Elsevier

The Lancet Oncology

Volume 14, Issue 7, June 2013, Pages 647-654
The Lancet Oncology

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

https://doi.org/10.1016/S1470-2045(13)70143-8Get rights and content

Summary

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).

Introduction

Basal-cell carcinoma is the most common form of skin cancer and is an important health problem worldwide, with a rapidly increasing incidence and health care costs.1, 2, 3 Although there are many histological subtypes, a simplified classification (Rippey) groups all basal-cell carcinomas into three histological subtypes: superficial, nodular, and infiltrative.4 A third of all basal-cell carcinomas are of the superficial subtype,5 which often appear on the trunk and resemble an eczema-like plaque. Because of the growing incidence in basal-cell carcinomas worldwide, a non-surgical treatment is often chosen for the superficial disease, since this subtype is easily accessible with topical treatment. An international consensus6 on the use of photodynamic therapy in non-melanoma skin cancer recommended it as first-line treatment for superficial basal-cell carcinoma.6 Photodynamic therapy is based on the activation of a topical applied photosensitiser by illumination of the skin lesion with light of an appropriate wavelength to destroy tumour cells. However, both fluorouracil cream and imiquimod cream can be considered as an alternative treatment.7 We assessed the effectiveness of imiquimod and fluorouracil cream versus photodynamic therapy for treatment of superficial basal-cell carcinoma.

Section snippets

Patients

Patients with a primary, histologically proven superficial basal-cell carcinoma were eligible to participate. Histology of the lesion was obtained by a 3 mm punch biopsy and was assessed by various dermatopathologists at the participating hospitals until a consensus on the definition of a superficial basal-cell carcinoma was reached. It was defined as an epidermal tumour existing of small, discrete islands of basaloid cells with peripheral palisading and stromal retraction, presenting

Results

Between March 1, 2008, and Aug 31, 2010, 601 patients with superficial basal-cell carcinoma were randomly assigned to treatment with MAL-PDT (n=202), topical imiquimod (n=198), or topical fluorouracil (n=201). Patient and tumour characteristics were similar between groups (table 1). 11 patients did not begin treatment and seven patients were treated but did not attend the first follow-up visit at 3 months. Data for relevant endpoints were not available for these patients. The remaining 583

Discussion

Topical fluorouracil was non-inferior to, and imiquimod was superior to, MAL-PTD in terms of treatment success after 1 year of follow-up. These results suggest that topical imiquimod should be the first choice for treatment of superficial basal-cell carcinoma.

This is the first randomised controlled trial that we know of that has compared the effectiveness of imiquimod, fluorouracil, and photodynamic therapy for treatment of superficial basal-cell carcinoma. Previously published studies on the

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