Has imiquimod 5% cream a role in the management of recurrent basal cell carcinoma?

ARTICLE

Auteur(s) : Ricardo Ruiz-Villaverde¹, Daniel Sánchez-Cano¹, Pilar Burkhardt-Pérez², Ramon Naranjo Sintes¹

¹Dermatology Unit, Complejo Hospitalario de Jaén, Jaén, Spain
²Dermatology Unit, Hospital Clínico San Cecilio, Granada, Spain

accepté le 5 Mai 2009

Basal cell carcinoma (BCC) is the most common malignant cutaneous tumour, with an incidence that has become progressively higher in Spain for the past few years [1]. Surgery continues to be the mainstay of treatment, although a necessity for less aggressive therapies has arisen due to an increasing aging population. Imiquimod (IMQ) is a potent cytokine inductor, mainly interferon, with immunomodulating properties over the innate and acquired immune systems [2]. Immunotherapy with IMQ 5% cream has proved to be effective in BCC, thus allowing an outpatient management [3, 4].

Surgical excision of the tumour with uninvolved surrounding tissue is currently deemed as the gold standard treatment modality [5]. Therapeutic outcome not only depends on the physician’s expertise, but also on the histological subset and the indemnity of surgical margins. When performed on superficial and nodular BCC, complete surgical excision has a 5-year recurrence rate of 3-14%, according to the sources consulted [6-8]. Lesions on the head and neck, and aggressive histological subtypes are more likely to recur, while preoperative curettage appeared to reduce the risk of incomplete excision in some studies. Mohs micrographic surgery (MMS), used in the management of those lesions larger than 2 cm in diameter, morphea-like, recurrent or localised on cosmetically difficult areas, features a low recurrence rate [9] – 1% in primary lesions and 6-10% in relapsing tumours –, although its usage is limited to only selected cases. Given the fact that MMS is not widely available, and there may be patients ineligible for surgery, we conducted a study on the efficacy of IMQ 5% cream in the treatment of recurrent BCC.

Materials and methodology

Subjects enrolled in the study had to meet the following inclusion criteria:

• a) Had a clinical diagnosis of recurrent BCC following conventional surgery;
• b) Had rejected to undergo a surgical procedure;
• c) Had accepted to be placed on IMQ, after a fully detailed explanation of the treatment, diagnostic procedures, frequency of follow-up, possible adverse effects, alternative therapeutic options and, finally, given their written consent;
• d) Had a relative contraindication to surgery owing to one or more of the following:
  • a) Patients on oral anticoagulants,
  • b) Patients on platelet aggregation inhibitors,
  • c) Patients with markedly deteriorated general well-being,
  • d) Patients with clinical evidence of significant unstable or uncontrolled chronic diseases.

Upon obtaining written consent, patients were prescribed IMQ 5% cream. We recommended this posology based on our previous results [3] in order to minimize the side effects and make the treatment more comfortable and tolerable for our patients, despite the posology labelled recommendations to use a regime dosage of 3 times/week during 6 weeks. All patients had a biopsy performed 10 weeks after the completion of treatment with IMQ 5% cream.

The variables included in the study protocol were the following: sex, age, use of platelet aggregation inhibitors or anticoagulants, time to tumour relapse since surgery, surgical margins in previous surgery, anatomical location, histological study 10 weeks after the end of treatment with IMQ, and finally, 1, 2 and 2± year relapse rate.

Results

Only 1 of the 34 patients (20 men and 14 women) was classified as being phototype III, while the rest were phototype II. Most of them (22 patients; 82.4%) admitted having used sun-blocks regularly, especially after having their tumour excised. On the other hand, 12 patients (35.3%) had platelet aggregation inhibitors and/or anticoagulants as part of their habitual medications.

Time to tumour relapse since surgery was over 1 year and a half in 22 patients (64.7%), less than 6 months in 4 patients (11.8%) and between 6-18 months in 8 patients (23.6%). Regarding anatomical distribution of the recurrent basal cell carcinoma, 17 patients had it on the nose (50%) and 8 located on the cheeks (23.5%). Nodular BCC was the diagnosis in 16 patients (47.05%), whereas superficial type was in found in 18 patients (53%). Histological tumour subsets and the percentage of excised lesions with tumour-free margins are shown in table 1.

Ten weeks after completion of treatment following the regimen described above, a skin biopsy specimen was obtained (figure 1). Only 2 patients had a persistent tumour. Recurrence rates at 10 weeks, 1, 2 and 3 years are displayed in table 2. Patients who had persistent tumours subsequently underwent a more appropriate surgical intervention according to tumour size and location. No systemic side effects developed in our patients and erythema, edema and mild serous crust were observed in most cases (25 patients; 74%).
Table 1 Histological subsets and surgical margins at the beginning the treatment with IMQ 5% cream.

Discussion and conclusion

Although conventional surgery is the technique most widely employed in Europe for the treatment of BCC, we should not undervalue curettage and electrodissection, which, when performed by experienced physicians, can yield cure rates of approximately 90%. This therapeutic modality has the drawback, however, of leaving the precise extent of tumour excision. This same disadvantage is also posed by two other therapeutic approaches increasingly used in dermatologists’ daily practice, namely photodynamic therapy (PDT) and immunomodulators such as IMQ [10].

Based on the fact that relapsing tumours usually have a higher potential to grow than those that do not relapse, and that there are more selective therapeutic modalities such as IMQ available, we report a case series of 34 patients treated with IMQ 5% cream. In this series, the one-year recurrence rate was over one year and a half in 65% of patients, tumours being preferentially located on the facial region.

In our case, IMQ yielded a more than acceptable outcome, with a three-year cure rate over 70%. This efficacy is comparable to that of other therapeutic modalities such as cryotherapy and PDT, with cure rates at 5 years of almost 75%. The latter has better outcomes when previous curettage is performed, or in non-treated tumours, whilst it is slightly inferior in relapsing ones.

The safety profile in our series was similar to that expected according to other case series and clinical trials. The highest intensity of side-effects observed in head and neck BCC may possibly be related to a greater incidence of other pre-malignant lesions in these locations, which may also respond to IMQ cream. We believe that several lines of research have been started in order to minimise these adverse effects, which may occasionally result in the discontinuation of an otherwise highly effective topical therapy for the treatment of BCC [11].

Lastly, we believe it important to redefine current practice guidelines for the treatment of primary or relapsing BCC, where IMQ might occupy an outstanding place in the treatment of BCC patients with important associated co-morbidities.

Acknowledgements

References

2 Novak N, Yu CF, Bieber T, Allam JP. Toll-like receptor 7 agonists and skin. Drug News Perspect 2008; 21: 158-65.

3 Bukhardt Pérez MP, Ruiz-Villaverde R, Naranjo Díaz MJ, Blasco Melguizo J, Naranjo Sintes R. Basal cell carcinoma: treatment with imiquimod. Int J Dermatol 2007; 46: 539-42.

4 Vidal D, Matías-Guiu X, Alomar A. Fifty-five basal cell carcinomas treated with topical imiquimod: outcome at 5-year follow-up. Arch Dermatol 2007; 143: 266-8.

5 Bøgelund FS, Philipsen PA, Gniadecki R. Factors affecting the recurrence rate of basal cell carcinoma. Acta Derm Venereol 2007; 87: 330-4.

6 Rodriguez-Vigil T, Vázquez-López F, Perez-Oliva N. Recurrence rates of primary basal cell carcinoma in facial risk areas treated with curettage and electrodesiccation. J Am Acad Dermatol 2007; 56: 91-5.

7 Silverman MK, Kopf AW, Grin CM, Bart RS, Levenstein MJ. Recurrence rates of treated basal cell carcinomas. Part 1: Overview. J Dermatol Surg Oncol 1991; 17: 713-8.

8 Silverman MK, Kopf AW, Grin CM, Bart RS, Levenstein MJ. Recurrence rates of treated basal cell carcinomas. Part 2: Curettage-electrodesiccation. J Dermatol Surg Oncol 1991; 17: 720-6.

9 Bath-Hextall F, Bong J, Perkins W, Williams H. Interventions for basal cell carcinoma of the skin: systematic review. BMJ 2004 Sep 25; 329: 705. Epub 2004 Sep 13.

10 Argila D, Rodriguez-Nevado I, Chaves A. Carcinoma Basocelular: respuesta al tratamiento como imiquinmod 5% crema. Actas Dermosifiliol 2003; 94: 155-60.

11 Ezughah FI, Dawe RS, Ibbotson SH, Fleming CJ. A randomized parallel study to assess the safety and efficacy of two different dosing regimens of 5% imiquimod in the treatment of superficial basal cell carcinoma. J Dermatolog Treat 2008; 19: 111-7.