Imiquimod 5% Cream as Pretreatment of Mohs Micrographic Surgery for Nodular Basal Cell Carcinoma in the Face
A Prospective Randomized Controlled Study
S. van der Geer; 1J. Martens; J. van Roij; E. Brand; J.U. Ostertag; M.E.J.M. Verhaegh;H.A.M. Neumann; G.A.M. Krekels
Abstract and Introduction
Materials and Methods
Abstract and Introduction
Background Imiquimod 5% cream can reduce or clear superficial and small nodular basal cell carcinoma (BCC). It could be used as a pretreatment of Mohs micrographic surgery (MMS) to decrease defect size.
Objectives To study if a pretreatment with imiquimod 5% cream decreases defect size after MMS. In addition, to study the effect on the number of Mohs stages and reconstruction time.
Methods Seventy patients aged >18 years with a primary nodular BCC in the face were included. The imiquimod group used imiquimod 5% cream for 4 weeks, before MMS. The control group was treated with MMS only. Tumour and defect sizes were measured. We noted the number of Mohs stages, reconstruction time and side-effects.
Results The median percentage increase in area from tumour size at baseline to the post-MMS defect for the imiquimod group was significantly less compared with the control group, 50% vs. 147% (P < 0·001). A tendency towards fewer Mohs stages in the imiquimod group was observed and the reconstruction time was significantly shorter in this group (P = 0·01).
Conclusions Imiquimod 5% cream as pretreatment of MMS significantly reduced the tumour size in primary nodular BCC and reduced the surgical defect size. Further research is necessary to investigate cost-effectiveness.
Basal cell carcinoma (BCC) is the most common malignancy of the skin. While the mortality rate due to this tumour is insignificant, an increasing group of especially younger patients is concerned about the cosmetic outcome of the treatment of a facial tumour. Various therapeutic modalities exist. In most cases surgical excision will take place. Mohs micrographic surgery (MMS) is an advanced technique used mainly for BCCs in the face that have a high risk for recurrence, are located in the H-zone or have a diameter of >2 cm. The size of the defect after excision of the tumour can be significantly reduced by using MMS, compared with the standard surgical excision. The cosmetic outcome is therefore overall better.
Mohs micrographic surgery has the lowest recurrence rate in the treatment of BCC. It is, however, a time-consuming method and therefore costs are higher.[1,3] Nonsurgical treatments for BCC are available, such as imiquimod 5% cream (Aldara®; Meda, Solna, Sweden), an immune response modifier. Studies have shown that imiquimod has a beneficial effect on small superficial and small nodular BCCs, and total or partial clearance is obtained.[4–9]
Adverse events that have been reported are mainly mild local skin reactions: these include erythema, itching, pain, erosions and excoriations. Systemic reactions are described as well.[4,5,7] Imiquimod has been used as an adjuvant treatment for MMS before.[10–12]
In this study we investigated the effect of a treatment with imiquimod 5% cream before MMS for medium-sized nodular (or nodular and partially superficial) BCC in the face. We hypothesized that this pretreatment could reduce the tumour size and could result in a smaller defect after MMS.
Materials and Methods
We included patients with histologically proven nodular (or nodular and partially superficial) BCC in the face. Patients above 18 years with a BCC of 1–5 cm in diameter were eligible to participate. All patients were included at the dermatology outpatient clinic at the Catharina Hospital in Eindhoven. Inclusion took place in the period between October 2007 and September 2011. All patients were randomly assigned in a ratio of 1 : 1 to the imiquimod group or control group according to a confidential computer-generated list (via http://www.randomization.com). This list was kept by the secretary; she informed the investigator about the type of treatment a patient would receive.
We excluded pregnant women, women who were breastfeeding, patients with recurrent BCC, aggressive growth pattern (squamous, morphoeiform, infiltrative), patients with BCC within 1 cm from the eyes, lips or mucosa of the nose, patients with another skin tumour within 5 cm of the target tumour, and patients with an allergy to imiquimod 5% cream or components of the cream. The study was approved by the Medical Ethical Committee and all patients gave written informed consent.
Patients were followed according to the intention-to-treat principle. Control visits were planned 3, 6 and 12 months after MMS; from then, follow-up took place according to the Dutch guidelines for BCC.
Baseline characteristics including age, sex, Fitzpatrick skin type and tumour localization were noted. Before treatment, the tumours were measured in two directions. The tumours were marked and then photographed. In addition, a template of the tumour was created with local landmarks, using a permanent marker on translucent paper divided into millimetre squares. A software program (Visitrak®; Smith & Nephew, Hull, U.K.) was used to calculate the exact area size in mm2 obtained with the template for all tumour and defect sizes. Defect sizes were measured prior to closure of the defects, while patients were lying down with their head and back slightly elevated. Measurement took place after coagulation had taken place and no correction was performed for skin relaxation.
Patients in the imiquimod group used the imiquimod 5% cream once a day, 5 days a week, for 4 weeks. The cream was applied at night, so that it was left in place for approximately 8 h. It had to be applied on the BCC and 1 cm around the tumour. Patients were asked to fill out a diary about the application of the cream and possible side-effects.
A control visit was planned after 2 weeks. Adverse events and local skin reactions were noted by the investigator. If no serious adverse events occurred, the patient was motivated to continue applying the cream. After treatment with imiquimod 5% cream for 4 weeks, adverse events were noted again during a control visit. Mohs micrographic surgery was performed 4–6 weeks after the last day of cream application by one of the Mohs residents and one of the three qualified Mohs surgeons of the Department of Dermatology. The control group only underwent MMS, at 12 weeks from baseline.
The tumours were measured, marked and photographed just before MMS was performed. After the MMS procedure, the defect was measured and photographed in both groups, and time needed for reconstruction was also measured.
The primary outcome was a difference in defect size after MMS between both groups. The increase in area from baseline lesion to post-MMS defect was calculated and compared between both groups. The secondary outcomes were differences in tumour size within the imiquimod group and between both groups. We also studied the number of Mohs stages and reconstruction times after MMS.
To calculate sample size, we used results from a previous study. The mean ± SD observed percentage increase in area from baseline lesion to post-MMS defect for the control group was 173 ± 134%. The mean ± SD percentage increase for the imiquimod group was 75 ± 104% (note: these numbers were obtained by pooling the data for the 4-week and 6-week dosing regimens). With a type 1 error rate set at 0·05 and a power of 90% to detect a difference of 98%, we needed 32 patients in each group. We assumed a drop-out rate of 10%, which led to a number of 35 patients in each group.
To analyse the data we used the software program SPPS version 19 (SPSS, Chicago, IL, U.S.A.). The Mann–Whitney U-test was used for continuous variables without a normal distribution. The independent t-test was used for variables with a normal distribution, and the chi square test was used for categorical variables.
Seventy patients, 46 men and 24 women, were included in the study. Thirty-five patients were placed in the imiquimod group, and 35 patients in the control group. The mean age was 69 and 68 years, respectively. Median tumour area at baseline was 95 mm2 in the imiquimod group and 110 mm2 in the control group. Baseline characteristics did not differ significantly between both groups. Most tumours in both groups were located in the H-zone (Table 1).
None of the patients was lost to follow-up or had to leave the study because of severe adverse events or other reasons. Median follow-up after treatment was 20 months for the control group and 19 months for the imiquimod group.
The median increase in area from tumour size at baseline to the post-MMS defect for the imiquimod group was 50%. The increase for the control group was 147%. This difference was statistically significant (P < 0·001) (Table 2). In two patients of the imiquimod group, total tumour clearance was clinically observed and MMS was not performed.
Within the imiquimod group, patients had a median decrease of tumour size (size of tumour at baseline, compared with tumour size before MMS) of 20 mm2. In the control group, median change in tumour size was 0. This difference was statistically significant (P = 0·02).
The median number of Mohs stages was 1 in both groups. In the imiquimod group the 75 percentile was also 1. In the control group the 75 percentile was 2. Therefore a tendency of a favourable effect for the imiquimod group was observed (P = 0·04).
The median reconstruction time in the control group was 30 min, as opposed to 20 min in the imiquimod group (P = 0·01). There were no significant differences between the groups concerning type of closure (Table 2).
The most important adverse events reported were local erythema, itching, crusting and irritation, with erythema occurring most often (Table 3). One patient, who had a tumour located on the proximal side-wall of the nose, reported irritation of the eye during the use of imiquimod cream. These complaints resolved completely after treatment.
None of the subjects needed to use pain medication or had to visit a general practitioner because of the side-effects. One patient reported severe diarrhoea during the use of imiquimod cream. In each group, one patient had a secondary bleeding after MMS.
This randomized controlled study showed a significant effect of imiquimod 5% cream as a pretreatment of MMS. We used imiquimod 5% cream with a shorter application period than is prescribed for the treatment of superficial BCC (6 weeks). With a shorter treatment period, fewer side-effects are reported.[4–7] In addition, it was not our goal to achieve complete clearance: our aim was to decrease the size of tumours and defects. Although clearance rates of imiquimod 5% cream are highest for superficial BCC, it has shown itself to be able to (partially) clear nodular BCC as well.[13–15] We focused our study on nodular (or partially superficial) BCC. The diagnosis was made by means of a biopsy that only represents a part of the tumour. It is known from literature that BCC tumours often consist of mixed subtypes and can have superficial areas.[11,16] Although the tumours in our study were histologically diagnosed as nodular BCC, it could be that the decrease in size was partially or mainly due to clearance of superficial parts. No aggressive tumour nests were found in the histology slides during the MMS procedures. Tumour size within the control group did not change during the 12-week period, from baseline to the MMS procedure. This supports the fact that BCCs grow very slowly, which is an important finding as we have waiting lists for MMS procedures of up to 3 months. In the imiquimod group, a significant decrease in tumour sizes was noticed, which resulted in significantly smaller defects after MMS (P < 0·001).
Torres et al. performed a study on imiquimod as a pretreatment of MMS for BCC as well. They compared pretreatment periods of 2, 4 and 6 weeks and control patients were treated with a vehicle. They reported significant reductions in the size of the target tumours and smaller surgical defects after MMS in patients treated with imiquimod 5% cream compared with patients treated with a vehicle. In another study, of Butler et al., a decrease in defect size was found as well, which was, however, not significant.
A treatment-free period of 6 weeks is advised after treatment with imiquimod, before excision or MMS is performed, to prevent the presence of excessive inflammation. In our study, the periods between the last day of imiquimod application and MMS were not exactly the same in all patients, and varied between 4 and 6 weeks. This difference in times could be important for our results. Interpreting fresh frozen sections of an MMS procedure is more difficult when there is still inflammation caused by treatment with imiquimod. It could lead to unnecessary extra Mohs stages, when there is doubt about clearance of the tumour, and the actual defect size could have been smaller.
One could argue to use imiquimod 5% cream as an adjuvant therapy after MMS, to clear remaining superficial areas. Then it would not interfere with the interpretation of the fresh frozen sections. It will need further investigation to see if defects then will still be significantly smaller, as parts of the superficial area will have already been cut out before the end of the MMS procedure. Some researchers state that a destructive therapy like imiquimod has a certain risk of incomplete cure, leaving behind independent tumour nests, which could lead to false-negative results if MMS is performed afterwards. Studies in which the complete area after treatment with imiquimod was excised did in some cases show remaining tumour nests which were found in the dermis.[5,19,20] We acknowledge this fact, but we believe risk is minimal, as MMS is performed around the tumour starting with a margin of 2–3 mm, taking subcutis with the first stage, and it shows nearly 100% of margins. If tumour nests did remain after treatment with imiquimod, they would have to be at a significant distance from the tumour if they had been missed in the MMS procedure. Moreover, no treatment provides a full 100% guarantee: recurrences are seen even after MMS. In order to lower these risks and as topical imiquimod is only approved for a low-risk histological type of BCC (superficial BCC), we excluded BCCs with an aggressive growth pattern. Patients are followed after treatment to screen for recurrences or new tumours; so far no recurrences have been seen. Thissen et al. used topical imiquimod after incomplete MMS and did not see any recurrences during a follow-up of 13–30 months.
Fewer Mohs stages were needed in the imiquimod group compared with the control group (P = 0·04). The number of Mohs stages could have been influenced by the operating Mohs surgeon. The size of the margin that was taken around the tumour was not standardized in this study and could have differed among the various surgeons. Fewer Mohs stages could reduce costs concerning MMS. In the study of Butler et al., 31 patients with nodular nasal BCC were randomized to imiquimod or vehicle treatment before MMS. The cream was applied for 6 weeks and after a treatment-free interval of 4 weeks MMS was performed. They did not find a significant effect of the pretreatment on the number of Mohs stages nor did they find a significant difference in costs.
Reconstruction time in the imiquimod group was statistically significantly shorter than in the control group. This could be related to the defect size, but the location of the defect and type of closure could be important as well. We compared both groups on localization and type of closure, and did not find significant differences for these variables (Table 2).
A pretreatment with imiquimod for 30 days costs 149 euros. Wanitphakdeedecha et al. reported about the costs of MMS and calculated that one Mohs stage costs U.S. $242 or 185 euros (exchange rate January 2012). This would mean that a pretreatment with imiquimod certainly is not more expensive than a regular MMS procedure. Next to costs that can be reduced when fewer Mohs stages are needed, dermatologists and supporting personnel will save time per patient that can be given to other patients and procedures. The pretreatment with imiquimod resulted not only in a tendency towards fewer Mohs stages, but also in significantly smaller defects, and significantly shorter reconstruction times. Taking these facts together, a higher level of efficiency and probably cost-effectiveness could be achieved, with more patients being treated on the same day. As a result, waiting lists will decrease as well. It will need further research to see whether these improvements will lead to a more cost-effective treatment.
Local inflammatory reactions were reported by the majority of patients, but none of them had to leave the study due to side-effects. Most adverse events consisted primarily of local reactions, with erythema and crusting occurring most often. In the literature, comparable figures are reported.[4,5,7] Sapijaszko reported that 87% of patients reported one or more side-effects. Besides local inflammatory reactions, one patient mentioned a systemic adverse event, diarrhoea. This has been described before.[4,5,7]
In two patients of the imiquimod group, total tumour clearance was concluded clinically, and MMS was not performed on these patients. They were seen at control visits and showed no signs of residual BCC. They were followed for 41 and 31 months, respectively, and still do not show signs of recurrence. Follow-up will be continued.
We cannot conclude about recurrence rates at this time. Five-year follow-up results will become available in the future. Median follow-up is 20 months for the control group and 19 months for the imiquimod, and no recurrences have been seen so far.
In conclusion, the application of imiquimod 5% cream as a pretreatment before MMS significantly reduces tumour sizes and surgical defect sizes in primary nodular BCCs in the face. Fewer Mohs stages and a significantly shorter reconstruction time are observed after the use of imiquimod 5% cream.
Long-term follow-up is necessary to be able to report on recurrence rates. Additional analyses on cost-effectiveness will give more insight into the clinical implication of this treatment process.