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Purpose: To assess the efficacy and safety of topical imiquimod 5% cream in the treatment of eyelid basal cell carcinoma.
Methods: Four patients with eyelid basal cell carcinoma were treated with imiquimod once daily, 5 days per week, for 6 weeks. Tissue biopsy was taken and clinical examination with slit-lamp microscopy was performed at the beginning of the study and after a follow-up of 12 weeks. Photographic follow-up was performed from the baseline visit to 6, 12 and 26 weeks.
Results: In the 12-week follow-up after imiquimod treatment, histopathological tissue sample analysis showed no signs of basal cell carcinoma in any of the patients.
Conclusions: The results indicate that 5% imiquimod cream with topical administration may represent a new therapy option for eyelid basal cell carcinoma.
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Basal cell carcinoma (BCC) is the most common skin malignancy, the incidence of which has increased during recent years. It represents 20% of eyelid tumours and 90% of eyelid malignancies (Goldberg 1997; Salomon et al. 2004; Allali et al. 2005). This type of locally invasive tumour does not usually metastasize in other tissues, but it may cause considerable morbidity when occurring in the eyelids and/or periocular tissue (Margo & Waltz 1993). In the eyelids, BCCs show a higher risk of recurrence and more aggressive biological behaviour, implying a worse prognosis (Margo & Waltz 1993). Eyelid surgery of BCC requires total tumour removal, maintenance of lid function, and good aesthetic results (Allali et al. 2005). However, it is usually difficult to clinically ensure the total excision of the BCC and achieve the latter two goals at the same time.
Imiquimod (Aldara™; 3M Pharmaceuticals, Minneapolis, MN, USA) is a novel synthetic compound that is a member of the imidazoquinolone family of drugs. It is applied as a topical 5% cream for adults against superficial BCC. It has been suggested that imiquimod functions as an agonist of toll-like receptor (TLR)-7, which belongs to the TLR family (Gibson et al. 2002; Dummer et al. 2003). Toll-like receptors play a critical role in host defence and inflammatory processes in cells. Currently, 10 different TLRs have been identified in humans. Moreover, imiquimod has been shown to increase the expression of many inflammatory mediators, such as interferon-α and the interleukins 1, 6, 8, 10 and 12. It also regulates the activation levels of natural killer cells, as well as Langerhans and B cells (Dahl 2002; Sapijaszko 2005). Imiquimod-induced regression of BCC involves the strong activation of both innate and cell-mediated immune responses that lead to the induction of apoptotic cell death (Miller 2000; Dummer et al. 2003; Sapijaszko 2005). In the skin lesion, imiquimod administration often induces an inflammatory reaction that peaks in intensity during the treatment period but is resolved after drug cessation (Geisse et al. 2004). Clinical trials of imiquimod have been carried out or initiated on basal cell carcinomas, actinic keratosis, invasive squamous cell carcinoma, lentigo maligna metastatic melanoma, mycosis fungoides, keratoacanthoma, and extramammary Paget's disease (Navi & Huntley 2004). In this study, we report four cases of nodular eyelid BCC that were cured in response to topical administration of imiquimod 5% cream.
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All patients were treated with imiquimod once daily, 5 days per week, for 6 weeks, leaving weekends free from drug administration. Patients were instructed to carefully apply cream only on the eyelid lesion, avoiding drug contact with the surface of the eye. In addition, to protect the eye surface, retinoid acid cream (Oftan A-Pant; Santen Oy, Tampere, Finland) was administered to the subfornical space prior to imiquimod application. Basal cell carcinoma was diagnosed from tissue samples according to routine histopathological analyses. Morphea-type BCCs and carcinomas located adjacent to lacrimal drainage systems were excluded from this study.
Our first patient was an 85-year-old man with a nodular BCC located in the medial part of the right upper lid (Table 1, Fig. 1). Prior to imiquimod administration, the tumour measured 8 mm at its largest diameter; its vertical and horizontal diameters measured 5 mm and 6 mm, respectively (Table 2, Fig. 1). In response to imiquimod treatment, the lesion gradually disappeared (Table 2, Fig. 1). No side-effects were observed. At 12 weeks, only a scar remained and histological analysis of tissue biopsy revealed no BCC. Clinical slit-lamp examination and photographs showed no recurrence of BCC after 26 weeks (Fig. 1).
Table 1. Subject demographics.
| ||Case 1||Case 2||Case 3||Case 4|
Figure 1. Photographs of imiquimod-treated eyelid basal cell carcinomas (from left to right baseline, 6 weeks, 12 weeks and 26 weeks, respectively). Case 1 first row, Case 2 second row, Case 3 third row, Case 4 fourth row.
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Table 2. Tumour diameters during follow-up.
|Diameter||Baseline||6 weeks||12 weeks|
|Longitudinal||8 mm||6 mm||Scar|
|Vertical||5 mm||4 mm|| |
|Horizontal||6 mm||5 mm|| |
|Longitudinal||7 mm||7 mm||Scar|
|Vertical||5 mm||7 mm|| |
|Horizontal||5 mm||4 mm|| |
|Vertical||10 mm|| || |
|Horizontal||14 mm|| || |
|Vertical||4 mm|| || |
|Horizontal||2 mm|| || |
The second patient was a 77-year-old woman with a nodular BCC located in the left lower lid adjacent to the nose (Table 1, Fig. 1). The tumour measured 7 mm at its largest diameter; its vertical and horizontal diameters measured 5 mm prior to imiquimod administration (Table 2, Fig. 1). An inflammatory reaction was clearly seen around the tumour in response to imiquimod. However, the treatment was allowed to continue for 6 weeks according to the study design. Only a scar was visible at 12 weeks, with no histopathological signs of BCC. Clinical slit-lamp examination and photographs showed no recurrence at 26 weeks (Fig. 1).
The third patient was a 76-year-old man with a nodular BCC located in the temporal part of the right upper lid (Table 1, Fig. 1). The largest diameter of the tumour was 15 mm; its vertical and horizontal diameters measured 10 mm and 14 mm, respectively, prior to imiquimod administration (Table 2, Fig. 1). In response to imiquimod treatment, severe skin inflammation was seen on the tumour area (Fig. 1). Therefore, oral cefalexine 750 mg twice daily for 1 week was initiated and fucidic acid cream was applied topically twice daily for 1 week. However, the imiquimod treatment was allowed to continue. The skin inflammation disappeared after 6 weeks of treatment (Fig. 1). Again, only a scar remained and histological analysis revealed no signs of BCC at 12 weeks. Clinical slit-lamp examination and photographs showed no recurrence at 26 weeks (Fig. 1).
The fourth patient was an 89-year-old man with a nodular BCC located adjacent to the nose on the right side (Table 1, Fig. 1). The largest diameter of the tumour was 4 mm; its vertical and horizontal diameters were 4 mm and 2 mm, respectively, prior to imiquimod administration (Table 2, Fig. 1). In response to imiquimod, inflammation clearly developed around the tumour, but the treatment was allowed to continue. After 6 weeks of treatment, a marked inflammation persisted. Therefore, oral cefalexine (750 mg twice daily for 1 week) and topical fucidic acid cream (twice daily for 1 week) were initiated. After a follow-up of 12 weeks, inflammation was detected but no signs of BCC in histopathological biopsy analysis. Clinical slit-lamp examination and photographs again showed no recurrence at 26 weeks (Fig. 1).
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Previous clinical studies have revealed the utility of imiquimod for treating both superficial BCC (Marks et al. 2001; Geisse et al. 2002) and nodular BCC (Shumack et al. 2002). Although a variety of doses have been employed, it seems that the optimal dosing regimen is once daily, 5 days per week (Geisse et al. 2004), as in the present study. In addition, different durations of treatment as well as occlusion have been studied with imiquimod (Sterry et al. 2002). Based on BCC clearance rates following imiquimod application, a 6-week treatment period has been suggested to be sufficiently long (Geisse et al. 2004) and was therefore also selected for this study.
Although imiquimod has been shown to be effective in treating BCC, it causes various side-effects, especially on the site of application. The most common side-effects include erythema, erosion and scabbing or crusting at the lesion; these are felt as burning, itching and pain (Geisse et al. 2004). These side-effects increase with dosing frequency. We observed inflammatory skin reactions in three of the four patients in this study. However, inflammation abated in two of them, whereas in one patient the erythema continued for the total duration of treatment. Interestingly, the eyelid and periocular BCCs disappeared in all imiquimod-treated patients after a 12-week follow-up and no recurrences were observed after 6 months follow-up when analysed by slit-lamp examination. According to the manufacturer's instructions, imiquimod has not been evaluated for the treatment of BCC within 1 cm of the eyelids, nose, lips or eyebrow line. To our knowledge, only one publication has reported imiquimod treatment on eyelid BCC cases (Blasi et al. 2005). That study revealed a promising efficacy for imiquimod in two cases, showing no local recurrence after a 1-year follow-up. As both these studies were carried out with a limited number of cases, larger patient material is required to confirm the efficacy of imiquimod administration and to address recurrence rates in eyelid and periocular BCC. In summary, imiquimod may provide an alternative therapy to surgery in certain BCC cases. Although no ocular side-effects were observed in this study, the use of retinoic acid cream to protect the eye surface is recommended with imiquimod therapy.