Pharmacology and therapeutics
5-Fluorouracil superficial peel for multiple actinic keratoses Edile´ia Bagatin, MD, PhD, Solange P. Teixeira, MD, MS, Karime M. Hassun, MD, MS, Taı´se Pereira, MD, Nilceo S. Michalany, MD, and Sergio Talarico, MD, MS
From the Department of Dermatology, Cosmetic Dermatology Unit, and Department of Pathology, Universidade Federal de Sao Paulo, Sao Paulo, Brazil
Abstract
Correspondence Edile´ia Bagatin, MD, PhD Rua Leandro Dupret 204, 11o. Andar 04025-010 – Sao Paulo – SP Brazil E-mail:
[email protected]
acid (GA) with 5% 5-fluorouracil (5-FU) solution for superficial pulse peeling used in the treatment of widespread AKs in 31 patients. Pulse peelings were performed at biweekly
Background Chronically photodamaged skin usually presents with multiple, widespread, actinic keratoses (AKs), and treatment of the entire affected area is recommended. Methods We report our experience with a combination of Jessner’s solution or 70% glycolic
intervals. The endpoint for treatment was complete or maximum clearance of the lesions at clinical evaluation. Pre- and post-skin biopsy and histopathologic examination were performed in three patients for the purpose of demonstrating the pulse peel effects. Results All patients achieved a satisfactory result, including the complete regression, or at least 80% clearing, of AK lesions and an overall improvement of photodamaged skin. Conclusion We consider this superficial 5-FU pulse peel to be a safe, well-tolerated, very effective, and highly inexpensive therapeutic option for the treatment of multiple, diffuse AKs. Its benefit/cost ratio will be of interest to public health services, mainly in developing countries.
Introduction
902
Actinic keratoses (AKs) are a clinical sign of advanced photoaging and are considered to be markers for the risk of development of malignant lesions, mainly squamous cell carcinoma (SCC). Extensive, severely photodamaged areas are considered to be fields of cancer development. The risk of untreated AKs becoming invasive carcinoma over time varies in the opinions of different authors: 5–11% of SCCs may result from the malignant transformation of AKs,1 and approximately one in 20 AK lesions will gradually progress to SCCs.2 The potential development of AKs into skin cancer justifies the early treatment of the entire photodamaged area, rather than only typical individual lesions.1–3 Single, well-delimited or hyperkeratotic AKs may be treated with cryotherapy, electrotherapy, electrodissection, or curettage.4 For patients with widespread AKs, treatment of the entire area is recommended. Good results can be obtained with the topical application of 5-fluorouracil (5-FU) twice daily for a period of 3–4 weeks for facial lesions or 6–8 weeks for arm lesions by standard5 or pulsed6 regimen. Nevertheless, severe local irritation is a limitation to patient treatment compliance. The entire area may also be treated by cryopeeling,7 dermabrasion,8 or medium-depth chemical peeling using a combination of 70% glycolic acid (GA) or Jessner’s solution International Journal of Dermatology 2009, 48, 902–907
and 35% trichloroacetic acid (TCA).9,10 Topical and oral retinoids may be associated with any of these treatments.11–16 Lasers and photodynamic therapy (PDT) are increasingly being used to treat disseminated AKs, mainly for the bald scalp and face. Specific blue or red light wavelengths are used to activate topical photosensitizer precursors: methyl aminolevulinate (MAL) or 5-aminolevulinic acid (ALA). These drugs must stay in contact with the skin for a variable period of time before light exposure. Short contact has also been proposed with good results.17 PDT has been used to treat nonhyperkeratotic AKs, Bowen’s disease, and superficial and thin nodular basal cell carcinoma (BCC), with an efficacy comparable with the classical use of 5-FU or cryotherapy,3,18 and cosmetic results superior to those achieved with existing standard therapies.3 The phase IV, ALA-PDT, multicenter clinical trial performed by the Actinic Keratosis Study Group19 demonstrated the efficacy and safety of this treatment, as well as an acceptable 19% rate of recurrence over a 12-month follow-up period. Adverse events included pain, stinging, burning, and the predicted nonserious phototoxic reactions, which may persist for up to 1 month after treatment, independent of skin phototype. Gilbert20 used topical 5-FU for 5 days before PDT with short-contact (30–45 min) ALA, followed by a single pass of 560–1200-nm intense pulsed light, with good results. ª 2009 The International Society of Dermatology
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5-FU peel for actinic keratosis
Table 1 Number of peels per patient required to achieve
Pharmacology and therapeutics
Table 2 Follow-up per patient
desirable results Number of peels
Number of patients
10 8 6 4 3 Median ¼ 6
2 10 12 2 2 31
An economical evaluation21 comparing cryotherapy, clinical response, cosmetic results, and cost of BCC excision concluded that PDT is a cost-effective intervention for multiple AKs; however, it is not available in the majority of public health services in developing countries. The use of 5-FU combined with superficial chemical peeling was first described by Katz22 to treat widespread AKs. He named this modality ‘‘fluor-hydroxy pulse peel.’’ Eight weekly pulse peels were used combining the application of Jessner’s solution followed by 5% 5-FU solution, with an average of 88.14% clearing of AKs. Three years later, Marrero and Katz23 presented a new peel modality by combining 70% GA gel with 5% 5-FU solution. The overall data showed an average of 91.94% clearing of AKs. The peeling mechanism involves the removal of the stratum corneum and the discohesion of keratinocytes by Jessner’s solution or 70% GA gel, thus allowing deeper penetration of 5% 5-FU solution in order to reach atypical cells. This method was also used in the treatment of disseminated superficial actinic porokeratosis,24 with a decrease in lesions and improvement in the overall appearance and texture of the skin. There were minimal adverse effects and remission for a long period of time.
Follow-up (months)
Number of patients
63 93 12 46 79 68 64 50 48 34 Median ¼ 60
10 6 4 3 2 2 1 1 1 1 31
Figure 1 Facial biopsy site
as, in widespread AKs, diffuse skin damage (the presence of early or incipient lesions among visible lesions) is high, making an attempt to count the lesions very difficult.
Materials and Methods We evaluated retrospectively (January 1998 to January 2006) the use of the 5-FU pulse peel for the treatment of widespread AKs at
Skin biopsies and histopathologic examinations were performed in three patients to confirm the diagnosis and clinical results. Before and after biopsies were taken from the same sites (Fig. 1). Persistent hyperkeratotic lesions were treated individually by
the Cosmetic Dermatology Unit, Dermatology Department,
excision, shaving, electrodissection and curettage, cryotherapy, or
Universidade Federal, Sao Paulo, Brazil.
90% TCA application, after the completion of peeling treatment.
During this period, 57 patients were referred for this treatment.
Patients did not use any specific antiaging products before or
For this report, we selected data from 31 patients who had
during the treatment schedule. They were allowed to use only
completed a minimum of three and a maximum of 10 consecutive biweekly sessions (Table 1), and had a minimum of 12 months of
sunscreen and a petrolatum-like or similar jelly.
follow-up (Table 2). The remaining 26 patients were excluded for
The pulse treatment guidelines used comprised skin grease removal with a solution containing acetone, ether, and 100
sessions, 13 had less than 12 months of follow-up, and seven did
ethanol (one-third volume each). Following skin degreasing, a first layer of 70% GA peel (DrogadermaTM, Sao Paulo, Brazil) was
not complete treatment.
applied, which was removed with laurylsulfate cleanser (CetaphilTM,
the following reasons: six had longer or irregular intervals between
The endpoint of treatment was total clearance or a minimum of
Cetaphil, Galderma, France) when a stinging sensation was
80% clearance of the lesions. The results were analyzed by overall
reported by the patient and/or redness was observed, or Jessner’s
clinical and photographic evaluations. We did not count the lesions
solution (DrogadermaTM), which was not removed. As a second
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International Journal of Dermatology 2009, 48, 902–907
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layer, we applied 5% 5-FU with propyleneglycol as vehicle (DrogadermaTM), which remained in contact with the skin for a minimum of 12 h and a maximum of 24 h according to patient tolerance. The patients were instructed to remove the peel at home and to apply a thin coat of petroleum jelly three times daily for skin dryness control for the first week. In addition, they were advised to use sunscreen before any sun exposure, and to avoid direct sunlight. The number of sessions was linked to the degree of photodamage, extension of compromised area, AK type, and clinical response. At the end of treatment, patients were entered into a lifetime follow-up program comprising the use of 0.05% tretinoin and emollient creams every other night and a broad-spectrum sunscreen, and consultation every 3 months in the first year, twice annually in the second year, and then annually. They were also allowed to return at any time if a suspected lesion appeared.
Results Data analysis of these 31 patients submitted to fluor-hydroxy pulse peel showed that 28 were women and three were men, aged between 44 and 89 years, with a mean age of 63 years. The treated areas were, most frequently, the face and/or the dorsal area of the forearms and hands. A number of patients received the same treatment on the chest. After each peel, we observed immediate redness and slight edema, mainly over the AK lesions (Fig. 2). After 3 days, desquamation started and lasted for 5–7 days. The predicted adverse effects were mild to moderate irritation with redness, burning, and edema after the third or fourth pulse. At the end of treatment, we observed general improvement of the clinical signs of photodamage and skin texture, as well as complete or minimum 80% clearance of AKs (Fig. 3a,b). In addition, as a consequence of field treatment, the remaining hyperkeratotic lesions were better delimited and were easier to excise or treat by a localized approach. The pre- and post-histopathologic findings in three patients showed resolution of typical epidermal AK features. Epidermal reorganization, disappearance of nuclear atypia, recovery of polarity, and restoration of the upper dermis structure, including partial replacement of solar elastosis by new collagen deposition, were observed (Fig. 4a,b). With regard to tolerance to treatment, patients did not complain about pain, severe burning, stinging, or irritation, even when a large number of sessions were necessary to achieve desirable results. The follow-up period ranged from 12 to 93 months, with a median of 60 months, until this report (Table 2). Recurrence of AKs was expected for some patients as the development of new lesions is a chronic and continuous process in skin as a result of prolonged, uncontrolled sun exposure. Five patients developed new lesions 36–60 months after treatment, but with a lesser degree of severity (Fig. 5a–c). International Journal of Dermatology 2009, 48, 902–907
Figure 2 Immediate diffuse erythema and slight edema after the
third application of fluor-hydroxy pulse peel, with Jessner’s and 5% 5-fluorouracil (5-FU) solution
Four patients required two and one three additional treatment cycles during follow-up. Discussion AKs are an important indicator of cumulative, uncontrolled exposure to UV-A and UV-B radiation and, in some cases, represent a risk for malignant transformation and the development of SCC.1,2,25 Despite the considered possibility of spontaneous remission, reported in the past by Marks and Foley,26 which could justify expectant management, the current guideline is the early treatment of affected areas. AK therapy starts with behavioral changes concerning sun exposure, including sun avoidance as much as possible, the daily use of sunscreens, and physical protection by clothes, hats, gloves, and an umbrella or any other existing means.2,4,12 Middle-aged and elderly people who, in the past, did not receive appropriate guidance are now visiting dermatologists worried about the risk of skin cancer, as well as for cosmetic purposes. 5-FU is a very effective antimetabolite, which inhibits DNA and RNA synthesis, thus having a cytotoxic effect leading to the destruction of AKs. An inflammatory reaction is not ª 2009 The International Society of Dermatology
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5-FU peel for actinic keratosis
Pharmacology and therapeutics
Figure 3 Advanced facial photoaging with multiple actinic keratoses (AKs): (a) before and after (b) eight fluor-hydroxy pulse peels
Figure 4 Pre- and post-treatment histopathologic features: (a) hyperkeratosis, loss of polarity, nuclear atypia in the epidermis, and
solar elastosis in the dermis; (b) epidermis with orthokeratosis, layer reorganization, absence of nuclear atypia, and new collagen deposition in the upper dermis (hematoxylin and eosin stain; ·400 original magnification)
necessary for the biologic effect and is probably secondary to cell death. To be effective, 5% 5-FU cream is used twice daily for at least 3 weeks. The main and most common side-effect is local irritation, which may be severe, leading to treatment ª 2009 The International Society of Dermatology
interruption. Some patients cannot tolerate the use of 5% 5-FU cream daily. Despite the irritation and temporary cosmetic disadvantage, it is easy to apply, inexpensive, and effective for multiple, diffuse, microscopic AK lesions.4,5,20 International Journal of Dermatology 2009, 48, 902–907
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Figure 5 Severe facial photoaging with multiple actinic keratoses (AKs): pre- (a) and post- (b) treatment with eight fluor-hydroxy pulse
peels, and recurrence of some slight lesions 5 years later (c)
Weekly, intermittent, pulse therapy with 5-FU, reported by Epstein,6 was expected to be a good alternative for the minimization of side-effects. The author performed a blind evaluation of before and after photographs, but the results were disappointing: only two of 13 patients showed a significant result. Although this criterion could not be considered to be precise, there is no standardized or more objective method to quantify multiple superficial AKs. Nevertheless, the efficacy of the use of standard 5% 5-FU cream for the treatment of widespread AKs is well recognized. The combination of Jessner’s solution or 70% GA and 5% 5-FU as a superficial combined peel was described by Katz22 and Marrero and Katz.23 We started to use it in 1998. In addition to the clinical results, we took advantage of the long-term contact and good relationship with the patients during the treatment pulses to educate them on photoprotection and the risk of skin cancer. In this article, we have summarized our experience with the use of the ‘‘fluor-hydroxy pulse peel’’ in 31 patients with AKs in sun-exposed areas of the face, forearms, and hands. We have been using this method for the treatment of multiple, diffuse, widespread AKs during the last 9 years with good patient compliance. We believe that the good compliance is probably a result of the lesser, noncontinuous irritation relative to that which occurs with the daily use of 5-FU cream. Moreover, this therapeutic option has a low cost, which is International Journal of Dermatology 2009, 48, 902–907
very important for public health services in developing countries. Our results were quite similar to those of Katz and Marrero.23 The difference between our approach and theirs was the number and frequency of peel pulses. They used a standard schedule of eight weekly pulses. We used peeling sessions every 2 weeks. The required number of pulses, in our opinion, varies according to the degree of photodamage and AK distribution. The lesions that persisted after 10 pulses were usually hyperkeratotic and required a different treatment regimen. Conclusion We believe that the combined superficial pulse peel is a useful approach for facial and nonfacial areas. It is an effective, wise, and inexpensive therapeutic option for the treatment of widespread AKs, and to stop the progress of cancer in severe photodamaged skin. The combined 5% 5-FU superficial pulse peel has few disadvantages: multiple applications are required and skin irritation is usually observed after the third pulse. In contrast, the ‘‘fluor-hydroxy pulse peel’’ has many advantages: high efficacy for the destruction of superficial multiple and microscopic AKs, overall amelioration of photodamaged skin appearance, acceptable tolerability, and low cost. It also ª 2009 The International Society of Dermatology
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offers the opportunity to educate patients about the risk of uncontrolled sun exposure, as well as possible photoprotection measures. References 1 Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet 1988; 1: 795–797. 2 Schwartz RA. The actinic keratosis: a perspective and update. Dermatol Surg 1997; 23: 1009–1019. 3 Braathen LR, Szeimies RM, Basset-Seguin N, et al. Guidelines on the use of photodynamic therapyfornonmelanomaskin cancer:aninternationalconsensus.J Am Acad Dermatol 2007; 56: 125–143. 4 Jeffes EW 3rd, Tang EH. Actinic keratosis. Current treatment options. Am J Clin Dermatol 2000; 1: 167–179. 5 Mackie RM, Quinn AG. Non-melanoma skin cancer and other epidermal skin tumors. In: Burns T, Breathnach S, Cox N, et al. Rook’s Textbook of Dermatology, 7th edn. Vol. 2. Malden, MA: Blackwell Science, 2004: 36.1–36.50. 6 Epstein E. Does intermittent ‘‘pulse’’ topical 5-fluorouracil therapy allow destruction of actinic keratosis without significant inflammation? J Am Acad Dermatol 1998; 38: 77–80. 7 Chiarello SE. Cryopeeling (extensive cryosurgery) for treatment of actinic keratoses: an update and comparison. Dermatol Surg 2000; 26: 728–732. 8 Benedetto AV, Griffin TD, Benedetto EA, et al. Dermabrasion: therapy and prophylaxis of the photoaged skin. J Am Acad Dermatol 1992; 27: 439–447. 9 Monheit GD. Medium-depthchemical peels. Dermatol Clin 2001; 19: 413–425. 10 Lawrence N, Cox SE, Cockerell CJ, et al. A comparison of the efficacy and safety of Jessner’s solution and 35% trichloroacetic acid vs 5% fluorouracil in the treatment of widespread facial actinic keratoses. Arch Dermatol 1995; 131: 176–181. 11 Humphreys TR, Werth V, Dzubow L, et al. Treatment of photodamaged skin with trichloroacetic acid and topical tretinoin. J Am Acad Dermatol 1996; 34: 638–644. 12 Gilchrest BA. Treatment of photodamage with topical tretinoin: an overview. J Am Acad Dermatol 1997; 36: S27–S36. 13 Olsen EA, Katz I, Levine N, et al. Tretinoin emollient cream for photodamaged skin: results of a 48-week, multicenter, double-blind study. J Am Acad Dermatol 1997; 37: 217– 226.
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14 Sander CA, Pfieffer C, Kligman AM, et al. Chemotherapy for disseminated actinic keratosis with 5-fluorouracil and isotretinoin. J Am Acad Dermatol 1997; 36: 236–238. 15 Nijsten TE, Stern RS. Oral retinoid use reduces cutaneous squamous cell carcinoma risk in patient with psoriasis treated with psoralen-UVA: a nested cohort study. J Am Acad Dermatol 2003; 49: 644–650. 16 Harwood CA, Leedham-Green M, Leig IM, et al. Low doses of retinoids in the prevention of squamous cell carcinoma in transplant patients: a 16 years retrospective study. Arch Dermatol 2005; 41: 456–464. 17 Touma D, Yaar M, Whitehead S, et al. A trial of short incubation, broad-area photodynamic therapy for facial actinic keratoses and diffuse photodamage. Arch Dermatol 2004; 140: 33–40. 18 Morton C, Campbell S, Gupta G, et al. Intraindividual, right-left comparison of topical methyl aminolaevulinatephotodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized, controlled study. Br J Dermatol 2006; 155: 1029–1036. 19 Tschen EH, Wong DS, Pariser DM, et al. Photodynamic therapy using aminolaevulinic acid for patients with nonhyperkeratotic actinic keratoses of the face and scalp: phase IV multicentre clinical trial with 12-month follow up. Br J Dermatol 2006; 155: 1262–1269. 20 Gilbert DJ. Treatment of actinic keratoses with sequential combination of 5-fluorouracil and photodynamic therapy. J Drugs Dermatol 2005; 4: 161–163. 21 Caekelbergh K, Annemans L, Lambert J, et al. Economic evaluation of methyl aminolaevulinate-based photodynamic therapy in the management of actinic keratosis and basal cell carcinoma. Br J Dermatol 2006; 155: 784–790. 22 Katz BE. The fluor-hydroxy pulse peel: a pilot evaluation of a new superficial chemical peel. Cosmet Dermatol 1995; 8: 24–30. 23 Marrero GM, Katz BE. The new fluor-hydroxy pulse peel. A combination of 5-fluorouracil and glycolic acid. Dermatol Surg 1998; 24: 973–978. 24 Teixeira SP, Nascimento MM, Bagatin E, et al. The use of fluor-hydroxy pulse peel in actinic porokeratosis. Dermatol Surg 2005; 31: 1145–1148. 25 Preston DS, Stern RS. Nonmelanoma cancers of the skin. N Engl J Med 1992; 327: 1649–1662. 26 MarksR, FoleyP, GoodmanG, et al. Spontaneous remission ofsolarkeratoses: the case for conservative management. Br J Dermatol 1986; 115: 649–655.
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