Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial.

BACKGROUND: Superficial basal-cell carcinoma is most commonly treated with topical non-surgical treatments, such as photodynamic therapy or topical creams. Photodynamic therapy is considered the preferable treatment, although this has not been previously tested in a randomised control trial. We assessed the effectiveness of photodynamic therapy compared with imiquimod or fluorouracil in patients with superficial basal-cell carcinoma. METHODS: In this single blind, non-inferiority, randomised controlled multicentre trial, we enrolled patients with a histologically proven superficial basal-cell carcinoma at seven hospitals in the Netherlands. Patients were randomly assigned to receive treatment with methylaminolevulinate photodynamic therapy (MAL-PDT; two sessions with an interval of 1 week), imiquimod cream (once daily, five times a week for 6 weeks), or fluorouracil cream (twice daily for 4 weeks). Follow-up was at 3 and 12 months post-treatment. Data were collected by one observer who was blinded to the assigned treatment. The primary outcome was the proportion of patients free of tumour at both 3 and 12 month follow up. A pre-specified non-inferiority margin of 10% was used and modified intention-to-treat analyses were done. This trial is registered as an International Standard Randomised controlled trial (ISRCTN 79701845). FINDINGS: 601 patients were randomised: 202 to receive MAL-PDT, 198 to receive imiquimod, and 201 to receive fluorouracil. A year after treatment, 52 of 196 patients treated with MAL-PDT, 31 of 189 treated with imiquimod, and 39 of 198 treated with fluorouracil had tumour residue or recurrence. The proportion of patients tumour-free at both 3 and 12 month follow-up was 72.8% (95% CI 66.8-79.4) for MAL-PDT, 83.4% (78.2-88.9) for imiquimod cream, and 80.1% (74.7-85.9) for fluorouracil cream. The difference between imiquimod and MAL-PDT was 10.6% (95% CI 1.5-19.5; p=0.021) and 7.3% (-1.9 to 16.5; p=0.120) between fluorouracil and MAL-PDT, and between fluorouracil and imiquimod was -3.3% (-11.6 to 5.0; p=0.435. For patients treated with MAL-PDT, moderate to severe pain and burning sensation were reported most often during the actual MAL-PDT session. For other local adverse reactions, local skin redness was most often reported as moderate or severe in all treatment groups. Patients treated with creams more often reported moderate to severe local swelling, erosion, crust formation, and itching of the skin than patients treated with MAL-PDT. In the MAL-PDT group no serious adverse events were reported. One patient treated with imiquimod and two patients treated with fluorouracil developed a local wound infection and needed additional treatment in the outpatient setting. INTERPRETATION: Topical fluorouracil was non-inferior and imiquimod was superior to MAL-PDT for treatment of superficial basal-cell carcinoma. On the basis of these findings, imiquimod can be considered the preferred treatment, but all aspects affecting treatment choice should be weighted to select the best treatment for patients. FUNDING: Grant of the Netherlands Organization for Scientific Research ZONMW (08-82310-98-08626).

Determinants of treatment duration in the prevention of recurrent venous thromboembolism: a protocol for a balanced vignette experiment.

INTRODUCTION: Venous thromboembolism (VTE) is a condition that annually occurs in approximately 1‰ of the world's population. Patients who have already had a VTE are at elevated risk for a recurrent VTE. Recurrent events increase the risk of long-term sequelae and can be fatal. Adequate secondary prophylaxis is thus needed to prevent such events. Patients with VTE are often prone to bleeding, and pharmacological prophylaxis exacerbates bleeding risk. Expert opinions on the optimum duration of secondary prophylaxis in VTE still vary substantially. The existence of treatment guidelines has not led to uniformity of VTE secondary prophylaxis strategies, which means that physicians still adhere to individual risk calculi in determining treatment duration. METHODS AND ANALYSIS: The aim of this study is to establish what factors lie at the root of this variance in VTE secondary prophylactic treatment strategies, and what risk factors are deemed of particular importance in determining the perceived risks and benefits of variable treatment durations. To do this, we created a survey based on a D-efficient and G-efficient balanced experimental vignette design. This protocol covers all aspects of how this survey was set up and how it was implemented. The analysis of the experimental data will be carried out using mixed-effects methods, which are beneficial in scenarios with high interindividual variance and correlated (eg, repeated-measures) responses. We propose the use of maximal random effects structures insofar as possible. ETHICS AND DISSEMINATION: All data are de-identified, and any identifying characteristics of the respondents will not be reported in a final manuscript or elsewhere. A paper describing the expert interviews is currently under peer review. A manuscript that contains the analysis of the results of the experiment described in this protocol is being drafted, and will also be submitted to a peer-reviewed journal.