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Single-blind, randomized controlled trial to evaluate the efficacy and safety of photodynamic therapy using aminolevulinic acid versus 5-fluorouracil in the management of actinic keratosis 1
P498
P500
SUCCESSFUL TREATMENT WITH TOPICAL 0.5% FLUOROURACIL AND IMIQUIMOD 5% CREAM IN THE TREATMENT OF A PATIENT WITH ACTINIC KERATOSIS AND SQUAMOUS CELL CARCINOMA Helen M Torok, MD, Trillium Creek Dermatology Center, Medina, OH, United States Actinic keratosis (AK) lesions are dysplastic epidermal lesions commonly identified in fair-skinned patients who have had excessive sun exposure. Compelling evidence of their premalignant status, underlines the need for close monitoring and early treatment of these lesions. Treatment of AK lesions with topical 0.5% fluorouracil is effective and may be most appropriate for patients with widespread actinic damage. A 60-year-old white male with Fitzpatrick skin type II presented with a history of squamous cell carcinoma and multiple AK lesions and reported a childhood history of numerous burns and blistering eruptions. The patient is bald, and as a result, frequently develops AK lesions and squamous cell carcinoma on the scalp. Previous treatment included cryosurgery on numerous occasions with limited success and frequent recurrences. Clinical examination revealed over 30 hypertrophic AK lesions on the scalp and a large squamous cell carcinoma measuring 1.2 cm by 1.2 cm. Due to the diffuse nature of the AK and squamous cell carcinoma, topical treatment with imiquimod 5% cream, once daily at bedtime was implemented. Following 10 days of therapy, no response was observed. At that time, topical 0.5% fluorouracil cream applied once daily was added to the treatment regimen. Concomitant treatment with both topical 0.5% fluorouracil cream (applied at bedtime) and imiquimod 5% cream (applied in the morning) continued for 2 weeks during which the patient developed a painful exuberant reaction that resulted in thickcrusted lesions and edema. Following compression of the area and application of petroleum jelly, the patient healed completely without sequelae and experienced no recurrences of lesions 1 year following treatment.
IMTD: AN ALGORITHM-BASED APPROACH TO OPTIMIZE DOSE-RESPONSE IN TREATMENT OF SKIN CANCER USING IMIQUIMOD Sarvenaz Zand, Harvard Medical School, Cambridge, MA, United States, William W. Li, MD, Institute for Advanced Studies, Angiogenesis Foundation, Cambridge, MA, United States, Vincent W. Li, MD, MBA, Institute for Advanced Studies, Angiogenesis Foundation, Cambridge, MA, United States Imiquimod is an immune response modifier that induces a variety of cytokines including interferons and interleukins which suppress angiogenesis. Several clinical studies have shown its effectiveness in treating actinic keratoses and superficial basal cell carcinomas (BCC). We have observed heterogeneity in both the anti-tumor response and the local tissue reaction (ranging from mild erythema to inflammation, vesiculation, or erosion) in individual patients across different lesions. Such biological heterogeneities are not addressed in clinical trial protocols mandating a single defined application frequency among the study cohorts. To optimize imiquimod’s efficacy while minimizing its side effects, we devised a treatment algorithm we have termed Individualized Maximal Tolerated Dose (IMTD). The IMTD algorithm guides the clinician in determining the optimal treatment frequency per patient and per individual lesion. Based on evaluation of tissue reaction and patient tolerability, imiquimod is applied in incremental levels: BIW ⫻ 2 weeks escalating to TIW ⫻ 2 weeks, then M-F ⫻ 2 weeks, then QD ⫻ 2 weeks. Further escalations range from QD to BID under occlusion ⫻ 2 weeks. We report two patients using the IMTD algorithm. Both patients had extensive BCC on the upper and lower extremities (⬎20 lesions on patient 1; and ⬎50 on patient 2). Given the number of lesions, both patients declined surgery or ablative interventions. Imiquimod was applied topically, with each patient and each anatomic location requiring different frequency levels of the IMTD algorithm. BCC on the legs of both patients achieved complete (100%) clearance with minimal local tissue reaction. Post-treatment biopsies were performed verifying histological absence of malignancy. Summary: We have developed a clinically useful treatment algorithm termed IMTD for imiquimod treatment of BCC. This approach optimizes the individualized treatment of lesions based on local tissue reaction, accounts for inter-individual and intra-anatomic variations, and provides greater anti-tumor dosing where tolerable. The IMTD algorithm is easily standardized for BCC intervention in our clinic.
Disclosure not available at press time. Medical writing supported by Dermik Laboratories.
Disclosure not available at press time.
P499 BASAL CELL CARCINOMA METASTATIC TO THE BONE Molly M Warthan, BS, University of Texas Medical Branch, Galveston, TX, United States, Mandy Warthan, MD, Medical College of Georgia, Augusta, GA, United States, Ronald Hearne, MD, University of Texas Medical Branch, Galveston, TX, United States, Jack Lesher, MD, Medical College of Georgia, Augusta, GA, United States Background: Basal cell carcinoma is well-known to be the most common malignancy in humans. In the United States, there have been over one million new cases occur each year. Only approximately 300 of metastatic basal cell carcinoma (BCCA) have been described in the literature. When metastatic BCCA does occur, the most common metastatic site is the regional lymph nodes, followed in descending order by the lungs, bones, and skin. Objectives: We describe a 60 year-old white male from East Texas with a history of BCCA on his right anterior chest. Originally, his BCCA was shaved followed by electrocautery and dessication. He had a local reccurence of the BCCA approximately two years later that was re-excised with negative margins. Then, 5 years later, he presented to his primary care physician complaining of back pain and bone pain. After an extensive work up for possible causes, it was determined that he had metastatic basal cell carcinoma to his bone marrow. Methods: A bone marrow biopsy was performed that showed osteoblastic metatstatic lesions. Then, a prostate biopsy was recommended to look for the primary cancer. The biopsy of the prostate gland showed no evidence of malignancy. A review of the histologic detail of the BCCA of the right upper chest revealed an architecture and cytology identical to that of the bone marrow cytology. A second opinion on the case was obtained from MD Anderson Cancer Center in Houston, Texas. They agreed that the metatstatic tumor in the bone marrow was consistent with metatstasis of the orginal BCCA of the chest. Results: After a complete evaluation for other possible sources for the primary cancer proved negative, it was determined that the source for this patient’s metatstatic bone marrow cancer was from the BCCA on his right anterior chest. Conclusion: We report a very rare case of metastatic BCCA to the bone marrow, with no demonstrable evidence of involvement of the lymphatic system. According to the most recent studies in the literature, the rate of metastatic basal cell carcinoma is approximately 0.03 percent. 1. Lo JS, Snow SN. Metastatic basal cell carcinoma: report of twelve cases with a review of the literature. J Am Acad Dermatol 1991; 24:715-9. 2. von Domarus H, Steven PJ. Metastatic basal cell carcinoma. J Am Acad Dermatol 1984; 10: 1043-60. Disclosure not available at press time.
MARCH 2004
P501 SINGLE-BLIND, RANDOMIZED CONTROLLED TRIAL TO EVALUATE THE EFFICACY AND SAFETY OF PHOTODYNAMIC THERAPY USING AMINOLEVULINIC ACID VERSUS 5-FLUOROURACIL IN THE MANAGEMENT OF ACTINIC KERATOSIS Aditya K Gupta, MD, PhD, University of Toronto, London, ON, Canada Photodynamic therapy using aminolevulinic acid (ALA-PDT), followed by illumination with a Blue Light Photodynamic Therapy Illuminator emitting in the 400-450 nm range, has been approved by the FDA for use in the treatment of actinic keratosis (AK). ALA is applied to the AKs using aminolevulinic acid, and is to be incubated for 14-18 hours prior to illumination. This period of illumination has been associated with significant adverse events (AEs) such as stinging, itching and burning of the skin during illumination. Recent studies have shown that shorter durations of ALA incubation have been equally effective in the treatment of AK, but with fewer AEs reported during treatment. A single-center, comparative, randomized single-blinded trial comparing topical 5% 5-fluorouracil (5-FU) with short-duration ALA-PDT is being performed, using an incubation period for ALA of 45-60 minutes before illumination. Subjects with moderate to severe actinic keratosis and 5-20 lesions were eligible for the study. Subjects were randomized in a 1:1 ratio to either 5-FU or ALA-PDT at baseline. For subjects receiving ALA-PDT, treatment was repeated at week 8 if the subject showed less than 75% reduction in AKs. 5-FU was applied to the face or scalp twice daily for 2-4 weeks as tolerated. No further 5-FU treatment was performed. Follow-up evaluation of actinic keratosis is to be performed at weeks 4, 8, 12 and 26. Fifty subjects are enrolled. Most subjects have completed up to week 4, and are continuing to be followed up. Most adverse events noted with short-duration ALA-PDT treatment were mild and transient, and consisted of erythema to the application site lasting for 2 to 3 days. Subjects undergoing short-duration ALA-PDT showed few visible signs of irritation (erythema, scaling, crusting) at a one-week post-treatment assessment, compared to 5-FU subjects who exhibited moderate to severe erythema, scaling and crusting between weeks 2-4. The short incubation period and the brief illumination period allow ALA-PDT to be performed in a single office visit, making ALA-PDT a convenient treatment for subjects. The milder and more transient range of AEs may also make short-duration ALA-PDT a more desirable alternative than 5% 5-FU. If short-duration ALA-PDT is shown to be as effective as 5% 5-FU at weeks 12 and 26, ALA-PDT may be a suitable treatment alternative for subjects with multiple moderate to severe AKs. Dr Gupta has conducted clinical trials for DUSA. 100% is sponsored by DUSA.
J AM ACAD DERMATOL
P129
P500
SUCCESSFUL TREATMENT WITH TOPICAL 0.5% FLUOROURACIL AND IMIQUIMOD 5% CREAM IN THE TREATMENT OF A PATIENT WITH ACTINIC KERATOSIS AND SQUAMOUS CELL CARCINOMA Helen M Torok, MD, Trillium Creek Dermatology Center, Medina, OH, United States Actinic keratosis (AK) lesions are dysplastic epidermal lesions commonly identified in fair-skinned patients who have had excessive sun exposure. Compelling evidence of their premalignant status, underlines the need for close monitoring and early treatment of these lesions. Treatment of AK lesions with topical 0.5% fluorouracil is effective and may be most appropriate for patients with widespread actinic damage. A 60-year-old white male with Fitzpatrick skin type II presented with a history of squamous cell carcinoma and multiple AK lesions and reported a childhood history of numerous burns and blistering eruptions. The patient is bald, and as a result, frequently develops AK lesions and squamous cell carcinoma on the scalp. Previous treatment included cryosurgery on numerous occasions with limited success and frequent recurrences. Clinical examination revealed over 30 hypertrophic AK lesions on the scalp and a large squamous cell carcinoma measuring 1.2 cm by 1.2 cm. Due to the diffuse nature of the AK and squamous cell carcinoma, topical treatment with imiquimod 5% cream, once daily at bedtime was implemented. Following 10 days of therapy, no response was observed. At that time, topical 0.5% fluorouracil cream applied once daily was added to the treatment regimen. Concomitant treatment with both topical 0.5% fluorouracil cream (applied at bedtime) and imiquimod 5% cream (applied in the morning) continued for 2 weeks during which the patient developed a painful exuberant reaction that resulted in thickcrusted lesions and edema. Following compression of the area and application of petroleum jelly, the patient healed completely without sequelae and experienced no recurrences of lesions 1 year following treatment.
IMTD: AN ALGORITHM-BASED APPROACH TO OPTIMIZE DOSE-RESPONSE IN TREATMENT OF SKIN CANCER USING IMIQUIMOD Sarvenaz Zand, Harvard Medical School, Cambridge, MA, United States, William W. Li, MD, Institute for Advanced Studies, Angiogenesis Foundation, Cambridge, MA, United States, Vincent W. Li, MD, MBA, Institute for Advanced Studies, Angiogenesis Foundation, Cambridge, MA, United States Imiquimod is an immune response modifier that induces a variety of cytokines including interferons and interleukins which suppress angiogenesis. Several clinical studies have shown its effectiveness in treating actinic keratoses and superficial basal cell carcinomas (BCC). We have observed heterogeneity in both the anti-tumor response and the local tissue reaction (ranging from mild erythema to inflammation, vesiculation, or erosion) in individual patients across different lesions. Such biological heterogeneities are not addressed in clinical trial protocols mandating a single defined application frequency among the study cohorts. To optimize imiquimod’s efficacy while minimizing its side effects, we devised a treatment algorithm we have termed Individualized Maximal Tolerated Dose (IMTD). The IMTD algorithm guides the clinician in determining the optimal treatment frequency per patient and per individual lesion. Based on evaluation of tissue reaction and patient tolerability, imiquimod is applied in incremental levels: BIW ⫻ 2 weeks escalating to TIW ⫻ 2 weeks, then M-F ⫻ 2 weeks, then QD ⫻ 2 weeks. Further escalations range from QD to BID under occlusion ⫻ 2 weeks. We report two patients using the IMTD algorithm. Both patients had extensive BCC on the upper and lower extremities (⬎20 lesions on patient 1; and ⬎50 on patient 2). Given the number of lesions, both patients declined surgery or ablative interventions. Imiquimod was applied topically, with each patient and each anatomic location requiring different frequency levels of the IMTD algorithm. BCC on the legs of both patients achieved complete (100%) clearance with minimal local tissue reaction. Post-treatment biopsies were performed verifying histological absence of malignancy. Summary: We have developed a clinically useful treatment algorithm termed IMTD for imiquimod treatment of BCC. This approach optimizes the individualized treatment of lesions based on local tissue reaction, accounts for inter-individual and intra-anatomic variations, and provides greater anti-tumor dosing where tolerable. The IMTD algorithm is easily standardized for BCC intervention in our clinic.
Disclosure not available at press time. Medical writing supported by Dermik Laboratories.
Disclosure not available at press time.
P499 BASAL CELL CARCINOMA METASTATIC TO THE BONE Molly M Warthan, BS, University of Texas Medical Branch, Galveston, TX, United States, Mandy Warthan, MD, Medical College of Georgia, Augusta, GA, United States, Ronald Hearne, MD, University of Texas Medical Branch, Galveston, TX, United States, Jack Lesher, MD, Medical College of Georgia, Augusta, GA, United States Background: Basal cell carcinoma is well-known to be the most common malignancy in humans. In the United States, there have been over one million new cases occur each year. Only approximately 300 of metastatic basal cell carcinoma (BCCA) have been described in the literature. When metastatic BCCA does occur, the most common metastatic site is the regional lymph nodes, followed in descending order by the lungs, bones, and skin. Objectives: We describe a 60 year-old white male from East Texas with a history of BCCA on his right anterior chest. Originally, his BCCA was shaved followed by electrocautery and dessication. He had a local reccurence of the BCCA approximately two years later that was re-excised with negative margins. Then, 5 years later, he presented to his primary care physician complaining of back pain and bone pain. After an extensive work up for possible causes, it was determined that he had metastatic basal cell carcinoma to his bone marrow. Methods: A bone marrow biopsy was performed that showed osteoblastic metatstatic lesions. Then, a prostate biopsy was recommended to look for the primary cancer. The biopsy of the prostate gland showed no evidence of malignancy. A review of the histologic detail of the BCCA of the right upper chest revealed an architecture and cytology identical to that of the bone marrow cytology. A second opinion on the case was obtained from MD Anderson Cancer Center in Houston, Texas. They agreed that the metatstatic tumor in the bone marrow was consistent with metatstasis of the orginal BCCA of the chest. Results: After a complete evaluation for other possible sources for the primary cancer proved negative, it was determined that the source for this patient’s metatstatic bone marrow cancer was from the BCCA on his right anterior chest. Conclusion: We report a very rare case of metastatic BCCA to the bone marrow, with no demonstrable evidence of involvement of the lymphatic system. According to the most recent studies in the literature, the rate of metastatic basal cell carcinoma is approximately 0.03 percent. 1. Lo JS, Snow SN. Metastatic basal cell carcinoma: report of twelve cases with a review of the literature. J Am Acad Dermatol 1991; 24:715-9. 2. von Domarus H, Steven PJ. Metastatic basal cell carcinoma. J Am Acad Dermatol 1984; 10: 1043-60. Disclosure not available at press time.
MARCH 2004
P501 SINGLE-BLIND, RANDOMIZED CONTROLLED TRIAL TO EVALUATE THE EFFICACY AND SAFETY OF PHOTODYNAMIC THERAPY USING AMINOLEVULINIC ACID VERSUS 5-FLUOROURACIL IN THE MANAGEMENT OF ACTINIC KERATOSIS Aditya K Gupta, MD, PhD, University of Toronto, London, ON, Canada Photodynamic therapy using aminolevulinic acid (ALA-PDT), followed by illumination with a Blue Light Photodynamic Therapy Illuminator emitting in the 400-450 nm range, has been approved by the FDA for use in the treatment of actinic keratosis (AK). ALA is applied to the AKs using aminolevulinic acid, and is to be incubated for 14-18 hours prior to illumination. This period of illumination has been associated with significant adverse events (AEs) such as stinging, itching and burning of the skin during illumination. Recent studies have shown that shorter durations of ALA incubation have been equally effective in the treatment of AK, but with fewer AEs reported during treatment. A single-center, comparative, randomized single-blinded trial comparing topical 5% 5-fluorouracil (5-FU) with short-duration ALA-PDT is being performed, using an incubation period for ALA of 45-60 minutes before illumination. Subjects with moderate to severe actinic keratosis and 5-20 lesions were eligible for the study. Subjects were randomized in a 1:1 ratio to either 5-FU or ALA-PDT at baseline. For subjects receiving ALA-PDT, treatment was repeated at week 8 if the subject showed less than 75% reduction in AKs. 5-FU was applied to the face or scalp twice daily for 2-4 weeks as tolerated. No further 5-FU treatment was performed. Follow-up evaluation of actinic keratosis is to be performed at weeks 4, 8, 12 and 26. Fifty subjects are enrolled. Most subjects have completed up to week 4, and are continuing to be followed up. Most adverse events noted with short-duration ALA-PDT treatment were mild and transient, and consisted of erythema to the application site lasting for 2 to 3 days. Subjects undergoing short-duration ALA-PDT showed few visible signs of irritation (erythema, scaling, crusting) at a one-week post-treatment assessment, compared to 5-FU subjects who exhibited moderate to severe erythema, scaling and crusting between weeks 2-4. The short incubation period and the brief illumination period allow ALA-PDT to be performed in a single office visit, making ALA-PDT a convenient treatment for subjects. The milder and more transient range of AEs may also make short-duration ALA-PDT a more desirable alternative than 5% 5-FU. If short-duration ALA-PDT is shown to be as effective as 5% 5-FU at weeks 12 and 26, ALA-PDT may be a suitable treatment alternative for subjects with multiple moderate to severe AKs. Dr Gupta has conducted clinical trials for DUSA. 100% is sponsored by DUSA.
J AM ACAD DERMATOL
P129