dear editor, Skin reactions occur frequently during and after treatment of actinic keratosis (AK) with 5% 5‐fluorouracil (5‐FU). Managing expectations is important to prevent patients from prematurely terminating treatment and to ensure patients’ adherence. The frequency and severity of skin reactions was evaluated using data from patients with AK who participated in a clinical trial comparing different field‐directed therapies for AK and who were randomized to 5‐FU cream. 1 A secondary objective was to evaluate whether more severe skin reactions were associated with a higher probability of treatment success.
5‐FU was prescribed twice daily for 4 weeks and patients scored presence of skin reactions on a four‐point scale or numeric rating scale (pain and burning sensation) during treatment and for 2 weeks post‐treatment. Maximum scores were used for analysis, and categorized into absent (0), mild/moderate (0·1–6·0) and severe (6·1–10·0) skin reaction. Risk ratios with 95% confidence intervals (CI) and P‐values were calculated to examine the association between the severity of skin reactions and probability of treatment success (≥ 75% reduction in lesion numbers) 3 months post‐treatment.
Of the 135 patients with complete diaries, 89·6% were male and the median age was 73 (range 48–90) years. Treatment success occurred in 111 patients for whom treatment response was known. Most patients (92·6%) reported full adherence to the treatment regimen. Severe erythema was reported most often, by 63 of 135 (46·7%) patients. Other commonly reported skin reactions were itching (28·9%), crusts (19·3%), burning sensation (21·5%) and scaling (18·5%) (Figure 1). The highest frequency and severity of skin reactions occurred in week 4 and the first week post‐treatment (Figure 1).
Figure 1.
Patient‐reported weekly presence of (a) any skin reaction, and (b) severe skin reactions during and post‐treatment in percentages. Skin reactions were scored on a four‐point scale (absent, mild, moderate or severe) or numeric rating scale (0–10; pain and burning sensation) and categorized into absent (0), mild/moderate (0·1–6·0) or severe (6·1–10·0).
Patients who reported severe or mild‐to‐moderate erythema had a higher probability of treatment success than patients without erythema. The relative chance of successful treatment was 1·90 (95% CI 1·02–3·55, P < 0·01) and 1·54 (95% CI 0·82–2·91, P = 0·10), respectively. After correction for potential confounding by age, number of AKs and adherence to the treatment regimen using multivariate logistic regression analysis, the adjusted odds ratios were very similar to the unadjusted odds ratios. Severe erythema occurred in 63·5% of patients with AK on the face vs. 36·5% of patients with AK on the vertex, but adjustment for location was not possible because none of the patients with AK on the face had a treatment failure.
Our results show that many patients experience skin reactions during and after 5‐FU treatment. All skin reactions showed a peak after 4 weeks. For most patients, skin reactions in the first 2 weeks were still acceptable regarding the impact on facial appearance as well as discomfort. This information may be useful to discuss with patients before treatment, as it may help them in scheduling the treatment period.
As mentioned in previous studies, (fear of) side‐effects can be a reason for nonadherence to patient‐applied topical treatments. 2 , 3 Although generally side‐effects cannot be avoided in order to achieve effective treatment, knowledge about the course of side‐effects can help to inform and educate patients, and ultimately increase adherence and thus the probability of a favourable treatment outcome.
Among the skin reactions to 5‐FU cream severe erythema stands out as the reaction that is most strongly and significantly associated with an increased probability of treatment success. Similar results were seen in patients treated with imiquimod cream in the trial (data not shown). This finding can be used to reassure patients who experience severe reactions, especially erythema. Erythema is an important indicator of inflammation and the hypothesis that inflammation is required to achieve a therapeutic effect has been corroborated by findings in previous publications. 4 , 5
In current guidelines, daily application of 5‐FU is recommended for 3 to 4 weeks. 6 , 7 , 8 In daily practice the treatment duration is often shorter as it depends on the severity of the skin reactions. However, it is unclear whether patients who end treatment prematurely owing to severe skin reactions achieve efficacy. 8 The initial treatment success rate after 5‐FU treatment twice daily for 4 weeks in this study population was 85·2%, and relatively high compared with other studies. 1 We would therefore not recommend a shorter treatment period in patients with severe skin reactions, unless new evidence suggests that a shorter treatment regimen suffices in these patients.
In conclusion, we highlight the importance of patient education on the frequency, severity and timing of skin reactions during and after treatment of AK with 5‐FU cream in order to increase patient adherence to the prescribed regimen and thus treatment effectiveness. Moreover, we found that more severe erythema as a skin reaction is associated with a higher probability of treatment success.
Author Contribution
Shima Ahmady: Conceptualization (equal); Formal analysis (equal); Investigation (equal); Methodology (equal); Project administration (lead); Writing‐original draft (lead). Ellen Oyen: Conceptualization (equal); Project administration (supporting); Writing‐original draft (equal). Maud H.E. Jansen: Conceptualization (equal); Investigation (equal); Writing‐original draft (supporting). Patty Nelemans: Conceptualization (equal); Investigation (equal); Methodology (equal); Supervision (equal); Writing‐original draft (supporting). Janneke Kessels : Investigation (equal); Writing‐original draft (supporting). Nicole WJ Kelleners‐Smeets: Supervision (supporting); Writing‐original draft (supporting). Klara Mosterd: Conceptualization (equal); Supervision (lead); Writing‐original draft (supporting).
Funding sources: the Netherlands Organization for Health Research and Development.
Conflicts of interest: the authors declare they have no conflicts of interest.
Data availability statement: the data that support the findings of this study are available from the corresponding author upon reasonable request.
References
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