By Chris Berrie
VIENNA, AUSTRIA -- May 18, 2007 -- The new orally administered 5-fluorouracil (5-FU) analogue fosfluridine tidoxil (FOS) shows good tolerability and provides significant clinical response over placebo for patients with actinic keratosis (AK), according to a randomised, placebo-controlled, combined phase 1 and 2 trial.
The findings were presented here on May 17th at the 16th Congress of the European Academy of Dermatology and Venereology (EADV).
AK represents an early stage of squamous cell carcinoma of the skin, and established options for its treatment include surgery, photodynamic therapy, and topical drug application. However, to date no oral treatment and no satisfactory topical treatments are available for severe stage AK, indicated principal investigator Eggert Stockfleth, MD, professor and head, skin cancer centre, department of dermatology, Charité University Hospital, Berlin, Germany.
FOS is a novel oral prodrug that contains the 5-FU molecule combined with ribose, phosphate, and lipid moieties. Its metabolism produces the same intracellular active principle as that for 5-FU, while providing almost no penetration into bone marrow and high protein binding. This results in a better haematological and liver safety profile. FOS also shows a greatly increase half-life over 5-FU (24 h vs 20 min, respectively), and at doses of up to 150 mg FOS, there have been no detectable plasma levels of 5-FU.
In their study, Dr. Stockfleth and colleagues compared FOS with placebo to determine its relative efficacy and safety in patients with AK.
The study included patients who were 55 years or older with advanced AK, defined as 10 or more lesions in a predefined area with stages 2 or 3 AK, as confirmed by biopsy. Efficacy measures included partial clearance of disease, an improving shift in the histological AK class, and a reduction in lesion counts.
The study analysis included a combination of 46 patients from the first part (50/100 mg FOS vs placebo) and 41 from phase 2 (150 mg FOS vs placebo). Three treatment cycles were followed, each as 1 week on treatment followed by 1 week off.
In the first part of the study, both the 50-mg dose and the 100-mg dose of FOS were seen to improve the responses to standard therapies after the end of the study itself, while indicating particular improvements in the patients with stage 3 AK, Dr. Stockfleth indicated.
In the final analysis, although there was no significant partial clearance or reduction in lesion count with 50-mg and 100-mg FOS, the highest dose of 150-mg FOS showed a significant partial clearance over placebo (21% vs 0%, P <.05). The full clearance that was seen with 150-mg FOS did not reach significance over placebo (5% vs 0%).
For the improving shift in disease severity, while again the 2 lower doses of FOS showed no significant effects, as Dr. Stockfleth said, "With the 150-mg [FOS], in terms of classification from AK 3 to AK 2 and 1, we got a significant improvement [P <.05] in 67% of the patients, where only 32% of the placebo [improved]."
Similarly, although an equal-or-worse disease rating at the end of the trial for 150-mg FOS was seen in 33% of these patients, no disease worsening was seen, and with placebo, this was 68%, which included 2 of 22 patients with worsening disease.
For the final safety analysis, the main effects were mild or moderate diarrhoea, seen in 68% of the patients on 150-mg FOS and 18% of placebo patients. Dr. Stockfleth also stressed that beyond these adverse gastrointestinal effects, there were none of the classical adverse effects seen with 5-FU.
"Oral fosfluridine tidoxil is beneficial in severe actinic keratosis, as indicated by partial response and improvement in safety," Dr. Stockfleth said, benefits that might be improved further by an increase in the treatment cycles.
Finally, he noted that the additional interim analysis performed suggested that consecutive standard therapies with topical treatments can also improve the effectiveness of FOS.
The study was supported by Heidelberg Pharma GmbH.
[Presentation title: A Randomised, Placebo-Controlled Trial of Orally Administered Fosfluridine Tidoxil in Actinic Keratoses -- a Systemic Approach. Abstract FC2.6]
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