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Does intermittent “pulse” topical 5-fluorouracil therapy allow destruction of actinic keratoses without significant inflammation?
Does intermittent "pulse" topical 5-fluorouracil therapy allow destruction of actinic keratoses without significant inflammation? Ernst Epstein, MD San Francisco, California Background: Topical 5-fluorouracil (5-FU) is effective in removing actinic keratoses but causes unsightly and painful erosions. Intermittent "pulse" 5-FU therapy has been described as being an effective and comfortable technique for destroying actinic keratoses. Objective: The purpose of this study was to determine the efficacy and cutaneous side effects of intermittent 5-FU therapy. Methods: Efficacy of treatment was evaluated by three experienced dermatologists separately comparing randomly arranged before and after photographs. Degree of skin reaction was graded from photographs taken during treatment. Results: Of 13 patients treated with intermittent 5-FU, two had an excellent result, three a good result, but eight failed to show discernible improvement. Efficacy was linked to the degree of skin irritation. Conclusion: Pulse 5-FU failed to clear actinic keratoses in most patients. Intermittent 5FU treatment does not dissociate its therapeutic efficacy from its undesirable erosive effects. Pulse therapy is a less intensive way of employing 5-FU and may be of value in patients unwilling to accept the erosions and discomfort that accompany the traditional course of daily 5-FU applications. (J Am Acad Dermatol 1998;38:77-80.)
The effectiveness of topical 5-fluorouracil (5FU) in the eradication of multiple actinic keratoses (AKs) has been established by more than 30 years' experience. In the traditional method, 5FU is applied twice daily for approximately 3 to 4 weeks with the desired end point being a matter of clinical judgment. Significant erosions must be produced for a satisfactory result.1-3 It is prudent to warn patients of these unsightly and uncomfortable erosions; this is usually done by showing photographs. Unfortunately, when shown what to expect, many patients reject 5-FU treatment. Those convinced to undergo a course of 5-FU often stop treatment prematurely. A claim4 that applications of 0.5% triamcinolone acetonide would prevent the undesirable erosions caused by 5-FU therapy has not been confirmed.2 Pearlman5 recently described weekly ("pulse") dosing with 5-FU as a technique for destroying From the author's private practice and the Department of Dermatology, University of California, San Francisco. Reprints not available from the author. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/1/86508
AKs without the severe irritation caused by conventional daily applications. In his "pulse" dosing regimen, patients applied 5% 5-FU solution morning and night on only 1 day a week. Treatment was continued until all lesions were smooth or for a maximum of 9 weeks. During treatment, patients were examined every 3 to 4 weeks; if progress was not satisfactory, the 5-FU applications were increased to 2 days each week. Weekly pulse dosing cleared 98% of AKs (range, 96% to 100%) in 10 patients. Pearlman concluded that weekly pulse dosing with topical 5-FU "…produces the same benefit with much less local irritation than the conventional daily dosing schedule." I am not aware of any published study either confirming or questioning these results. After encouraging experience with 5-FU pulse therapy in my practice, I decided to evaluate its effectiveness in an objective manner by blinded viewing of before and after photographs. To determine whether 5-FU pulse therapy accomplishes its goal of destruction of AKs without severe inflammation, two questions were asked: How 77
78 Epstein
Fig. 1. Plot of effectiveness versus reaction severity in 13 patients treated with pulse 5-FU (●) and five patients treated with conventional daily 5-FU (X). Correlation between efficacy and severity: rs = 0.555. Efficacy score: 0 = no significant difference; 1 = a clearly visible difference; 2 = a striking difference. Reaction severity score (see text for details): 0 = normal or slight redness; 1 = definite erythema, no erosions, cosmetically acceptable; 2 = marked erythema, some erosions, borderline tolerability; 3 = marked erosions, not acceptable by any patient; 4 = severe reaction with crusting, exudation, and edema.
effective is pulse 5-FU therapy in destroying AKs? How severe is the inflammatory reaction with 5-FU pulse therapy? Global evaluation of photographs was used to score both treatment efficacy and the severity of the skin reaction. MATERIAL AND METHODS From December 1991 through August 1992, all patients in my private practice who received topical 5FU treatment of facial AKs had before and after photographs taken. During this 8-month period, 13 patients who had completed a course of pulse 5-FU had adequate before and after photographs. All patients receiving pulse 5-FU had only mild to moderately infiltrated AKs. To provide optimal conditions for pulse 5-FU, patients with markedly hyperkeratotic lesions were excluded from this pulse 5-FU study. Pulse therapy was initiated with 5% 5-FU solution (Efudex, Roche) applied morning and evening 1 day a week in 11 patients and 2 days a week in the other two
Journal of the American Academy of Dermatology January 1998
patients. Patients were seen at 2- to 4-week intervals until there was definite flattening of the lesions or significant erosions had appeared. Following Pearlman's procedure, patients whose lesions failed to respond increased their treatment to 2 consecutive days a week. Pulse therapy was continued for a mean of 10.5 weeks (range, 7 to 15 weeks). Patients were photographed before, during, and after completing the course of 5-FU (mean, 5 months; range, 1.5 to 11 months). A 35 mm camera equipped with a 55 mm Micro Nikkor lens and camera-mounted electronic flash was used with the same lot of Kodachrome 25 film. The maximal area of involvement (forehead in nine patients, cheek in four) was photographed at a constant reproduction ratio of 1:5. Three experienced practicing dermatologists, individually and under identical conditions, viewed randomly arranged before and after photographs simultaneously projected by identical projectors. Using a tally sheet, the clinicians compared before and after photographs and scored them as follows: 0 = no significant difference, 1 = a clearly visible difference, or 2 = a striking difference. When there was a discernible difference, they indicated whether the left or right photograph was better. After completing the blinded before and after comparisons, the same observers viewed slides of each patient taken when the erosive reaction to 5-FU was maximal. They scored the severity of the reaction as follows: 0 = normal, or slight redness; 1 = definite erythema, no erosions, cosmetically acceptable; 2 = marked erythema with some erosions, borderline tolerability; 3 = marked erosions not acceptable by any patient; 4 = severe reaction with crusting, exudation, and swelling requiring immediate cessation of 5-FU treatment. Five patients underwent the traditional twice-daily course of 5-FU treatment. Three patients elected to undergo daily treatment instead of pulse therapy; they used 5% 5-FU cream. Two patients who entered the pulse study mistakenly applied the 5% 5-FU solution twice daily. Before and after as well as maximal severity photographs of these five patients were included in the projected photographs. Before and after photographs of three untreated patients were included to check on the influence of photographic variation on the results. These three patients had their untreated keratoses photographed at intervals of 2 to 3 months while being treated for conditions affecting other sites. RESULTS
Fig. 1 summarizes the relation between efficacy and reaction severity (r = 0.555). The overall
Journal of the American Academy of Dermatology Volume 38, Number 1
results of pulse therapy were disappointing; only 2 of the 13 patients treated with pulse doses had a striking result, with an additional three showing a clearly visible difference. Of the remaining eight subjects, two had questionable improvement, whereas six failed to show any difference between the before and after photographs. In sharp contrast, three of five of the daily-treated patients had a striking result; the other two showed a clearly visible effect. Individual effectiveness and severity scores for the 13 pulse-treated and the five daily-treated patients are presented in Fig. 2. Although there was significant interobserver scoring variation, there were no false-positive results. Whenever the observers noted a significant difference in the two photographs, they correctly identified the "after" photograph. All three observers found no significant difference in the three "control" untreated before and after photographs. For most pulse-treated patients, the effectiveness score correlated with their severity score. The two patients with impressive results (cases 2 and 11; see Fig. 2) also had irritation scores of 2 or higher. However, there were exceptions. In case 1, two of the three observers recognized a significant difference in the before and after photographs with virtually no irritation. However, in case 9, although all three observers gave an irritation score of 2, only one observed any benefit of treatment. Cases 14 through 18 demonstrated the wellknown effectiveness of daily 5-FU. The high severity score accompanying daily treatment is inherent in the standard treatment end point of marked erosions. DISCUSSION
This study demonstrated that pulse therapy will eradicate AKs in some patients while causing only mild skin irritation. In others it proved effective but caused significant erosions and crusts. It failed in approximately two thirds of patients; this result is inferior to the accomplishment with daily 5-FU therapy.2,6 I was both surprised and disappointed by these results. Before this controlled trial, it was my impression from clinical observation that 5FU pulse therapy was effective in most patients. This study failed to duplicate Pearlman's success in "comfortably" clearing 98% of keratoses in 9 weeks or less. Although Pearlman and I used
Epstein 79
Fig. 2. Individual effectiveness and reaction severity scores as determined by three dermatologists represented by ■, ▲, and ● (scoring described in Fig. 1).
the same technique, we differed in the way we measured the response. Pearlman used changes in counts of AKs, which produced numeric results with an impression of precision. However, counting AKs is not precise. What is a bit of dry or irritated scaly skin, and what is an AK? In diagnosing individual AKs, Whited et al.7 found positive interobserver agreement in only 26%. Because counting AKs involves evaluation of individual lesions, their data cast doubt on the reliability of AK counts. Controlled studies on topical treatment of AKs have shown a significant decrease in the number of placebo-treated AKs.8,9 How much of this is observer bias and how much a nonspecific emollient effect is unknown. Not only is the accuracy of counting AKs in question, it fails as a clinically relevant measure. Assigning the same importance to a small, slightly scaling spot as to a large hyperkeratotic lesion does not reflect clinical realities. Many of our elderly white patients have literally hundreds of small superficial AKs that are of little concern. It is the infiltrated lesions that are worrisome because they may be squamous cell or basal cell carcinomas masquerading as AKs. Although we lack a way of quantifying the severity of AKs, this does not mean we cannot objectively evaluate treatment of AKs. There is no standardized method of numerically quantifying the severity of wrinkling or of actinic lentigines; however, we have objective data on their treatment. Visual evaluation of the effect of topical tretinoin on fine wrinkling and on actinic lentigines has been performed with the use of vehicle application for control subjects with blinded observers.10,11 In the absence of controls, "blinding" can be achieved through the use of randomly arranged before and after photographs. Blinded evaluation of before and after photographs showed liquid nitrogen cryotherapy to be superior
80 Epstein to either carbon dioxide or argon laser therapy in treating lentigines.12 Visual assessment is clinically straightforward and distinguishes between trivial and clinically significant AKs. Observer bias can be excluded by viewing randomly arranged before and after photographs. Admittedly, this has drawbacks because viewing a photograph—no matter how good—is not the same as examining a patient. Nevertheless, blinded viewing of photographs permits detection of significant changes while eliminating observer bias. Pearlman5 did not measure the severity of skin reactions but reported that 9 of 10 patients rated the treatment as "comfortable." However, patients often reject 5-FU treatment because of its unsightliness. The two photographs illustrating his article5 show changes that would be unacceptable to some patients, especially those with heavy public exposure. In the present study, observers were asked to rate the degree of skin reaction on a numeric scale. AKs have been treated topically with isotretinoin,9 masoprocol,6 and other agents13 in attempts to find a treatment without the undesirable local effects of 5-FU. All have proved inferior to 5-FU. Unfortunately, up to now efforts to dissociate the therapeutic efficacy of 5-FU from its erosive and destructive action have failed. Any study involving treatment of AKs has limitations. It is impossible to eliminate arbitrariness, usually termed clinical judgment, in choosing patients to be treated and the end point of treatment. We lack a standardized measure for severity of AKs because not only their number but also their size and degree of infiltration are important. Significant discomfort varies from patient to patient. With so many uncontrollable variables, elimination of observer bias is essential for a meaningful evaluation of any treatment of AKs. The present study rigorously eliminated observer bias and provides clinically relevant information as to whether intermittent 5-FU therapy meets its goals of destroying AKs without significant inflammation. Pulse dosing is a less intensive method of 5-FU treatment. What is its role in managing the patient with multiple AKs? It is clearly less effective than
Journal of the American Academy of Dermatology January 1998
the traditional daily application of 5-FU. Furthermore, it was not always free of significant side effects. Pulse 5-FU may be useful for patients with superficial lesions who are not prepared to endure the unsightliness and discomfort of daily 5-FU and are willing to continue treatment for a longer time. I thank Nikolajs Lapins, MD, Bruce Maltz, MD, and Peter Webb, MD, for performing the blinded evaluation of photographs. REFERENCES 1. Bennet R, Epstein E, Goette D, et al. Current management using 5-fluorouracil: 1985. Cutis 1985;36:218-36. 2. Goette DK. Topical chemotherapy with 5-fluorouracil. J Am Acad Dermatol 1981;4:633-49. 3. Salasche SJ. Actinic keratosis. In: Provost TT, Farmer ER, editors. Current therapy in dermatology-2. Toronto: BC Decker; 1988. p. 74-5. 4. Breza T, Taylor R, Eaglstein WH. Noninflammatory destruction of actinic keratoses by 5-FU. Arch Dermatol 1976;112:1256-8. 5. Pearlman DL. Weekly pulse dosing: effective and comfortable 5-fluorouracil treatment of multiple facial actinic keratoses. J Am Acad Dermatol 1991;25:665-7. 6. Kulp-Shorten CL, Konnikov N, Callen JP. Comparative evaluation of the efficacy and safety of masoprocol and 5-fluorouracil cream for the treatment of multiple actinic keratoses of the head and neck. J Geriatr Dermatol 1993;1:161-8. 7. Whited JD, Horner RD, Hall RP, Simel DL. The influence of history on interobserver agreement for diagnosing actinic keratoses and malignant skin lesions. J Am Acad Dermatol 1995;33:603-7. 8. Olsen EA, Abernethy L, Kulp-Shorten C, et al. A doubleblind vehicle-controlled study evaluating masoprocol cream in the treatment of actinic keratoses on the head and neck. J am Acad Dermatol 1991;24:738-43. 9. Alirezai M, Dupuy P, Amblard P, Kalis B, Souteyrand P, Frappaz A, et al. Clinical evaluation of topical isotretinoin in the treatment of actinic keratoses. J Am Acad Dermatol 1994;30:447-51. 10. Weiss JS, Ellis CN, Headington JT, Tincoff T, Hamilton TA, Voorhees JJ. Topical tretinoin improves photoaged skin: a double-blind vehicle-controlled study. JAMA 1988;259:527-32. 11. Rafal ES, Griffiths CEM, Ditre CM, Finkel LJ, Hamilton TA, Ellis CN, et al. Topical tretinoin (retinoic acid) treatment for liver spots associated with photodamage. N Engl J Med 1992;326:368-74. 12. Stern RS, Dover JS, Levin JA, Arndt KA. Laser therapy versus cryotherapy of lentigines: a comparative trial. J Am Acad Dermatol 1994;30:985-7. 13. Misiewicz J, Sendagorta E, Golebiowska A, Lorenc B, Czarnetzki BM, Jablonska S. Topical treatment of multiple actinic keratoses of the face with arotinoid methyl sulfone (Ro 14-9706) cream versus tretinoin cream: a double-blind, comparative study. J Am Acad Dermatol 1991;24:448-51.
The effectiveness of topical 5-fluorouracil (5FU) in the eradication of multiple actinic keratoses (AKs) has been established by more than 30 years' experience. In the traditional method, 5FU is applied twice daily for approximately 3 to 4 weeks with the desired end point being a matter of clinical judgment. Significant erosions must be produced for a satisfactory result.1-3 It is prudent to warn patients of these unsightly and uncomfortable erosions; this is usually done by showing photographs. Unfortunately, when shown what to expect, many patients reject 5-FU treatment. Those convinced to undergo a course of 5-FU often stop treatment prematurely. A claim4 that applications of 0.5% triamcinolone acetonide would prevent the undesirable erosions caused by 5-FU therapy has not been confirmed.2 Pearlman5 recently described weekly ("pulse") dosing with 5-FU as a technique for destroying From the author's private practice and the Department of Dermatology, University of California, San Francisco. Reprints not available from the author. Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/1/86508
AKs without the severe irritation caused by conventional daily applications. In his "pulse" dosing regimen, patients applied 5% 5-FU solution morning and night on only 1 day a week. Treatment was continued until all lesions were smooth or for a maximum of 9 weeks. During treatment, patients were examined every 3 to 4 weeks; if progress was not satisfactory, the 5-FU applications were increased to 2 days each week. Weekly pulse dosing cleared 98% of AKs (range, 96% to 100%) in 10 patients. Pearlman concluded that weekly pulse dosing with topical 5-FU "…produces the same benefit with much less local irritation than the conventional daily dosing schedule." I am not aware of any published study either confirming or questioning these results. After encouraging experience with 5-FU pulse therapy in my practice, I decided to evaluate its effectiveness in an objective manner by blinded viewing of before and after photographs. To determine whether 5-FU pulse therapy accomplishes its goal of destruction of AKs without severe inflammation, two questions were asked: How 77
78 Epstein
Fig. 1. Plot of effectiveness versus reaction severity in 13 patients treated with pulse 5-FU (●) and five patients treated with conventional daily 5-FU (X). Correlation between efficacy and severity: rs = 0.555. Efficacy score: 0 = no significant difference; 1 = a clearly visible difference; 2 = a striking difference. Reaction severity score (see text for details): 0 = normal or slight redness; 1 = definite erythema, no erosions, cosmetically acceptable; 2 = marked erythema, some erosions, borderline tolerability; 3 = marked erosions, not acceptable by any patient; 4 = severe reaction with crusting, exudation, and edema.
effective is pulse 5-FU therapy in destroying AKs? How severe is the inflammatory reaction with 5-FU pulse therapy? Global evaluation of photographs was used to score both treatment efficacy and the severity of the skin reaction. MATERIAL AND METHODS From December 1991 through August 1992, all patients in my private practice who received topical 5FU treatment of facial AKs had before and after photographs taken. During this 8-month period, 13 patients who had completed a course of pulse 5-FU had adequate before and after photographs. All patients receiving pulse 5-FU had only mild to moderately infiltrated AKs. To provide optimal conditions for pulse 5-FU, patients with markedly hyperkeratotic lesions were excluded from this pulse 5-FU study. Pulse therapy was initiated with 5% 5-FU solution (Efudex, Roche) applied morning and evening 1 day a week in 11 patients and 2 days a week in the other two
Journal of the American Academy of Dermatology January 1998
patients. Patients were seen at 2- to 4-week intervals until there was definite flattening of the lesions or significant erosions had appeared. Following Pearlman's procedure, patients whose lesions failed to respond increased their treatment to 2 consecutive days a week. Pulse therapy was continued for a mean of 10.5 weeks (range, 7 to 15 weeks). Patients were photographed before, during, and after completing the course of 5-FU (mean, 5 months; range, 1.5 to 11 months). A 35 mm camera equipped with a 55 mm Micro Nikkor lens and camera-mounted electronic flash was used with the same lot of Kodachrome 25 film. The maximal area of involvement (forehead in nine patients, cheek in four) was photographed at a constant reproduction ratio of 1:5. Three experienced practicing dermatologists, individually and under identical conditions, viewed randomly arranged before and after photographs simultaneously projected by identical projectors. Using a tally sheet, the clinicians compared before and after photographs and scored them as follows: 0 = no significant difference, 1 = a clearly visible difference, or 2 = a striking difference. When there was a discernible difference, they indicated whether the left or right photograph was better. After completing the blinded before and after comparisons, the same observers viewed slides of each patient taken when the erosive reaction to 5-FU was maximal. They scored the severity of the reaction as follows: 0 = normal, or slight redness; 1 = definite erythema, no erosions, cosmetically acceptable; 2 = marked erythema with some erosions, borderline tolerability; 3 = marked erosions not acceptable by any patient; 4 = severe reaction with crusting, exudation, and swelling requiring immediate cessation of 5-FU treatment. Five patients underwent the traditional twice-daily course of 5-FU treatment. Three patients elected to undergo daily treatment instead of pulse therapy; they used 5% 5-FU cream. Two patients who entered the pulse study mistakenly applied the 5% 5-FU solution twice daily. Before and after as well as maximal severity photographs of these five patients were included in the projected photographs. Before and after photographs of three untreated patients were included to check on the influence of photographic variation on the results. These three patients had their untreated keratoses photographed at intervals of 2 to 3 months while being treated for conditions affecting other sites. RESULTS
Fig. 1 summarizes the relation between efficacy and reaction severity (r = 0.555). The overall
Journal of the American Academy of Dermatology Volume 38, Number 1
results of pulse therapy were disappointing; only 2 of the 13 patients treated with pulse doses had a striking result, with an additional three showing a clearly visible difference. Of the remaining eight subjects, two had questionable improvement, whereas six failed to show any difference between the before and after photographs. In sharp contrast, three of five of the daily-treated patients had a striking result; the other two showed a clearly visible effect. Individual effectiveness and severity scores for the 13 pulse-treated and the five daily-treated patients are presented in Fig. 2. Although there was significant interobserver scoring variation, there were no false-positive results. Whenever the observers noted a significant difference in the two photographs, they correctly identified the "after" photograph. All three observers found no significant difference in the three "control" untreated before and after photographs. For most pulse-treated patients, the effectiveness score correlated with their severity score. The two patients with impressive results (cases 2 and 11; see Fig. 2) also had irritation scores of 2 or higher. However, there were exceptions. In case 1, two of the three observers recognized a significant difference in the before and after photographs with virtually no irritation. However, in case 9, although all three observers gave an irritation score of 2, only one observed any benefit of treatment. Cases 14 through 18 demonstrated the wellknown effectiveness of daily 5-FU. The high severity score accompanying daily treatment is inherent in the standard treatment end point of marked erosions. DISCUSSION
This study demonstrated that pulse therapy will eradicate AKs in some patients while causing only mild skin irritation. In others it proved effective but caused significant erosions and crusts. It failed in approximately two thirds of patients; this result is inferior to the accomplishment with daily 5-FU therapy.2,6 I was both surprised and disappointed by these results. Before this controlled trial, it was my impression from clinical observation that 5FU pulse therapy was effective in most patients. This study failed to duplicate Pearlman's success in "comfortably" clearing 98% of keratoses in 9 weeks or less. Although Pearlman and I used
Epstein 79
Fig. 2. Individual effectiveness and reaction severity scores as determined by three dermatologists represented by ■, ▲, and ● (scoring described in Fig. 1).
the same technique, we differed in the way we measured the response. Pearlman used changes in counts of AKs, which produced numeric results with an impression of precision. However, counting AKs is not precise. What is a bit of dry or irritated scaly skin, and what is an AK? In diagnosing individual AKs, Whited et al.7 found positive interobserver agreement in only 26%. Because counting AKs involves evaluation of individual lesions, their data cast doubt on the reliability of AK counts. Controlled studies on topical treatment of AKs have shown a significant decrease in the number of placebo-treated AKs.8,9 How much of this is observer bias and how much a nonspecific emollient effect is unknown. Not only is the accuracy of counting AKs in question, it fails as a clinically relevant measure. Assigning the same importance to a small, slightly scaling spot as to a large hyperkeratotic lesion does not reflect clinical realities. Many of our elderly white patients have literally hundreds of small superficial AKs that are of little concern. It is the infiltrated lesions that are worrisome because they may be squamous cell or basal cell carcinomas masquerading as AKs. Although we lack a way of quantifying the severity of AKs, this does not mean we cannot objectively evaluate treatment of AKs. There is no standardized method of numerically quantifying the severity of wrinkling or of actinic lentigines; however, we have objective data on their treatment. Visual evaluation of the effect of topical tretinoin on fine wrinkling and on actinic lentigines has been performed with the use of vehicle application for control subjects with blinded observers.10,11 In the absence of controls, "blinding" can be achieved through the use of randomly arranged before and after photographs. Blinded evaluation of before and after photographs showed liquid nitrogen cryotherapy to be superior
80 Epstein to either carbon dioxide or argon laser therapy in treating lentigines.12 Visual assessment is clinically straightforward and distinguishes between trivial and clinically significant AKs. Observer bias can be excluded by viewing randomly arranged before and after photographs. Admittedly, this has drawbacks because viewing a photograph—no matter how good—is not the same as examining a patient. Nevertheless, blinded viewing of photographs permits detection of significant changes while eliminating observer bias. Pearlman5 did not measure the severity of skin reactions but reported that 9 of 10 patients rated the treatment as "comfortable." However, patients often reject 5-FU treatment because of its unsightliness. The two photographs illustrating his article5 show changes that would be unacceptable to some patients, especially those with heavy public exposure. In the present study, observers were asked to rate the degree of skin reaction on a numeric scale. AKs have been treated topically with isotretinoin,9 masoprocol,6 and other agents13 in attempts to find a treatment without the undesirable local effects of 5-FU. All have proved inferior to 5-FU. Unfortunately, up to now efforts to dissociate the therapeutic efficacy of 5-FU from its erosive and destructive action have failed. Any study involving treatment of AKs has limitations. It is impossible to eliminate arbitrariness, usually termed clinical judgment, in choosing patients to be treated and the end point of treatment. We lack a standardized measure for severity of AKs because not only their number but also their size and degree of infiltration are important. Significant discomfort varies from patient to patient. With so many uncontrollable variables, elimination of observer bias is essential for a meaningful evaluation of any treatment of AKs. The present study rigorously eliminated observer bias and provides clinically relevant information as to whether intermittent 5-FU therapy meets its goals of destroying AKs without significant inflammation. Pulse dosing is a less intensive method of 5-FU treatment. What is its role in managing the patient with multiple AKs? It is clearly less effective than
Journal of the American Academy of Dermatology January 1998
the traditional daily application of 5-FU. Furthermore, it was not always free of significant side effects. Pulse 5-FU may be useful for patients with superficial lesions who are not prepared to endure the unsightliness and discomfort of daily 5-FU and are willing to continue treatment for a longer time. I thank Nikolajs Lapins, MD, Bruce Maltz, MD, and Peter Webb, MD, for performing the blinded evaluation of photographs. REFERENCES 1. Bennet R, Epstein E, Goette D, et al. Current management using 5-fluorouracil: 1985. Cutis 1985;36:218-36. 2. Goette DK. Topical chemotherapy with 5-fluorouracil. J Am Acad Dermatol 1981;4:633-49. 3. Salasche SJ. Actinic keratosis. In: Provost TT, Farmer ER, editors. Current therapy in dermatology-2. Toronto: BC Decker; 1988. p. 74-5. 4. Breza T, Taylor R, Eaglstein WH. Noninflammatory destruction of actinic keratoses by 5-FU. Arch Dermatol 1976;112:1256-8. 5. Pearlman DL. Weekly pulse dosing: effective and comfortable 5-fluorouracil treatment of multiple facial actinic keratoses. J Am Acad Dermatol 1991;25:665-7. 6. Kulp-Shorten CL, Konnikov N, Callen JP. Comparative evaluation of the efficacy and safety of masoprocol and 5-fluorouracil cream for the treatment of multiple actinic keratoses of the head and neck. J Geriatr Dermatol 1993;1:161-8. 7. Whited JD, Horner RD, Hall RP, Simel DL. The influence of history on interobserver agreement for diagnosing actinic keratoses and malignant skin lesions. J Am Acad Dermatol 1995;33:603-7. 8. Olsen EA, Abernethy L, Kulp-Shorten C, et al. A doubleblind vehicle-controlled study evaluating masoprocol cream in the treatment of actinic keratoses on the head and neck. J am Acad Dermatol 1991;24:738-43. 9. Alirezai M, Dupuy P, Amblard P, Kalis B, Souteyrand P, Frappaz A, et al. Clinical evaluation of topical isotretinoin in the treatment of actinic keratoses. J Am Acad Dermatol 1994;30:447-51. 10. Weiss JS, Ellis CN, Headington JT, Tincoff T, Hamilton TA, Voorhees JJ. Topical tretinoin improves photoaged skin: a double-blind vehicle-controlled study. JAMA 1988;259:527-32. 11. Rafal ES, Griffiths CEM, Ditre CM, Finkel LJ, Hamilton TA, Ellis CN, et al. Topical tretinoin (retinoic acid) treatment for liver spots associated with photodamage. N Engl J Med 1992;326:368-74. 12. Stern RS, Dover JS, Levin JA, Arndt KA. Laser therapy versus cryotherapy of lentigines: a comparative trial. J Am Acad Dermatol 1994;30:985-7. 13. Misiewicz J, Sendagorta E, Golebiowska A, Lorenc B, Czarnetzki BM, Jablonska S. Topical treatment of multiple actinic keratoses of the face with arotinoid methyl sulfone (Ro 14-9706) cream versus tretinoin cream: a double-blind, comparative study. J Am Acad Dermatol 1991;24:448-51.