NEW YORKA topical sustained-release fluorouracil
product for actinic keratosis that is applied once a day is now available from
Dermik Laboratories (Beryn, Penn). The concentration of active ingredient in
the new product, Carac, is 0.5%, or one tenth that in most fluorouracil creams.
In clinical trials, use of the preparation cleared more than 70% of actinic
keratoses within 1 week.
"Early data suggest that it works just as well as a 5%
product," Sharon Levy, MD, Dermik’s director of clinical research and
medical affairs, said at a press conference introducing Carac. "Less is
more in this case." The 5% products, she noted, are usually applied twice
a day. The new product was approved by the FDA at the end of 2000 and became
commercially available in March 2001.
The two pivotal phase III double-blind placebo-controlled
clinical trials of Carac enrolled 384 patients, who had an average of 15
actinic keratoses each, Dr. Levy said. All had more than 5 lesions. Equal
numbers of patients were assigned to 1-week, 2-week, and 4-week regimens. Four
weeks after treatment stopped, physicians re-counted the number of actinic
keratoses on each patient.
In patients treated for a week, 73.9% of the lesions
disappeared, Dr. Levy reported. With 2 weeks of treatment, the clearance rate
rose to 85% and with 4 weeks, to 90.4%. "Actually we were really surprised
at this," she said, "because going into this program, we had no idea
that we would get such a big effect just by a week of treatment."
A 27.8% reduction occurred in the placebo group, which Dr. Levy
described as a typical response that may be due to activity of the body’s
immune surveillance system or to the flaking of superficial lesions.
Skin irritation with use of Carac was expected Dr. Levy said,
and takes the form of redness, dryness, and swelling, and sometimes crusting of
the actinic keratoses. The irritation usually begins on the fourth day of
treatment, she said, and increases as the applications continue but plateaus at
2 to 3 weeks in courses running 4 weeks.
"The most remarkable part is how quickly the irritation
subsides once you stop the application," she said. "The irritation
starts dropping off right away." Within 2 weeks, the irritation is about
the same as that seen when the patient began treatment, she noted, and 4 weeks
after stopping applications, the skin is smoother than before therapy.
Joseph L. Jorizzo, MD, professor and chair, Department of
Dermatology, Wake Forest University School of Medicine, contrasted the skin
irritation seen with Carac with the generally longer-lasting and more severe
irritation seen with twice-daily use of 5% fluorouracil creams, which typically
call for a 4-week course.
With the standard 5% creams, Dr. Jorizzo said, "the
patient looks like a lobster for 4 to 8 weeks afterwards. That’s not an
acceptable therapy from the patient’s standpoint."
The lower concentration of fluorouracil and once-a-day dosing
of Carac, Dr. Levy noted, are made possible by the Microsponge delivery system.
Developed by Advanced Polymer Systems, Micro-sponge facilitates a sustained
rate of release of active ingredients.
Dr. Jorizzo, who participated in the clinical trials of Carac,
said that the monitoring and treatment of sun-damaged skin should be a
three-step process. The first step, he said, is to check for skin cancers. Any
melanomas or squamous or basal cell carcinomas, he stressed, must be surgically
resected. The second step, is to remove any hypertrophic actinic keratosis
The third step, chemical treatment with a fluorouracil cream,
he said, is useful for removal of flat superficial actinic keratoses and also
as an adjunct to cryosurgery for targeting areas of invisible "pre-actinic
Between the visible actinic keratoses, which may be removed
with cryosurgery or a cream, Dr. Levy said, undoubtedly lie other areas with
damaged cells. "They’re just waiting to pop up, and the use of a
fluorouracil creama blanket kind of treatmenthas the advantage of
potentially targeting those other sites that you don’t see today, those
actinic keratoses you could see in the future."
It is important for dermatologists "to follow the sequence
correctly," he said. "You do not want to miss cancers and jump ahead
to freezing. You do not want to miss freezing the thickest lesions that might
not respond to a topical agent. And for just about everyone, you want to
consider using a chemical chemotherapy treatment to mop up those in-between and
While actinic keratoses have long been considered precancerous
lesions, Dr. Jorizzo pointed out that recent molecular research has determined
damaged cells seen in actinic keratoses are identical to those taken from
invasive squamous cell carcinomas. A diagnosis of actinic keratosis, he
advised, therefore should prompt the same marshaling of the medical
armamentarium as a positive Pap smear does for cervical cancer.
"Actinic keratosis is not yet invasive," he said.
"It has not yet spread. But it can evolve into an invasive squamous cell
carcinoma that can spread and be fatal. By treating the actinic keratosis, we
stop that progression."