patients to a dark room for 4 to 6 weeks, making it slightly unacceptable. The search for a better photosensitizer is ongoing. A topical photosensitizer would avoid the problem of systemic photosensitivity. In Europe, PDT is more widely used, especially 5-aminolevulinic
acid methyl ester (MAL) with an increased lipophilicity, enabling better penetration. It may soon be available in the United States. A recent, randomized, prospective trial compared MAL to surgical excision. Onehundred and five BCC patients were treated, with one group receiving 2 to 4 treatments of MAL and the other group receiving standard, surgical excision. There were roughly the same amount of patients in each
group. At a five-year follow up, there was a 14-percent recurrence rate in the MAL PDT group versus a twopercent recurrence rate among the excision group. Clearly, excision is better, but patients might choose MAL because the cosmetic result is more desirable. Some patients may be willing to accept a 12-percent greater probability of recurrence as long as they do not develop a scar from treatment.
Dr. Spencer is Clinical Professor, Department of Dermatology, Mount Sinai School of Medicine, New York, New York.
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N E W D E R M AT O L O G Y T R E AT M E N T R E G I M E N S : A T H E R A P E U T I C U P D AT E
James Q. Del Rosso, DO, FAOCD
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atients often ask for information about dermatologic treatments that they have received from various sources, such as websites, stores, pharmacies, or even cosmetic counters. Most dermatologists and dermatology practitioners receive questions daily about new medical options. The following is a brief therapeutic update on newer dermatology treatment regimens. MOISTURIZER USE AND TOPICAL MEDICATIONS FOR ACNE AND ROSACEA Patients suffering from acne vulgaris often want to know whether they should be using a moisturizer before or after applying additional topical therapies. Questions regarding efficacy and tolerability often arise, mainly to inquire if applying the moisturizer before a topical retinoid has any affect on efficacy when applied before the active agent. Does it impact the tolerability profile? In a recent, multicenter, investigator-blinded, 16-week study among 119 patients with mild-to-moderate acne vulgaris, investigators looked at one group that applied moisturizer in addition to using tazarotene 0.1% cream (Tazorac®, Allergan, Inc., Irvine, California). The moisturizer in the study was CeraVe™ cream (Coria Laboratories, Fort Worth, Texas) applied twice daily. The moisturizer was applied in the morning and then at night before the tazarotene 0.1% cream, which was used only once a day. In another group, patients used only tazarotene 0.1% cream at night. If they perceived some dryness or flak-
ing, they could use CeraVe lotion on an as-needed basis. Cleanser use was controlled, and all patients in the study used the CeraVe cleanser. Cosmetics were also controlled. Other than study-allowed topical agents, patients were not allowed to use other therapeutic agents or cosmeceuticals for their condition. With regard to efficacy, which was based primarily on measuring inflammatory lesion reduction and noninflammatory lesion reduction, there was no difference between the two groups. Thus, applying the CeraVe cream before the tazarotene cream did not reduce the efficacy of the retinoid. This is new and important information, since many practitioners have always believed that patients should not apply a moisturizer before active medications because the moisturizer application may impair the penetration of the active ingredients in the medication. Patients were told to wait 20 minutes between moisturizer application and tazarotene cream use. Importantly, the visible signs of retinoid dermatitis, such as peeling and redness, were reduced in the group that regularly used the moisturizer first, without affecting efficacy. Diseases like acne vulgaris and rosacea benefit from regular use of moisturizers in order to keep the barrier intact. Percutaneous penetration data may be measured in vitro. A membrane of human skin in vitro, utilizing a recognized assay known as a modified Frantz cell chamber assay, may reveal active ingredient penetration in skin.
Azelaic acid 15% gel (Finacea®, Intendis, Pine Brook, New Jersey) was applied and independently tested along with three different moisturizers. Cetaphil Lotion® (Galderma Laboratories, Fort Worth, Texas), CeraVe lotion, and Dove® lotion were selected. Each was tested independently with azelaic acid 15% gel. In the model, after a single application of azelaic acid 15% gel is applied to the skin, there is initial rapid uptake, which then slowly dissipates over time. When Cetaphil Lotion is added, the skin penetration is the same whether the moisturizer is applied before or after azelaic acid 15% gel. It did not make any difference which was applied first. There was no decrease in the penetration of the azelaic acid by applying the Cetaphil lotion first. These data again show that the moisturizer does not block penetration of the active ingredient. In the case of CeraVe lotion, if CeraVe was applied first, before azelaic acid 15% gel, there was slightly better penetration of the azelaic acid. Even if applied in the opposite order, there was still penetration of azelaic acid. The same scenario occurred with Dove lotion. Thus, the data reveal that there is no reduction in penetration of active ingredient by applying a moisturizer first. Potentially, with some moisturizers, there may actually be better penetration of the active ingredient by applying the moisturizer first. The added importance of this scientific data is that tolerability may be improved by applying the moisturizer first. This is a clinically relevant issue with rosacea.
DISCLOSURE: Dr. Del Rosso is a consultant and speaker for Allergan, Coria, Galderma, Graceway, Intendis, Medicis, Ortho Dermatology, Ranbaxy, Stiefel, Triax, Unilever, and Warner Chilcott. ADDRESS CORRESPONDENCE TO: James Q. Del Rosso, DO, FAOCD; e-mail: jqdelrosso@yahoo.com
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SKIN BARRIER CARE There are many new, nonsteroidal products for care and repair of the epidermal barrier. The barrier dysfunction seen in atopic dermatitis has been a topic of great interest with investigators over the last several years. Topical treatments are being developed to help repair components of the epidermal barrier and the intercellular lipid membrane. Some of these agents are prescription products that are barrier repair creams, such as MimyX® (Stiefel Laboratories, Inc., Coral Gables, Florida), Atopiclair® (Graceway Pharmaceuticals LLC, Bristol, Tennessee), Eletone® (Ferndale Laboratories Inc., Ferndale, Michigan), and EpiCeram® (Promius™ Pharma, LLC). Unlike traditional topical treatments for atopic dermatitis, which target the inflammatory pathway, these creams work by restoring the lipid components of the stratum corneum and re-establishing barrier function of the outer layers of the epidermis. They add lipid back into the skin and repair the barrier to reduce transepidermal water loss to a physiologic level. These products are involved in barrier repair while the body is trying to replenish the epidermal barrier on its own. In addition to barrier care and repair, there is also barrier protection, which is not necessarily replacing lipid, but rather, protecting the barrier from breakdown in the first place. Barrier repair is a component of active treatment while barrier protection introduces the component of prevention. There is an aluminum magnesium hydroxide steroid-based, skin-barrier protection cream called Tetrix™ cream (Coria Laboratories, Ltd., Fort Worth, Texas). It is an aqueous emulsion that is waterimpermeable and contains silicates (dimethicone, cetyl dimethicone, and cyclomethicone). Yet, the emulsion absorbs quickly, without any greasy
residue. Its indication is to manage and relieve burning associated with contact dermatitis, atopic dermatitis, and irritant or allergic contact dermatitis. The product is primarily used for hand eczema, which is a commonly encountered problem in clinical practice. It can be used with other topical medications or used alone to protect against irritants and allergens that may cause repeat flare ups. In a 21-day cumulative irritation study, Tetrix was found to have a very low potential for irritation. In fact, as far as grading of irritation, Tetrix rated better than the control, which was Johnson’s ® Baby Oil (Johnson & Johnson). Tetrix has also been shown to help protect against common allergens in patients with contact dermatitis induced by allergy to nickel, neomycin, or fragrance by acting as a barrier against skin penetration. Using bilateral comparison patch testing, the study showed that Tetrix was able to decrease the number of positive tests at 24 and 48 hours, which was statistically significant. In real life, these patients would be applying the product 2 to 3 times a day, especially if they often work with their hands or if their hands are always in contact with water and other irritants. In another trial, a visual analog scale (VAS) was used by patients to rate itching and burning at affected areas of hand dermatitis treated with Tetrix cream as compared to nontreated sites. Tetrix-treated areas improved at all time points. Patients that had chronic hand dermatitis on the Tetrix-treated sides reported markedly better improvement with both itching and burning. In the case of hand eczema, substantivity and staying power for a protectant is important. Is the hand protectant going to stay on the skin as patients continue to wash their hands? A study measuring substan-
tivity with Tetrix cream was performed to see if the product persists on the skin after hand washing. Vaseline® Intensive Care cream and Tetrix cream were mixed along with a brown iron oxide pigment foundation. Patients washed their hands in a standardized fashion, and after 15 minutes, rated whether there was residual pigmentation reflective of substantivity. Tetrix cream, as compared to the active control, in this particular study, was far superior. Washing did not remove Tetrix. With the Vaseline Intensive Care cream, nearly the entire product was rinsed away with hand washing. Tetrix cream demonstrated markedly superior substantivity based on this analysis. ORAL THERAPY FOR ROSACEA A multicenter, randomized, doubleblind study compared the efficacy and safety of 40mg delayed-release doxycycline (Oracea®, Galderma Laboratories, Fort Worth, Texas) and immediate-release doxycycline (Vibramycin®, Pfizer, New York, New York) in adult subjects with inflammatory (papulopustular) rosacea. One group received doxycycline 40mg delayedrelease capsule once daily, which is an anti-inflammatory agent with no antibiotic effect, and approved by the US Food and Drug Administration for inflammatory rosacea. The other group received nonenteric-coated doxycycline 100mg one capsule daily. All patients were also treated once daily with metronidazole 1% gel (Metrogel® 1%, Galderma Laboratories). The study lasted for 16 weeks, and the results showed that both formulations of doxycycline had the same onset of effect and the same degree of efficacy at all study time points. The difference was with side effects, especially gastrointestinal (GI) side effects. All cases of nausea, vomiting, and abdominal discomfort were reported with the 100mg-per-day doxycycline.
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When considering maintenance and remission of inflammatory rosacea, there are data from a study of initial management of an active flare with azelaic acid 15% gel (Finacea) and doxycycline 100mg twice daily for up to three months. If patients demonstrated at least 75-percent inflammatory lesion reduction between 4 and 12 weeks, they then went into a double-blind, randomized, maintenance phase for six months. Close to 82 percent of the patients achieved at least 75-percent inflammatory-lesion reduction by 12 weeks, some as early as four weeks. Almost 71 percent of patients had at least 50-percent lesion reduction by Week 4, and more than 90-percent reduction by Week 12. During the six-month maintenance phase, patients applied either azelaic acid 15% gel (Finacea) or the vehicle gel twice daily. Over this sixmonth maintenance phase, the investigators were able to show that 75 percent of the patients that continued utilizing the azelaic acid 15% gel did not have a flare, with a 33-percent lower relative risk of flaring as compared to vehicle. A recent study looked at the possibility of Demodex dermatitis (demodicidosis) in 60 subjects with “rosacea” (unresolved facial eruption with erythema) refractory to conventional therapies. The average age of the patients was 50 years, with even distribution between males to females. Several subjects presented with erythema, scaling, dryness, and inflammatory lesions. Approximately half exhibited a positive potassium hydroxide (KOH) preparation for Demodex mites. The rest either were not tested or were negative. All were treated with topical crotamiton 10% (Eurax®, Ranbaxy) cream or lotion twice daily as monotherapy. The results showed that 91 percent
of the patients had at least a 50-percent improvement within the first follow-up visit (usually Week 2). Surprisingly, 98 percent had at least 50-percent improvement by the second follow up (usually Week 4). Even patients that were negative on KOH for Demodex mites, or were not tested, showed a similar response to topical crotamiton. Thus, if rosacea patients are not responding to conventional therapy as anticipated, topical crotamiton may be a safe and well-tolerated alternate treatment to try. There are many topical treatments for actinic keratosis (AK), including topical 5-fluorouracil (5-FU) 5% cream (Efudex®, Valeant Pharmaceuticals, Aliso Viejo, California) or 0.5% microsphere cream (Carac®, Dermik, Bridgewater, New Jersey), imiquimod 5% cream (Aldara®, Graceway Pharmaceuticals, LLC), and diclofenac 3% gel (Solaraze®, PharmaDerm, Florham Park, New Jersey). However, with AK, initial versus long-term therapy should be considered. Many dermatologists make the assumption that when they “freeze” an AK lesion with liquid nitrogen, the lesion clears almost 100 percent of the time. Certainly, a lot of the lesions resolve, but not 100 percent of them. Additionally, the adjacent field of actinic damage with subclinical AKs is not being treated with cryotherapy. Cryotherapy is an important modality, but one must be cognizant of the actual cure rates and hopefully choose to also manage the entire field with a medical therapy to optimize both short-term and longterm treatment results. One study looked at cycle therapy with imiquimod 5% cream (Aldara), three times a week for “four weeks on followed by four weeks off” representing a single cycle of therapy. If patients had residual lesions, they could receive a second
cycle. A second group in the study received 5-FU 5% cream (Efudex) twice daily for four weeks. These patients were allowed to take a oneweek rest period if the inflammatory reaction was too severe. A third group received cryotherapy for 20 to 40 seconds for the individual lesions. At two weeks later, if any lesions were still present, cryotherapy could be repeated. Clinical and histologic clearance were reported at the end of the initial treatment, which was approximately at one month after patients finished the course of therapy. Imiquimod cleared about 85 percent of the lesions, 5-FU cleared 96 percent, and cryotherapy cleared about 70 percent of the lesions. One year later, patients returned for clinical evaluation. The sustained clearance of the lesions that were treated initially was about 70 percent with imiquimod, 50 percent with 5-FU, and about 30 percent with cryotherapy. A recent study included patients with AKs involving both the cutaneous and mucosal lip (vermllion region). These patients were treated with diclofenac 3% gel (Solaraze) twice daily for three months, then followed one month later to assess lesion clearance. Most patients had complete or marked clearance with very little irritation. At study endpoint, 80 percent of the total lesions (including the subclinical AKs) cleared and 90 percent of the initial lesions cleared. Tolerability was very favorable. SUMMARY Choices are wonderful things. Hopefully, this review article has offered relevant clinical information about some of the newer therapeutic options and also has put new information on some older therapies into perspective.
Dr. Del Rosso is Dermatology Residency Director, Valley Hospital Medical Center, Las Vegas, Nevada, Touro University College of Osteopathic Medicine, Henderson, Nevada; Clinical Associate Professor, Dermatology, University of Nevada School of Medicine, Las Vegas, Nevada; Las Vegas Skin & Cancer Clinics, Las Vegas and Henderson, Nevada.
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