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Alert Number 90

Aldara: a Promising New Drug for Actinic Keratosis

  — (Early Skin Cancer)

Date: April 21, 2005

We have discussed before the real and serious risk of skin cancer in CLL patients - Dying to Get a Tan?. I am constantly amazed how little attention is paid to this potentially deadly complication by community oncologists. If you want to be part of the solution, please make the effort to print out the Mayo best practices article and present it to your local guy. The next CLL patient who walks in will owe you. Here is the link: Mayo Best Practices.

'Actinic Keratosis' is an early version of full blown and invasive squamous cell carcinoma. The latest issue of Archives of Dermatology has announced a new topical cream that looks to be quite effective in clearing up actinic keratosis, with little or no adverse effects. It is a prescription drug and expensive (what else is new?), but easy to use at home. The trade name is 'Aldara', and the chemical name is 'imiquimod'. Please read the Medscape report below on this important ally in our fight against skin cancer.

Aldara is also approved for treating human papilloma virus (HPV) that causes warts. Warts that pop up on the back of your hands are ugly and no one likes them, but the issue is a lot more serious when HPV is implicated in cervical cancer in women, head and neck skin cancer, especially in immune compromised patients. Did you know there are many varieties of papilloma virus? And that it is possible for the virus to spread from one location to another by contact? Taking steps to get rid of warts on your hands becomes more than a question of vanity when you are a CLL patient with less than perfect immune system.

Aldara has a very interesting mechanism of action. Unlike more conventional topical chemotherapy drugs used to treat actinic keratosis, Aldara activates and uses the 'langerhans cells' just under your skin to bring the virus to the not-so-tender attention of the immune system. In fact, there is a great deal of interest in this drug as an adjuvant to cancer vaccines. In the next few weeks I will be writing about a cancer vaccine clinical trial specifically for CLL patients, and it uses Aldara as an adjuvant. Stay tuned folks, this could be an interesting approach.

If you are prone to get periodic flare-ups of squamous cell carcinoma, please make sure you do not neglect it. And do discuss with your doctor the use of Aldara to take care of the pre-cancerous actinic keratosis right away. The picture below is not for the squeamish or faint-hearted. A patient sent this to me, and gave me permission to publish it, to see if it can knock some sense into those of you who are still inclined to dismiss real risks of sun damage. The full color version is a lot more graphic and scary, I had to tone it down quite a bit to reduce the download time.

Be well,

Chaya
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Medscape Medical News

Imiquimod May Be Safe, Effective for Actinic Keratosis

News Author: Laurie Barclay, MD
CME Author: Désirée Lie, MD, MSEd

April 19, 2005 — Imiquimod (Aldara) is safe and effective for actinic keratosis (AK), according to the results of two randomized, double-blind trials published in the April issue of the Archives of Dermatology.

"The only treatment for AK that works by enhancing the immune response against dysplastic cells is 5% imiquimod cream," write Neil Korman, MD, PhD, from Case Western Reserve University in Cleveland, Ohio, and colleagues. "Since imiquimod works through an immunological mechanism, regimens with infrequent dosing for an extended duration have been evaluated to minimize potentially intolerable adverse effects."

These two phase 3, parallel-group trials took place at 26 ambulatory care offices, including dermatologists in private practice or research centers. Of 654 patients who were 18 years and older and were screened, 162 patients were ineligible. The remaining 492 patients each had four to eight AK lesions in a 25-cm2 treatment area on the face or the balding scalp, and they were randomized to receive an application of 5% imiquimod or vehicle cream to the treatment area once daily, three times per week, for 16 weeks, followed by an eight-week posttreatment period.

Complete clearance rate, which was defined as the proportion of patients at the eight-week posttreatment visit with no clinically visible AK lesions in the treatment area, was statistically significantly higher with imiquimod (48.3%) than with vehicle (7.2%). Partial clearance rate or the proportion of patients at the eight-week posttreatment visit with at least a 75% reduction in the number of baseline AK lesions in the treatment area was 64.0% vs 13.6%.

The median percentage reduction of baseline lesions was 86.6% vs 14.3%, respectively. Overall efficacy was higher for dosing three times per week than for twice weekly, but the rate of local skin reactions was also higher.

"The 5% imiquimod cream dosed three times weekly for 16 weeks is safe and effective for the treatment of AK," the authors write. "An additional benefit from imiquimod treatment appears to be improved skin quality compared with vehicle treatment."

One of the limitations of this study was incomplete blinding because of local skin reactions in the active treatment group, which may have biased the investigators' assessments.

"Because imiquimod works by enhancing the innate and adaptive immune responses, individual patient responses will vary depending on many intrinsic and extrinsic factors, such as the number and responsiveness of Langerhans cells and extent of solar damage," the authors conclude. "These results, in addition to results from previously published studies, suggest that many different dosing regimens are effective and that dosing could be tailored to minimize drug exposure and adverse effects."

Seven of the authors report financial arrangements with 3M Pharmaceuticals, the maker of imiquimod, which helped support this study. Three of the authors have received funding from companies with competing products.

Arch Dermatol. 2005;141:467-473

Study Highlights

Inclusion criteria were healthy men and women 18 years or older with a clinical diagnosis of 4 to 8 AK lesions within a contiguous 25-cm2 treatment area on the face or balding scalp.
Patients were recruited in 2 independent studies from 26 U.S. centers (13 centers per study) from ambulatory primary care private practice or research centers. 242 were randomized to receive 5% imiquimod cream, and 250 were randomized to receive vehicle once daily, 3 times a week, for 16 weeks, applied to the entire treatment area at the same time of day (just before sleeping) and left in place for 8 hours. The study consisted of prestudy (2 weeks), treatment (16 weeks), and posttreatment (8 weeks) periods. Assessments were made at treatment weeks 1, 2, 4, 6, 8, 10, 12, 14, and 16 and posttreatment weeks 4 and 8.
Primary outcome was complete clearance rate defined as proportion of patients at 8 weeks' posttreatment with no clinically visible AK lesions in the treatment area. Secondary outcomes were partial response rate defined as proportion with at least 75% reduction in number of baseline AK lesions and median percentage of reduction in number of AK lesions. Adverse effects were monitored.
Analysis was by intent-to-treat.
Median age was 67 years, all were white, and 87.6% were men. Two thirds had fair skin. The 2 groups were similar for age, sex, and skin type.
210 patients in the imiquimod group vs 237 of the vehicle group completed the treatment period.
Complete clearance occurred in 48.3% of the imiquimod vs 7.2% of the vehicle group (P < .001). The difference was 41.1% (95% confidence interval, 34.1% - 48.2%). Partial clearance occurred in 64.0% of the imiquimod vs 13.6% of vehicle-treated patients (P < .001).
In the imiquimod group, there was a statistically significant relationship between complete or partial clearance and intensity of local skin reaction. Clearance rate increased with increased intensity of erythema. Complete blinding to treatment allocation was not ensured because of this effect.
Complete clearance rate was higher in imiquimod-treated patients with an increase in number of AK lesions from baseline (54.4%) vs those without an increase in count (43.9%).
Half the patients receiving imiquimod had at least an 86.6% reduction in number of baseline AK lesions. The median percentage reduction in number of AK lesions was 86.6% for the imiquimod and 14.3% for the vehicle-treated group.
At least 1 treatment-related adverse event was noted in 43.0% of imiquimod and 8.8% of vehicle-treated patients (P < .001). The most common adverse event was itching at the target site. Application site reactions were reported by 38.8% of imiquimod and 7.2% of vehicle-treated patients (P < .001).
The rate of severe skin reactions was higher in the imiquimod group. Overall, skin reactions were well-tolerated and resolved after treatment cessation.
During the treatment period, 13.2% of imiquimod vs 5.2% of vehicle-treated patients discontinued the study mainly because of adverse events or personal reasons. Treatment rest periods were taken by 40.9% of imiquimod and 0.8% of vehicle-treated patients. 86.9% of imiquimod and 100% of vehicle-treated patients returned to treatment after the rest period.
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