Comparison of imiquimod 5% cream versus radiotherapy as treatment for eyelid basal cell carcinoma
- E Garcia-Martin1,2,
- L M Gil-Arribas1,
- M Idoipe1,
- J Alfaro3,
- V Pueyo1,2,
- L E Pablo1,2,
- F J Fernandez1
- 1Ophthalmology Department, Miguel Servet University Hospital, Zaragoza, Spain
- 2Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain
- 3Anatomical Pathology Department, Miguel Servet University Hospital, Zaragoza, Spain
- Correspondence to Dr Elena Garcia-Martin, Hospital Universitario Miguel Servet, Consultas Externas de Oftalmología, C/ Padre Arrupe, s/n 50009 Zaragoza, Spain;
- Accepted 28 November 2010
- Published Online First 17 January 2011
Background To compare the efficacy, cosmesis and tolerance of two non-surgical treatments—imiquimod (IMQ) 5% cream and radiotherapy (RT)—to combat periocular nodular basal cell carcinoma (BCC).
Methods Twenty-seven patients with clinical and histopathological diagnosis of nodular BCC on the eyelid were included and randomly selected: 15 patients were treated with IMQ 5% cream once daily, 5 days/week for 6 weeks, and 12 patients were treated with RT.
Results All tumours showed histopathological remission within 3 months of the treatment, and sustained clinical remission was documented in each patient after 24 months' follow-up. Treatment tolerability was rated as moderate with IMQ and good with RT. Functional results were better in patients treated with IMQ. Loss of eyelashes was reported for most of the patients treated with RT.
Conclusions IMQ and RT therapies are effective for treating eyelid nodular BCCs. Cosmesis and functional results were better with IMQ, while tolerability was higher with RT.
- Basal cell carcinoma
- immunomodulatory drug therapy
- eye lids
- treatment medical
Basal cell carcinomas (BCCs) are the most common malignant tumours of the skin,1 and their incidence is increasing,2 particularly in fair-skinned persons with significant sun exposure.3 Primary BCC tumours are usually slow-growing and locally invasive, but recurring tumours tend to be more aggressive, infiltrative and destructive, and have substantially poorer cure rates.1 Nodular BCC is the most common histological variant.2 A periocular location is considered a high-risk area in terms of 5-year recurrence rates, especially if the tumour had a diameter larger than 6 mm or was located in the free margin of the eyelid.1 4
Several therapeutic modalities are used to treat this neoplasm: radiotherapy (RT), excisional surgery, Mohs surgery, electrodesiccation with curettage, and cryosurgery. The choice of the treatment technique is contingent on various factors, such as tumour characteristics, the general condition of the patient, cosmetic considerations, and the skill and preference of physicians. Surgical excision and RT are commonly used5 6 and achieve cure rates of between 90% and 98%.4 7 8 Mohs micrographic surgery, a specialised technique of tumour excision with frozen-section margin control, remains the gold standard treatment for nodular BCC, but in eyelids RT has been sometimes recommended for cosmetic reasons or when patients refuse surgery.9
New topical treatments such as imiquimod (IMQ) have the advantage of assisting in the removal of a tumour without causing collateral structural damage. IMQ is an immune response modifier that acts through toll-like receptor 7 by stimulating antigen presenting cells to produce cytokines such as interferon-α.10 Studies related to BCCs of the trunk or extremities have reported that IMQ is almost as effective as surgical treatment in terms of clinical cure rates and typically achieves good to excellent cosmetic outcomes.11–14 Numerous studies have reported its use in nodular BCC at other locations,12 15–19 and phase II and III, multicentre, randomised studies and open-label studies with IMQ 5% monotherapy have reported complete histological clearance rates ranging from 42 to 100% for nodular BCC.11 12 16–19 In a multicentre study, Rigel et al reported a clinical clearance rate of 100% at 1 year for 57 BCCs treated with curettage followed by IMQ.20 Some authors have studied the efficacy of IMQ in treating BCCs with a periocular location, although sample numbers were extremely low.21–24
The objectives of the current study were to examine the effectiveness of RT and IMQ for periocular BCCs, and to compare these treatments with regard to adverse effects, and functional and cosmetic outcomes.
Twenty-seven patients prospectively histologically diagnosed as having nodular BCC on the eyelid were enrolled in the study. Each subject was randomised to be treated with IMQ 5% cream (patients born on even days of the month) or with RT (patients born on odd days of the month).
Exclusion criteria were previous therapies for the BCC, the presence of other dermatological diseases such as Gorlin syndrome, psoriasis or constitutional dermatitis, and immunocompromised status. All lesions were analysed by biopsy using a punch of diameter 4 mm. More aggressive varieties of BCC such as morpheaform (sclerosing or infiltrative) BCC were excluded.
The use of IMQ 5% cream (Aldara, Meda Pharma, Madrid, Spain) in the periocular region was approved by the ethics committee of the Institutional Review Board, and the study was performed in accordance with the Declaration of Helsinki. All subjects provided written informed consent prior to participation in the study.
IMQ 5% cream was applied once daily, five times per week for 6 weeks without occlusion. Patients were instructed to apply IMQ cream to the target tumour with the aid of cotton swabs, to avoid contact of the cream with the conjunctiva or cornea, and to apply carbomer 0.2% cream (Lipolac, Farma Lepori, Barcelona, Spain) before applying IMQ. Carbomer is a highly viscous ophthalmic gel that provides protection to the eye's surface by maintaining the eye's tear film in a moist state.
Prior to treatment, the ophthalmologist used a scalpel blade to scrape off skin around the lesion, thereby removing smaller fragments of tumour from the surrounding stroma.
Conventional radiotherapy was performed with 50–100 kV. The field size was delineated for each case. Treatment fractions delivered two or three times per week for 5 weeks, up to a dose of 300 cGy per session. Patients were not hospitalised. Based on the radiologist's criteria, the total administered dose was 4000–7000 cGy.
All the subjects were examined, and the status of their BCC was documented photographically at the beginning of therapy and every 2 weeks during the treatment period. Six weeks after completing the therapy, all patients were examined for the presence of any residual tumour, and a biopsy was performed. All patients were followed up at 3, 6, 12 and 24 months post-treatment.
Cosmetic results in the 27 participating patients were evaluated by the same ophthalmologist 6 weeks after the end of IMQ treatment or RT; these were classified as ‘excellent’ (clinical remission without skin alterations), ‘good’ (clinical remission with hypo or hyperpigmentation of the skin) or ‘bad’ (clinical remission with retraction or other skin alterations). All adverse effects were recorded at each visit to the clinic, and at the same time, overall tolerability was rated as ‘excellent,’ ‘good’ or ‘bad’ by the patients. Cosmetic results were also evaluated by the patients 6 weeks after the completion of treatment, and classified as ‘excellent,’ ‘good’ or ‘bad.’
Twenty-seven patients (16 men and 11 women) with histologically confirmed nodular BCCs on the eyelids were included in the study. The mean age was 73.78±7.39 years (range: 53–84 years). Fifteen patients were treated using IMQ and 12 received RT. The characteristics and results of the patients who participated in the study are summarised in table 1. All subjects completed the treatment.
Most of the lesions presented a nodular macroscospic appearance with superficial telangiectatic vessels and central depression. Two patients had a history of recurrent ulceration of their lesions with partial regression. Thirteen of the 27 BCCs were located in periocular areas, such as the internal canthus (four patients) or eyelid margin (nine patients), where a poorer response to treatment was anticipated. Histological examination revealed basaloid lobules with tumour cells, consistent with the diagnosis of nodular BCC in all cases (figure 1A).
After 4 weeks' treatment with IMQ, tumours showed ulceration and necrosis, and the adjacent skin appeared erythematous in all patients (figure 2). Nine patients reported discomfort when they blinked, but only two patients reported considerable conjunctival irritation during IMQ application; in these cases, the patients were treated with a combination of tobramycin and dexamethasone applied directly to the eye in the form of drops to reduce inflammation and prevent infection. No alterations of the skin around the tumour target, cornea, eyelid or eyelashes were found during the study. All patients had complete clinical clearance at the final evaluation, and no vessels or ulcerations were detected (figure 2). The cosmetic result was scored as excellent by all patients.
All patients presented progressive loss of eyelashes from the upper or lower eyelid (depending on the tumour location) from the first or second session and a decrease in tumour mass size. Six of the patients reported symptoms of dry eye and discomfort with blinking, and one patient complained of slight pain in the lower eyelid during the treatment. All patients had complete clinical clearance at the final evaluation. The cosmetic result was scored as good by all patients.
Histological examination showed no tumour persistence 6 weeks after the end of both treatments with no histologically evident BCC component (figure 1B) present in any of the 27 tumours. Giant-cell reparative granulomas were found in seven tissue biopsies following treatment. Evaluations carried out at 3, 6, 12 and 24 months after treatments revealed clinical remission in all tumours. Aesthetic and functional results were excellent in the IMQ group. All the patients treated with RT presented a loss of eyelashes in one or both eyelids, two of the 12 patients had inferior eyelid retraction with secondary ectropion, and three of the patients reported dry eye symptoms after RT.
As shown in table 1, tolerability during the treatment was better in the RT group. Seven of the 15 patients treated with IMQ reported ‘bad’ tolerability, but these symptoms disappeared when the period of cream application ended.
Our results support the emerging tendency for non-surgical techniques to be used to treat nodular and superficial BCC with typical histology. As the behaviour of these neoplasms tends to be local and moderate, several authors have suggested that less aggressive therapies to remove them may be used.
The main objective in the treatment of BCC is complete tumour removal to prevent recurrences.1 However, we have observed that most of the patients with BCC are of an advanced age or have important associated pathologies that can contraindicate surgery. In these patients, non-surgical approaches may be a good option because, although cure rates are lower those achieved with Moh micrographic surgery or surgical extirpation, these treatments achieve clinical remission in most tumours, thereby improving quality of life in the latter years for many of these patients. Also, as the preservation of function and cosmetic outcomes are better with these non-surgical therapies, they must be taken into account when a treatment modality for nodular eyelid BCCs1 is being considered.
With the mean age of BCC diagnosis having declined in recent years, younger people are requesting treatments that provide good functional and cosmetic results. The cosmetic outcomes are excellent when IMQ is used, although permanent hypopigmented macules in the tumour target area have been detected in 67% of cases.16 In our study, only one patient showed a hypopigmented area, and this was smaller than 1 mm in diameter. The patients treated with RT had poorer cosmetic outcomes, with all of them losing eyelashes and some of them presenting with alterations of the eyelid skin, such as retraction or ectropion.
Radiotherapy has been frequently used to treat periocular BCCs,21 but IMQ has been recently studied in these locations and found to yield good results: Carneiro et al reported that eight of 10 lesions resolved clinically and histologically in eight patients (studied by biopsy at 12 weeks).22 Choontanom et al reported a similar cure rate in the treatment of five patients with nodular BCC.23 Leppälä et al and Blasi et al reported 100% clinical cure of eyelid basal cell carcinoma when four and two patients, respectively, were treated with IMQ.24 25
Another important aspect regarding the treatment choice for BCCs is tolerability and safety. In our study, IMQ patients protected the cornea by applying carbomer cream, but treatment of BCCs located near the margin often gave rise to conjunctival irritation and discomfort with blinking. These symptoms disappeared when treatment ended.
Although the overall power of the study is limited to some degree by the small sample size, we have provided good evidence of the efficacy of non-surgical therapies in the treatment of nodular periocular BCCs. We acknowledge that 5- and 10-year recurrence rates would provide a more reliable indication of outcome than 2-year rates.7
Based on our experience, we have designed a model protocol (figure 3), even though therapy should be decided on an individual basis that is dictated by patient status, concurrent systemic diseases, cosmetic needs, tumour characteristics and the preferences of each subject.
Competing interests None.
Patient consent Obtained.
Ethics approval Ethics approval was provided by the Miguel Servet University Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.