Recurrence rate of superficial basal cell carcinoma following treatment with imiquimod 5% cream: conclusion of a 5-year long-term follow-up study in Europe

ARTICLE

Auteur(s) : Harald Gollnick¹, Carlos Guillén Barona², Ronald GJ Frank³, Thomas Ruzicka⁴, Mosaad Megahed⁴, Joachim Maus⁵, Ullrich Munzel⁵

¹Clinic for Dermatology and Venereology, Otto von Guericke University of Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
²Instituto Valenciano de Oncología, Profesor Beltrán Báguena, 19, 46009-Valencia, Spain
³Medisch Spectrum Twenty, Ariensplein 1, 7511 JX, Enschede, Netherlands
⁴Department of Dermatology and Allergy, University of Aachen, Pauwelsstr. 30, 52057 Aachen, Germany
⁵MEDA Pharma GmbH & Co. KG, Benzstr. 1, 61352 Bad Homburg, Germany

accepté le 4 Juin 2008

Basal cell carcinomas (BCC), the most frequently occurring cutaneous malignancies, generally do not metastasize but can be locally invasive. The treatment aim is to completely cure the tumour, but the cosmetic outcome is a reasonable concern for patients [1]. The immune response modifier, imiquimod, acts through Toll-like receptor (TLR)-7 (and to a lesser extent, TLR-8) signalling and has been shown to induce interferon (IFN-α) production in human blood cell cultures and when administered orally in humans [2]. IFN-α appears to act upon natural killer (NK) cells and conventional dendritic cells (DCs) to stimulate IFN-γ, tumour necrosis factor (TNF)-α, monocyte chemoattractant proteins (MCPs) and other cytokines [3, 4]. Locally, imiquimod stimulates the production of various cytokines at the cellular level that increase immunity and afford anticancer activity [5-7]. In addition, imiquimod also appears to directly induce apoptosis in various tumour cell lines, including squamous cell carcinoma and BCC via the cytochrome C pathway [8]. This observation of the ability of imiquimod to induce a local immune response has resulted in imiquimod being widely studied for the treatment of actinic keratosis and external genital warts as well as BCC [9-13] and squamous cell carcinomas [14, 15]. Its clinical utility as a topical treatment for treating superficial BCC (sBCC) lesions has been established when used 5 × per week or 7 × per week for 6 weeks [10, 12]; the 5 × per week regimen is currently approved in the EU and the USA for treatment of sBCC. However, follow-up data on the long-term effectiveness of the treatment have been lacking. It was, therefore, considered valuable to assess the long-term outcome of imiquimod treatment of sBCCs under conditions similar to those used during routine therapy.

In 2005, we reported the interim 2-year results from an open label, Phase III, 5-year follow-up study estimating the initial clearance rate and sustained clearance rate of sBCCs treated with imiquimod 5% cream 5 × per week for 6 weeks [16]. Initial clearance rates were evaluated 12 weeks following treatment using clinical assessment of the treated tumour areas. Patients who achieved clinical clearance at that point were asked to return annually thereafter for up to 5 years for the re-assessment of clinical clearance. Similarly, the 2-year interim results of a 5-year long-term study using 7 ×/week dosing have also been reported [17]. This current paper now reports the final 5 year follow-up results from the study evaluating the 5 ×/week dosing.

Methods

Results

Study population

The majority of patients were male (66%), the mean age was 65 years and ranged from 21 to 89 (table 1). Most frequent skin types were II (tans minimally) and III (tans gradually).
Table 1 Baseline demographic characteristics (ITT)

Efficacy outcomes

Of the 165 patients who entered the long-term follow-up period, 162 patients were included in the estimate for the sustained clearance rate. By the end of the 60-month follow-up period, 18 patients had had a clinical recurrence of their target tumour. Eight (44.4%) of these 18 clinical recurrences occurred during the first 6 months of follow-up, and 10 (55.5%) clinical recurrences occurred by 12 months of follow-up.

The estimated sustained clearance rate at 60 months follow-up was estimated based on the protocol-defined Kaplan-Meier product limit method as 84.5% (SE = 5.0; 95% CI: 74.8%-94.2%; figure 1); the rate estimated by the life-table analysis was 86.9% (SE = 3.1; 95% CI: 79.5%-91.8%) (table 2).

As compared to the Kaplan-Meier estimate, the life-table method revealed a more precise estimate for the last visit (SE = 3.1). The results of the life table method were therefore used to determine the overall probability of treatment success, i.e. the probability for a patient starting treatment with imiquimod to become and remain completely clear. These probabilities were calculated by multiplying the life-table results by the initial clearance rate at 12-weeks PT (89.6%). As of the 60-month follow-up visit, the probability of overall treatment success was 86.9% × 89.6% = 77.9% (table 2).

An amendment set in force when most patients had completed the 12-week PT visit required a histological examination of suspicious target lesions during follow-up. Of the 20 sBCCs diagnosed clinically at 12-week PT (N = 2) or during the follow-up (N = 18), data from 19 histological examinations were available, confirming the diagnosis in 15 cases. Recurrence of sBCC was histologically excluded for the other 4 patients. On the other hand one clinically cleared patient exhibited histological recurrence. Consequently, apart from the clinical outcome, the time to recurrence was also estimated based on the histological picture, leading to a Kaplan-Meier estimate of 90.3% (CI 85.6-95.0%) and to a similar life table estimate of 90.3% (CI 84.4-94.0%). Further, the respective probability of overall treatment success was 90.3% × 89.6% = 80.9%.
Table 2 Initial clearance rate and sustained clearance (life-table method)

Safety outcomes

Skin quality assessments at the 60 month follow-up assessment have remained essentially unchanged from the ratings made at the 12-month and 24-month follow-up visits that have been previously reported [16]. At the 24-month follow-up these assessments indicated an increase from baseline in the intensity ratings of hypopigmentation, and decreases in the intensity ratings of hyperpigmentation, degree of scarring, skin surface, mottled or irregular pigmentation, and atrophy at the target tumour site (figure 2). Local skin reaction assessments have demonstrated that all LSRs have returned to baseline and have been stable since the 2-year follow-up assessment. Two typical cases of BCC treatment with imiquimod over the time course of 5 years are shown in figure 3.

Discussion

The differences in the sustained clearance rate produced by the Kaplan-Meier method, in contrast to the life-table method, are likely a reflection of censoring effects, which can be generated due to the timing of visits. It is a well-known phenomenon that the Kaplan-Meier estimate becomes less reliable at the tail of a life-table curve because the number of patients at risk becomes very small. As figure 1 indicates, the standard error at the last recurrence is doubled as compared with that at Month 48, since only 20 patients were at risk at that point of time. In contrast, the life-table method provides estimates based on intervals (i.e. it uses the interval these events occur and not the date of the actual event), making it less sensitive to censoring effects. Thus, the Kaplan-Meier estimates are more precise for the points of time during the follow-up and the life table estimates are more precise for the end of the 5^th year. In light of this, we consider, as the most reasonable estimates provided by this study, the figure of 86.9% for sustained clearance of a follow-up of 60 months, once the lesion was cleared initially, and 77.9% for the overall clinical clearance success rate.

The 5-year recurrence data resulting from this study demonstrate a higher rate of sBCC recurrence during the first 9 months (counting from the end of actual treatment) than at later periods. Similar findings regarding the general pattern of recurrences following other treatments for sBCC have been suggested [18]. The timing of recurrences in this study may reflect a small overestimation of initial efficacy at the 12-week PT visit due to the initial clinical assessment being hampered, in some cases, by lingering localised erythema. However, as years have passed since the initial clinical assessment, it is evident that the majority of clinical diagnoses of the absence of sBCC 12 weeks following imiquimod treatment were quite accurate. This accuracy in the investigators’ ability to clinically diagnose early treatment failures has been previously validated [10]. This adds a measure of reassurance that the likelihood of a false-negative diagnosis is low. It also indicates that follow-up of sBCCs treated with imiquimod is quite important during the first year following treatment.

One study recently reported the 5-year follow-up results of patients treated with imiquimod [19] under 2 different dosing regimens (3 ×/week for 8 weeks or 5 ×/week for 5 weeks). The 5-year recurrence rate was only 2% (1 of 37). The results are difficult to interpret in the context of the results from our study, mainly due to very different tumour selection criteria (only 4 superficial, but 8 nodular and 43 infiltrative BCC were enrolled) and different methods for analysing the data.

There are currently no data with which to directly compare the recurrence rates after imiquimod with that of other treatment modalities in sBCC. Historical data summarising long-term recurrence rates for surgical excision, the current gold standard of BCC treatment, are inconsistent [20]. Most of the studies reported in the literature focus on analyses of small, retrospective database audits from various dermatology clinics or hospitals where patient selection, tumour location, size, and type were either not specified or not controlled in the analysis. For example, in one of the larger retrospective analyses evaluating recurrence rates of BCCs over 5-years of follow-up (588 primary BCCs, type not specified), the overall recurrence rate for surgical excision was found to be 4.8% [21]. It was noted that recurrence rates on the ear and nasal-labial groove were 43% and 20%, respectively, while there were no recurrences noted on tumours of the trunk, chin-mandible, pre-/post-auricular, perioral, canthi, or extremities. A retrospective analysis of 1635 excised BCCs found that 92.7% could be completely excised at the first time [22]. Of the incompletely excised tumours, 91/119 (76%) were re-excised with residual tumour still occurring in 48/91 (53%). Recently, the 5-year follow-up of a randomised trial comparing photodynamic therapy (PDT) vs. surgery in the treatment of the nodular type of BCC was reported. For the ITT population, the initial clearance was 88% (46/52) and 96% (47/49), and the sustained patient clearance rates was 78% (36/46) and 96% (45/47), for an overall treatment success of 69% (36/52) and 92% (45/49) for PDT and cryosurgery, respectively [23]. However, surgery was inferior to PDT concerning cosmetic outcome. Thus, the initial and sustained clearance rates as well as the overall treatment success observed following imiquimod treatment in our study are in between the results reported for surgery and PDT.

With respect to the incidence of various skin quality parameters, patients in our study had shown the greatest changes between the 12-week PT visit and the 1 year follow-up visit. Skin quality intensities have remained stable since then. The biggest increase from baseline occurred in the category of hypopigmentation. This change in pigmentation may simply be a result of the skin renewal process in an area that is surrounded by sun damaged skin and thus appears light. Overall, the cosmetic outcome was excellent.

The results show that the sustained clearance rate 5 years following imiquimod treatment is promising and patients are not at undue risk of false negative diagnoses following the initial assessment. When choosing a treatment for sBCC, the physician and patient should take into consideration the long-term clearance rates for various modalities and patient risk factors for recurrence as well as the cost and number of re-treatments required [24]. As sBCC generally do not metastasize, the cosmetic outcome is also an important factor. Hence immuno-biological options like imiquimod should be considered in particular when cosmetic outcome is an important factor for the case in question.

Acknowledgements

References

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