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Weekly pulse dosing: Effective and comfortable topical 5-fluorouracil treatment of multiple facial actinic keratoses
Therapv Weekly pulse dosing: Effective and comfortable topical 5-fluorouracil treatment of multiple facial actinic keratoses Dale Lawrence Pearlman, MD Palo Alto, California Ten patients completed a weekly pulse dosing regimen for topical 5-fluorouracil therapy for multiple facial actinic keratoses. The method cleared an average of 98% of the lesions, without the severe irritation usually caused by the conventional, daily dosing regimen. Nine patients described the therapy as comfortable. Local irritation was limited to erythema. None of the patients suffered disruption in their social or business lives because of altered appearance. Patients had an average of 6.7 weeks of treatment and applied the medication 1 t02 days per week; significant remissions were achieved. The longest available follow-up is with six patients who at 9 months remained 86% clear of lesions. This new method offers a significant advance in topical5-fluorouracil therapy by reducing irritation to an acceptable level while maintaining efficacy. (J AM ACAD DERMATOL 1991;25:665-7.) Actinic keratoses often occur on the sun-exposed skin of adults. 1-3 A standard treatment for multiple actinic keratoses is topical 5-fluorouracil (5-FU) applied twice daily for 2 to 4 weeks until maximal inflammation is achieved. 4 Although effective,4-7 extreme local irritation makes it unacceptable to many patients. 4, 8,9 Previous attempts to modify the daily dosing regimen for topical 5-FU therapy have not adequately resolved the problem of severe local irritation. These have included reducing the frequency of application from twice to once daily, reducing the concentration of the medication, and temporarily stopping treatment before resuming it. Physicians have also tried to decrease irritation by concomitant andjor subsequent use of emollients and topical steroid creams.4, 7,9 To try to find a more acceptable approach to treating actirIic keratoses, I studied a weekly "pulse" dosing regimen for topical 5~ FU. In this dosirIg schedule the patient applies the medication only 1or 2 days per week. A pilot study of 42 patients suggested that pulse dosing could produce excellent clearirIg of multiple From the Department of Dermatology, Palo Alto Medical Foundation. Supported by the Palo Alto Medical Foundation. Reprint requests: Dale Lawrence Pearlman, MD, Department of Dermatology, Palo Alto Medical Foundation, 300 Homer Ave., Palo Alto, CA 94301. 16/1/30065
facial actinic keratoses with mirIimallocal irritation. On the basis of these encouragirIg preliminary results, a more formal study was conducted. MATERIALAND METHODS
Eleven patients participated in this study after giving signed, informed consent. Each patient had 20 or more facial actinic keratoses. None ofthe patients had received liquid nitrogen therapy for at least 3 months. Patients applied 5% 5-FU solution (Efudex) to all affected areas. No placebo treatment was used. Prior studies have shown that, when untreated, the total number of actinic keratoses increases.3 Thus any statistically valid decrease in the total number oflesions during therapy can be considered a result of the treatment. The results were compared with those previously reported for continuous 5-FU regimens. The study had a treatment phase that could last 9 weeks depending on patient response. Follow-up examinations were performed at 3,6, and 9 months after ther~ apy was completed. The area treated consisted of the entire face up to the frown lines of the mid forehead. Patients applied the medication sparingly with their fingertips morning and evening one day per week. Patients were reexamined every 3 to 4 weeks to assess response and decide subsequent treatment. Ifthe lesions were flattening and desquamating, then treatment continued unchanged. Ifnot, the weekly pulse was increased to two consecutive days oftreatment per week. Treatment continued until either all lesions appeared smooth or the patient reached a maximum of 9 weeks of treatment. The number of lesions was counted before treatment, 2 to 4 weeks after completion of treatment, and at each
665
Journal of the American Academy of Dermatology
666 Pearlman
Fig. 1. Patient 6. At end of 6 weeks oftreatment with application of 5-FU 1 day per week. Patient was comfortable. Inflammation was limited to erythema. Ninety-seven percent clearing was achieved with treatment; at 9 months' follow-up, 90% was still clear. Fig. 2. Patient 2. At end of 9 weeks oftherapy with initial application of 5-FU one and later two days per week. Patient was smiling and comfortable. Inflammation was limited to erythema. One hundred percent clearing was achieved with treatment, patient was still 89% clear at 9-month follow-up.
Table I. Results of topical 5-FU weekly "pulse" treatment of facial actinic keratoses No. of actinic keratoses Patient No.
1 2 3
4
5
6 7
8 9 10 Average
Before therapy
50 27 85 21 23 108
57
121
34 36
56
I
After therapy
1 0 0 0 1 3
0 12 0 1 2
% Clearing of actinic keratoses during treatment
98 100 100 100 96
97 100 90 100 97
98
follow-up examination. Local irritation was scored at each treatment phase visit for visible inflammation and subjective discomfort. Patients were photographed at each visit to facilitate evaluation. Lesions present on follow-up examination after treatment were counted and then treated with liquid nitrogen.
RESULTS
Of the 11 patients who entered the study, one was dropped because of noncompliance with the protocol. The data for the remaining 10 patients were available for analysis. The patients received an average of 6.7 weeks of treatment. Five patients needed one day per week of treatment and five patients needed two consecutive days per week of treatment. The patients applied the 5-FU an average of 10 days during the course of therapy. The response to treatment is summarized in Table I. During therapy patients showed an average 98% clearing ofthe lesions, which is statistically significant compared with pretreatment values (p < 0.005 with a one-sided t test). Local irritation was limited to erythema. Nine patients rated the treatment as comfortable. One patient found it uncomfortable but achieved relief with bland emollients. None of the patients experienced swelling, oozing, necrosis, ulceration, or pain requiring systemic analgesics. Local irritation from "pulse" treatment was usually resolved in 2 weeks
Volume 25 Number 4 October 1991
and in all cases by 4 weeks after stopping therapy. Figs. I and 2 show two patients at the height ofthe inflammatory process during their treatment. Their local irritation is limited to varying degrees of erythema. They both rated the treatment as comfortable. The longest available follow-up is in the first six patients who entered the study. They have reached 9 months of follow-up and are on average 86% clear of lesions compared with their conditions before treatment. DISCUSSION
These results show that weekly "pulse" dosing of topical 5-FU of multiple facial actinic keratoses produces the same benefit with much less local irritation than the conventional daily dosing schedule. Patients apply 5-FU one day or two consecutive days per week. The observed 98% clearing of multiple facial actinic keratoses with pulse dosing compares favorably with the approximate 93% rate reported with the conventional daily dosing regimen. 1O In view of its efficacy, relative comfort, lower cost, and simplicity of use, weekly "pulse" dosing may be preferable. This study refutes the belief that severe local inflammation is required to achieve significant benefit from treatment. This reduction in inflammation was achieved solely by changing the dose schedule and not by simultaneous or subsequent use of a corticosteroid cream. It is still too early to compare the remission time produced by conventional, daily dosing with that produced by the new weekly "pulse" regimen. Previous studies have shown that conventionally treated patients will require repeat treatment with 5-FU between 2 and 4 years after their initial treatment,11-13 Even if it becomes apparent that pulse dosing leads to a somewhat shorter remission period, it would still be valuable treatment for the many patients who will not accept the severe local irritation of conventional treatment.
Weekly pulse dosing with 5 -FU 667 The overall duration from the start of treatment to recovery after treatment is similar in pulse and conventional treatment. The average duration of pulse therapy is longer than that of conventional therapy (6.7 weeks vs 2 to 4 weeks, respectively). However, because the irritation is much milder with pulse therapy, pulse-treated patients recovered more quickly. Their recovery period was 2 to 4 weeks, much shorter than the 4- to 8-week recovery period needed after conventional, daily-dose therapy.s I thank Kimberly Mourning, medical assistant, for her help with this project. Curtis Engelhard, MA, performed the statistical analysis.
REFERENCES 1. Marks R. Nonmelanotic skin cancer and solar keratoses. The Quiet 20th century epidemic. Int J Dermatol 1987; 26:201-5. 2. Marks R, Ponsford MW, Se1wood TS, et al. Nonmelanotic skin cancer and solar keratoses in Victoria. Med J Aust 1983;2:619-22. 3. Marks R, Foley P, Goodman G, et a1. Spontaneous remission of solar keratoses: the case for conservative management. Br J Dermatol 1986;115:649-55. 4. Goette DF. Topical chemotherapy with 5-f1uorouracil. J AM ACAD DERMATOL 1981;4:633-49. 5. Dillaha CJ, Jansen GT, Honeycutt WM, et al. Selective cytotoxic effect of topical 5-f1uorouracil. Arch Derrnatol 1963;88:247-56. 6. Dillaha CJ, Jansen T, Honeycutt MW, et al. Further studies with topical 5-f1uorouracil. Arch Derrnatol 1965;92: 410-7. 7. Belisario JC. Topical cytotoxic therapy of solar keratoses with 5-fluorouracil. Med J Aust 1969;2:1136-40. 8. Robinson JK, Skin problems of aging. Geriatrics 1983;38(5):63-5. 9. Breza T, Taylor R, Eaglstein WHo Noninflammatory destruction of actinic keratoses by 5-FU. Arch Dermatol 1976;112:1256-8. 10. Dowd AL, ed. Physicians desk reference 1990. New Jersey, Medical Economics, 1990:1772. 11. Jansen TG. Topical therapy with 5-fluorouracil. J Surg Oneol 1971;3:317-23. 12. Bennet R, Epstein E, Goette D, et al. Current management using 5-fluorouracil: 1985. Cutis 1985;36:218-36. 13. Simmonds WL. Topical management of actinic keratoses with 5-fluorouracil: results of a 6-year follow-up study. Cutis 1972;10:737-41.
facial actinic keratoses with mirIimallocal irritation. On the basis of these encouragirIg preliminary results, a more formal study was conducted. MATERIALAND METHODS
Eleven patients participated in this study after giving signed, informed consent. Each patient had 20 or more facial actinic keratoses. None ofthe patients had received liquid nitrogen therapy for at least 3 months. Patients applied 5% 5-FU solution (Efudex) to all affected areas. No placebo treatment was used. Prior studies have shown that, when untreated, the total number of actinic keratoses increases.3 Thus any statistically valid decrease in the total number oflesions during therapy can be considered a result of the treatment. The results were compared with those previously reported for continuous 5-FU regimens. The study had a treatment phase that could last 9 weeks depending on patient response. Follow-up examinations were performed at 3,6, and 9 months after ther~ apy was completed. The area treated consisted of the entire face up to the frown lines of the mid forehead. Patients applied the medication sparingly with their fingertips morning and evening one day per week. Patients were reexamined every 3 to 4 weeks to assess response and decide subsequent treatment. Ifthe lesions were flattening and desquamating, then treatment continued unchanged. Ifnot, the weekly pulse was increased to two consecutive days oftreatment per week. Treatment continued until either all lesions appeared smooth or the patient reached a maximum of 9 weeks of treatment. The number of lesions was counted before treatment, 2 to 4 weeks after completion of treatment, and at each
665
Journal of the American Academy of Dermatology
666 Pearlman
Fig. 1. Patient 6. At end of 6 weeks oftreatment with application of 5-FU 1 day per week. Patient was comfortable. Inflammation was limited to erythema. Ninety-seven percent clearing was achieved with treatment; at 9 months' follow-up, 90% was still clear. Fig. 2. Patient 2. At end of 9 weeks oftherapy with initial application of 5-FU one and later two days per week. Patient was smiling and comfortable. Inflammation was limited to erythema. One hundred percent clearing was achieved with treatment, patient was still 89% clear at 9-month follow-up.
Table I. Results of topical 5-FU weekly "pulse" treatment of facial actinic keratoses No. of actinic keratoses Patient No.
1 2 3
4
5
6 7
8 9 10 Average
Before therapy
50 27 85 21 23 108
57
121
34 36
56
I
After therapy
1 0 0 0 1 3
0 12 0 1 2
% Clearing of actinic keratoses during treatment
98 100 100 100 96
97 100 90 100 97
98
follow-up examination. Local irritation was scored at each treatment phase visit for visible inflammation and subjective discomfort. Patients were photographed at each visit to facilitate evaluation. Lesions present on follow-up examination after treatment were counted and then treated with liquid nitrogen.
RESULTS
Of the 11 patients who entered the study, one was dropped because of noncompliance with the protocol. The data for the remaining 10 patients were available for analysis. The patients received an average of 6.7 weeks of treatment. Five patients needed one day per week of treatment and five patients needed two consecutive days per week of treatment. The patients applied the 5-FU an average of 10 days during the course of therapy. The response to treatment is summarized in Table I. During therapy patients showed an average 98% clearing ofthe lesions, which is statistically significant compared with pretreatment values (p < 0.005 with a one-sided t test). Local irritation was limited to erythema. Nine patients rated the treatment as comfortable. One patient found it uncomfortable but achieved relief with bland emollients. None of the patients experienced swelling, oozing, necrosis, ulceration, or pain requiring systemic analgesics. Local irritation from "pulse" treatment was usually resolved in 2 weeks
Volume 25 Number 4 October 1991
and in all cases by 4 weeks after stopping therapy. Figs. I and 2 show two patients at the height ofthe inflammatory process during their treatment. Their local irritation is limited to varying degrees of erythema. They both rated the treatment as comfortable. The longest available follow-up is in the first six patients who entered the study. They have reached 9 months of follow-up and are on average 86% clear of lesions compared with their conditions before treatment. DISCUSSION
These results show that weekly "pulse" dosing of topical 5-FU of multiple facial actinic keratoses produces the same benefit with much less local irritation than the conventional daily dosing schedule. Patients apply 5-FU one day or two consecutive days per week. The observed 98% clearing of multiple facial actinic keratoses with pulse dosing compares favorably with the approximate 93% rate reported with the conventional daily dosing regimen. 1O In view of its efficacy, relative comfort, lower cost, and simplicity of use, weekly "pulse" dosing may be preferable. This study refutes the belief that severe local inflammation is required to achieve significant benefit from treatment. This reduction in inflammation was achieved solely by changing the dose schedule and not by simultaneous or subsequent use of a corticosteroid cream. It is still too early to compare the remission time produced by conventional, daily dosing with that produced by the new weekly "pulse" regimen. Previous studies have shown that conventionally treated patients will require repeat treatment with 5-FU between 2 and 4 years after their initial treatment,11-13 Even if it becomes apparent that pulse dosing leads to a somewhat shorter remission period, it would still be valuable treatment for the many patients who will not accept the severe local irritation of conventional treatment.
Weekly pulse dosing with 5 -FU 667 The overall duration from the start of treatment to recovery after treatment is similar in pulse and conventional treatment. The average duration of pulse therapy is longer than that of conventional therapy (6.7 weeks vs 2 to 4 weeks, respectively). However, because the irritation is much milder with pulse therapy, pulse-treated patients recovered more quickly. Their recovery period was 2 to 4 weeks, much shorter than the 4- to 8-week recovery period needed after conventional, daily-dose therapy.s I thank Kimberly Mourning, medical assistant, for her help with this project. Curtis Engelhard, MA, performed the statistical analysis.
REFERENCES 1. Marks R. Nonmelanotic skin cancer and solar keratoses. The Quiet 20th century epidemic. Int J Dermatol 1987; 26:201-5. 2. Marks R, Ponsford MW, Se1wood TS, et al. Nonmelanotic skin cancer and solar keratoses in Victoria. Med J Aust 1983;2:619-22. 3. Marks R, Foley P, Goodman G, et a1. Spontaneous remission of solar keratoses: the case for conservative management. Br J Dermatol 1986;115:649-55. 4. Goette DF. Topical chemotherapy with 5-f1uorouracil. J AM ACAD DERMATOL 1981;4:633-49. 5. Dillaha CJ, Jansen GT, Honeycutt WM, et al. Selective cytotoxic effect of topical 5-f1uorouracil. Arch Derrnatol 1963;88:247-56. 6. Dillaha CJ, Jansen T, Honeycutt MW, et al. Further studies with topical 5-f1uorouracil. Arch Derrnatol 1965;92: 410-7. 7. Belisario JC. Topical cytotoxic therapy of solar keratoses with 5-fluorouracil. Med J Aust 1969;2:1136-40. 8. Robinson JK, Skin problems of aging. Geriatrics 1983;38(5):63-5. 9. Breza T, Taylor R, Eaglstein WHo Noninflammatory destruction of actinic keratoses by 5-FU. Arch Dermatol 1976;112:1256-8. 10. Dowd AL, ed. Physicians desk reference 1990. New Jersey, Medical Economics, 1990:1772. 11. Jansen TG. Topical therapy with 5-fluorouracil. J Surg Oneol 1971;3:317-23. 12. Bennet R, Epstein E, Goette D, et al. Current management using 5-fluorouracil: 1985. Cutis 1985;36:218-36. 13. Simmonds WL. Topical management of actinic keratoses with 5-fluorouracil: results of a 6-year follow-up study. Cutis 1972;10:737-41.