Efficacy, Safety, and Tolerability of 4% 5-Fluorouracil Cream in a Novel Patented Aqueous Cream Containing Peanut Oil Once Daily Compared With 5% 5-Fluorouracil Cream Twice Daily: Meeting the Challenge in the Treatment of Actinic Keratosis

October 2016 | Volume 15 | Issue 10 | Original Article | 1218 | Copyright © October 2016

Magdalene A. Dohil MD

Department of Dermatology and Pediatrics, University of California, San Diego, CA

BACKGROUND: Actinic keratosis (AK) is a neoplastic keratosis and a precursor of squamous cell carcinoma (SCC). OBJECTIVE: We are presenting data on a novel formulation of 4% 5-Fluorouracil (5-FU) in an aqueous vehicle cream containing peanut oil (Tolak) with once daily application versus treatment with 5% 5-FU twice daily for 4 weeks. METHODS: 1) A dose ranging study of 4% 5-FU cream once or twice daily for 2 or 4 weeks and its vehicle, compared to 5% 5-FU cream twice daily for 4 weeks in 121 subjects. 2) A double-blinded multicenter study involving 841 subjects for non-inferiority and safety of 4% 5-FU cream once daily vs 5% 5-FU cream twice daily over 4 weeks with 100% and 75% clinical clearance of AK’s. RESULTS: 4% 5-FU qd q4wks achieved 100% clearance in 80% and 75% clearance in 100% of subjects vs 75% and 95% respectively with 5% 5-FU bid q4wks. 4% 5-FU qd2wks achieved 100% clearance in 60% and 75% clearance in 85% of subjects. 4% 5-FU qd q4wks recorded 65 adverse events and 30% application site skin irritation versus 71 events and 60% with 5% 5-FU bid q4wks. 4% 5-FU exceeded non-inferiority by 1.32% with sub-analysis for higher percentage of severely affected patients. 4% 5-FU showed 75% clearance of AK’s in 80.5% vs 80.2% for 5% 5-FU with superior tolerability. CONCLUSIONS: 4% 5-FU cream is a novel, efficacious, superior tolerated once daily topical treatment for better compliance and treatment outcome. The peanut oil component is safe even in peanut-allergic patients.

J Drugs Dermatol. 2016;15(10):1218-1224.


Actinic keratosis (AK) is a lesion of the epidermis comprised of rapidly proliferating neoplastic keratinocytes.1 AK most commonly occurs on the skin in areas of sun exposure, namely the face, scalp, ears, arms, and back of hands,2 specifically in fair-skinned individuals. It produces epidermal mutations that can subsequently develop into tumors.3,4 Lesions extending more deeply to involve the papillary and /or reticular dermis are termed squamous cell carcinoma (SCC).5,6 AK is considered a major precursor of SCC. Both entities are related on clinical, histological and biological grounds given known common mutations.7 Anywhere between 0.025 and 16% of AK’s can progress to invasive SCC – extrapolation suggesting the risk of progression to be around 8% varying according to age, gender, chronic UV exposure, and location.8,9 The occurrence rate of invasive SCC is 5-20% over follow-up periods of 10-25 years with a 0.1% and 0.24% transformation rate in one year.3,10,11 Conversely, 82.4-100% patients with invasive SCC on sun-exposed areas have a history of AK. More importantly, AK’s are no longer limited to the elderly. Patients present increasingly in their thirties and fourties. Treatment of AK’s is therefore paramount to avoid progression to more aggressive malignancy.12,13,14 It is compelling that treatment is no longer simply directed at visible lesions but rather anticipatory aimed at what we know will evolve.15,16,17Approved treatments for AK’s include different modalities including surgical excision, cryotherapy, curettage, laser ablation, and a variety of topical agents.18,19,20 The location, body surgace area (BSA) involved, and number of lesions are the primary variables to take into account in determining the choice of treatment. 5-fluorouracil (5-FU) has been the mainstay in topical treatment of multiple AK’s since its approval in 1970 and is currently available in various formulations of concentration and vehicle. While all of the currently marketed formulations of 5-FU have proven variable efficacy, it is common clinical knowledge that this often comes at the cost of increased adverse events. To date the main hurdle to improving treatment outcomes has been the difficulty to get patients to comply with the prescribed treatment recommendations. Patients struggle with the decision if the treatment may be worse than the disease knowing compliance will result in visible skin irritation and will require a complete change of lifestyle. Additionally, adequately powered trials comparing the different formulations have been lacking to date further complicating the clinical decision as to the right agent for patients and practitioners alike.21, 22