Use of complete clearance for assessing treatment efficacy for 5-fluorouracil interventions in actinic keratoses: how baseline lesion count can impact this outcome

Figures & data

Table 1. Feasibility assessment network for quantitative comparative analyses of 5-FU: exclusion criteria of trials identified from the SLR.

Non-approved interventions No common comparator, leading to exclusion of some dose-ranging arms/trials Interventions not meeting the dosing and treatment period recommendations No surgery: exclusion of treatment arms assessing cryotherapy or laser (or trial, if all arms are excluded) No combination: exclusion of treatment arms evaluating combination therapy (or trial, if all arms are excluded) No prior treatment: exclusion of trials evaluating treatment efficacy when used after a defined prior treatment^a

^aTrials included if one or more arms did not have prior treatment.

Table 2. Trial and participant characteristics of trials included in the correlation analysis.

Trial	Trial phase	Blinding status	Treatments	Sample size, n	Age (SD)	Male, %	Baseline lesion count (SD)	Mean baseline lesion count across treatment arms
HDFUDR045 [15]	2	Single	5-FU 4% (4 weeks; OD)	20	65.9 (8.3)	85	11.6 (4.2)	10.6
			5-FU 5% (4 weeks; BID)	20	65.2 (11.3)	95	10.5 (3.5)
			Placebo (4 weeks BID)	20	65 (11.8)	90	9.7 (2.2)
HDFUP3B048 [17]	3	Single	5-FU 4% (4 weeks; OD)	353	67.7 (9.8)	81	14.4 (10.8)	15.1
			5-FU 5% (4 weeks; BID)	349	67.4 (10)	81	14.8 (10.6)
			Placebo (4 weeks; OD)	70	68 (10.1)	83	16.2 (15.1)
HDFUP3S049 [16]	3	Double	5-FU 4% (4 weeks; OD)	50	67.9 (11.7)	78	19.2 (15.0)	21.2
			Placebo (4 weeks; OD)	50	66.9 (11.7)	92	23.2 (18.5)
Krawtchenko 2007 [13]	Unclear	Unclear	5-FU 5% (4 weeks; BID)	24	70.4 (6.7)	79	8.3 (NR)	8.1
			IMQ (4 weeks; TIW)	26	70.8 (5.6)	85	7.9 (NR)
Weiss 2002 [14]	3	Double	5-FU 0.5% (4 weeks; OD)	40	62.7 (NR)	75	14.1 (8.2)	15.3
			Placebo (4 weeks; OD)	58	63.6 (NR)	95	16.4 (11.1)

BID = twice daily; NR = not reported; OD = once daily; SD = standard deviation; TIW = three times a week.

Figure 1. Trial selection flowchart.

^a128 non-priority trials from database searching and 15 trials from ClinicalTrials.gov that were included, but not extracted. ^bHDFUDR045 and HDFUP3S049 results were reported by Dohil et al. [12] and not discussed separately. ^cHDFUP4LTS050 was an uncontrolled, single-group trial that assessed patients from previous trials (HDFUP3B048 and HDFUP3S049). CTR = clinical trial report; SGA = subgroup analysis.

Figure 2. Correlation between complete clearance rate at 8 weeks and baseline lesion count in trials with 5-FU 4%, 5%, or 0.5% [13–17].

Table 3. Complete and partial clearance rates in relation to mean number of lesions at baseline in clinical trials with 5-FU.

Trial	Treatments	Baseline lesion count (SD)	Complete clearance rate at week 8 (except IMQ: at week 24), %	Partial clearance rate at week 8, %
HDFUDR045 [15]	5-FU 4% (4 weeks; OD)	11.6 (4.2)	80	100
	5-FU 5% (4 weeks; BID)	10.5 (3.5)	75	95
HDFUP3B048 [17]	5-FU 4% (4 weeks; OD)	14.4 (10.8)	54	81
	5-FU 5% (4 weeks; BID)	14.8 (10.6)	58	80
HDFUP3S049 [16]	5-FU 4% (4 weeks; OD)	19.2 (15)	24	74
Krawtchenko 2007 [13]	5-FU 5% (4 weeks; BID)	8.3 (NR)	96	NR
	IMQ (4 weeks; TIW)	7.9 (NR)	85	NR
Weiss 2002 [14]	5-FU 0.5% (4 weeks; OD)	14.1 (8.2)	48	NR

Pierre Fabre data on file. HD-FUDR-045: A Randomized, Evaluator Blinded, Vehicle Controlled, Parallel Group, Dose Ranging Study of the Safety and Efficacy of 4% 5-FU Cream Versus its Vehicle Cream Versus Efudex in the Treatment of Actinic Keratosis. 2005.

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Pierre Fabre data on file. HD-FUP3B-048: A Randomized, Evaluator Blinded, Vehicle-Controlled Multi-Center Study of the Safety and Efficacy of 4% 5-FU Cream Versus its Vehicle Cream Versus Efudex Cream in the Treatment of Actinic Keratosis. 2007.

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Pierre Fabre data on file. HD-FUP3S-049: A Randomized, Double-Blind, Vehicle-Controlled Multi-Center Study of the Safety and Efficacy of 4% 5-FU Cream Versus its Vehicle Cream in the Treatment of Actinic Keratosis. 2007.

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Krawtchenko N, Roewert-Huber J, Ulrich M, et al. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol. 2007;157(Suppl 2):34–40. .

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Weiss J, Menter A, Hevia O, et al. Effective treatment of actinic keratosis with 0.5% fluorouracil cream for 1, 2, or 4 weeks. Cutis. 2002;70(2Suppl):22–29.

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Dohil MA. 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. J Drugs Dermatol. 2016;15(10):1218–1224.

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Data availability statement

Data derived from public domain resources for published trials. Data available on request from the authors for unpublished trials.