Imiquimod Treatment of Superficial and Nodular Basal Cell Carcinoma: 12-Week Open-Label Trial K ETTY P ERIS , MD, n E LENA C AMPIONE , MD, w TAMARA M ICANTONIO , MD, n G EORGIANA C LARE M ARULLI , MD, w M ARIA C ONCETTA FARGNOLI , MD, n w AND S ERGIO C HIMENTI , MD Department of Dermatology, University of L’Aquila, L’Aquila, Italy; wDepartment of Dermatology, University of Rome ‘‘Tor Vergata,’’ Rome, Italy n
BACKGROUND. Imiquimod is an immune response modifier shown to be effective in basal cell carcinoma (BCC). OBJECTIVE. To evaluate the efficacy, tolerability, and response durability of imiquimod 5% cream in selected patients with superficial and/or nodular BCCs. METHODS. Seventy-five superficial and 19 nodular BCCs in 49 patients were treated with imiquimod once daily three times a week for up to 12 weeks. RESULTS. Of the 49 enrolled patients, 1 discontinued the study and 1 was lost to follow-up. After 12 weeks of treatment, a complete response occurred in 70 of 75 (93.3%) superficial BCCs and a partial response in 4 of 75 (5.3%) superficial BCCs.
Ten of 19 (52.6%) nodular BCCs cleared after 12 weeks, whereas 7 (36.8%) showed partial remission. Adverse side effects were limited to local skin reactions. Recurrence was observed in 2 of 70 (2.9%) successfully treated superficial BCCs 6 and 8 months after treatment discontinuation. No recurrence was detected in 68 of 70 (97.1%) superficial BCCs and in 10 successfully treated nodular BCCs after 12 to 34 months of follow-up (mean 23 months). In our patient population, treatment of superficial BCCs with topical imiquimod for 12 weeks produced an excellent clinical response overall, with complete remission maintained after a mean of 23 months.
CONCLUSIONS.
KETTY PERIS, MD, ELENA CAMPIONE, MD, TAMARA MICANTONIO, MD, GEORGIANA CLARE MARULLI, MD, MARIA CONCETTA FARGNOLI, MD, AND SERGIO CHIMENTI, MD, HAVE INDICATED NO SIGNIFICANT INTEREST WITH COMMERCIAL SUPPORTERS.
DESPITE THE effectiveness of surgical modalities for treatment of basal cell carcinoma (BCC), a medical need exists for effective biologic therapies in patients with multiple BCC lesions and in patients who are poor surgical candidates owing to systemic underlying disease (eg, cardiomyopathies, pulmonary insufficiency), wound healing disorders, needle or surgery phobia, or medication with blood thinners.1–4 In addition, a noninvasive, self-administered topical treatment may be preferred for lesions in older patients in whom aggressive treatments are unnecessary, for BCC lesions with nonaggressive histology, and for lesions that are difficult to excise because of their location and size. Imiquimod, an immune response modifier that shows antitumor and antiviral activity through stimulation of both innate and cell-mediated local immune responses, was initially introduced for treatment of genital warts (condylomata acuminata).5 Several reports have since demonstrated the therapeutic Address correspondence and reprint requests to: Ketty Peris, MD, Department of Dermatology, University of L’Aquila, Via Vetoio, Coppito 2, 67100 L’Aquila, Italy, or e-mail:
[email protected]. r 2005 by the American Society for Dermatologic Surgery, Inc. ISSN: 1076-0512 Dermatol Surg 2005;31:318–323
efficacy and good safety profile of topical imiquimod 5% cream in the treatment of cutaneous malignant neoplasms such as BCC,6,7 actinic keratosis,8–11 keratoacanthoma,12,13 squamous cell carcinoma,14–17 lentigo maligna,18,19 and cutaneous melanoma metastases.20–22 The first randomized double-blind pilot study evaluating imiquimod for treatment of BCC showed a complete response of target lesions in all 15 patients who received imiquimod cream 5% under dosing regimens of twice daily, once daily, and 3 times weekly.6 A series of phase II and III, multicenter randomized trials, as well as other open-label studies, subsequently assessed the clinical efficacy and tolerability of imiquimod for the treatment of BCCs.23–27 These studies differed in dosing regimens, which ranged from twice-daily to weekly applications, the overall duration of treatment (6–16 weeks), and the use of occlusion. The various studies reported a complete response in 69 to 100% of superficial BCCs and in 42 to 100% of nodular BCCs.6,7,23–27 Successful imiquimod treatment of multiple BCCs occurring in the context of nevoid basal cell carcinoma syndrome (NBCCS) has also been reported.28,29 In most
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studies, post-treatment surgical excision at the tumor site confirmed the absence of residual neoplastic cells.6,7,23,25–29 The excellent clinical results described in these reports suggest that imiquimod may represent a valid alternative treatment for both superficial and nodular BCC. We performed an open-label clinical trial to further evaluate the efficacy and tolerability of imiquimod 5% cream in selected patients with superficial and nodular BCCs. The objectives of our study were to determine whether topical imiquimod applied once daily three times a week for 12 weeks would further increase the response rate compared with that in previously reported 6-week studies and to assess long-term recurrences.
Patients and Methods Patients with superficial and/or nodular BCC lesions were selected for treatment with imiquimod 5% cream from all BCC patients who attended the outpatient dermatology clinic at the Department of Dermatology at the University of L’Aquila and the University of Rome ‘‘Tor Vergata,’’ Italy, from October 2000 to January 2003. Patients were eligible to participate in the trial if they had multiple or recurrent BCC lesions, if surgical excision was not feasible because of age or general health status, or if they requested treatment other than surgery. Women of childbearing potential were not included in the study. Written informed consent was obtained from all patients. The study protocol conformed to the ethical guidelines of the Declaration of Helsinki. In all cases, the clinical diagnosis of BCC was unequivocal and was further confirmed by digital dermoscopic analysis, which showed the presence of prototypic features specific for BCC.30,31 Pretreatment histopathologic examination was not performed in any BCC lesions owing to the clear-cut clinical and dermoscopic diagnosis, to a previous histopathologic diagnosis in recurrent BCC lesions, and, in some cases, to the patients’ refusal to undergo any type of surgical procedure, or to the small size of BCC lesions. The study consisted of a screening visit; a treatment period with regular visits at weeks 2, 4, 6, 8, and 12; and a follow-up period, with post-treatment clinical evaluation every 4 weeks for at least 12 months after treatment discontinuation. Pre- and post-treatment clinical laboratory evaluations included hematologic and blood chemistry examinations and urinalysis. Treatment consisted of topical application of imiquimod 5% cream without occlusion once-daily three times a week on alternate days. Treatment with imiquimod was continued until the BCC lesion was clinically cleared or until 12 weeks of treatment were completed.
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Efficacy and safety evaluations of the treatment were performed at each visit. The treated lesions were measured and photographed to assess the clinical efficacy. The clinical end point of the study was to assess clinical remission at the end of treatment and recurrences occurring during the post-treatment observation period. Post-treatment histopathologic examination was not performed. Efficacy was rated as (1) a complete response, clinically corresponding to disappearance of the BCC; (2) a partial response, clinically corresponding to a 40% and a o100% reduction in tumor size; (3) no response, defined as a o40% reduction in tumor size compared with the initial clinical examination; and (4) worsening, defined as an increase in tumor size from baseline. The presence and severity of symptoms such as pruritus and burning sensation and local skin reactions such as erythema, edema, induration, vesicles, erosion, ulceration, excoriation or flaking, and scabbing were evaluated by the investigators at each visit and were rated on a 4-point scale (0 5 none, 1 5 mild, 2 5 moderate, 3 5 severe).
Results
Patient Population Forty-nine patients with superficial and/or nodular BCC lesions (31 males, 18 females; age range 45–83 years, mean age 62.9 years) were included in the study and received the study drug. The patients had a total of 94 BCCs, including 75 superficial and 19 nodular BCC lesions. Individual lesions ranged in size from 0.5 to 6 cm (mean 1.3 cm). Target BCC lesions were located on the head and neck region (38), trunk (45), and lower (6) and upper (5) extremities. Multiple BCCs were present in 10 of 49 patients, including 2 patients with NBCCS and 1 patient who developed 10 superficial BCC lesions at the site of previous radiotherapy for a seminoma. Eleven BCCs (9 superficial and 2 nodular) in 11 patients were recurrent and had been previously treated with surgical excision (n 5 8), surgical excision followed by intralesional interferon (IFN)-a (n 5 1), cryosurgery (n 5 1), and CO2 laser (n 5 1).
Clinical Response to Therapy Of the 49 enrolled patients, 1 patient with two nodular BCCs discontinued the study because of severe local skin reactions and 1 patient with one superficial BCC was lost to follow-up. The overall complete response rate was 85.1% (80 of 94 BCCs), whereas partial remission was observed in 11.7% (11 of 94) of the lesions. No patients experienced no response or worsening during treatment.
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Figure 1. Two superficial basal cell carcinomas on the face of an 82-year-old woman (A) before treatment and (B) after 8 weeks of treatment with imiquimod 5% cream.
A complete response was achieved in 70 of 75 (93.3%) superficial BCCs in 26 patients treated with imiquimod once daily three times a week for up to 12 weeks (Figure 1), and a partial response was observed in 4 of 75 (5.3%) superficial BCCs in 4 patients. Of 70 successfully treated superficial BCC lesions, 26 of 70 (37.1%) regressed after 6 weeks of treatment, 30 of 70 (42.9%) cleared after 2 more weeks of treatment, and 14 of 70 (20%) regressed after 12 weeks of treatment. Complete clearance was seen in 10 of 19 nodular BCCs (52.6%) in 10 patients after 12 weeks of imiquimod treatment (Figures 2 and 3). Partial remission was seen in the remaining seven (36.8%) lesions. Two of the seven patients with partial remission were treated for an additional 4 weeks without further clinical improvement. No associations were observed between clinical response in successfully treated lesions and tumor size, the location and duration of the neoplasm, or previous treatment. Recurrence has been observed in 2 of 70
(2.9%) successfully treated superficial BCCs 6 and 8 months after treatment discontinuation. No recurrence was detected in the remaining 68 superficial BCCs and in 10 successfully treated nodular BCCs after a followup period of 12 to 34 months (mean 23 months).
Adverse Events The presence of at least one adverse local side effect was observed in 33 of 49 (67.3%) patients. None of the patients experienced systemic adverse events or lymphadenopathy. Local skin reactions consisted of erythema (31 of 49 patients; 63.3%), erosion (26 of 49 patients; 53.1%), ulceration (12 of 49 patients; 24.5%), vesicle formation (7 of 49 patients; 14.3%), and edema (3 of 49 patients; 6.1%). In addition, pruritus and burning were reported by 33 of 49 (67.3%) patients and 12 of 49 (24.5%) patients, respectively. Hyper- and hypopigmentation at the treatment site were each observed in 1 of 49 (2%) patients and in 15 of 49 patients (30.6%) 6 months after treatment discontinuation.
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Figure 2. Nodular basal cell carcinoma on the nose of an 80-year-old man (A) before treatment and (B) after 12 weeks of treatment.
All skin reactions, as well as pruritus and burning, were considered mild to moderate, according to a 4point scale, with the exception of a 67-year-old woman with a recurrent nodular BCC on the nose who had a severe local reaction with erythema, vesiculation, pus, and crusting. The patient recovered fully after application of mupirocin and completed the treatment with clearing of the BCC lesion.
Discussion Imiquimod belongs to a family of imidazoquinolines that have been shown to enhance innate and acquired immunity through stimulation and release of a wide variety of cytokines that are important in cellmediated local immune response, such as IFN-a; interleukin (IL)-1, -6, -8, and -12; and tumor necrosis factor a.32,33 Imiquimod also induces the functional maturation of Langerhans’ cells and increases their migration from skin to regional lymph nodes, a process that is crucial for antigen presentation in the
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Figure 3. Noduloulcerative basal cell carcinoma (A) before and (B) after 12 weeks of treatment. Post-treatment hypopigmentation can be observed.
development of adaptive immune responses.34 Lore and colleagues recently demonstrated that binding of imiquimod to Toll-like receptors 7 and 9 on plasmacytoid dendritic cells induces enhanced expression of IFN-a and IL-12p70 and a memory T-cell response.35 Although the mechanism of action of imiquimod needs to be further characterized, the potent antiviral and antitumor activities seem to be related to its immunomodulating effects. However, it has been recently demonstrated in nonmelanoma skin cancer cell lines that imiquimod can induce tumor-selective apoptosis through Bcl2-dependent mitochondrial cytochrome-c release and activation of caspases 9 and 3.36,37 In the last few years, several studies have evaluated the efficacy and tolerability of topical imiquimod for treatment of both superficial and nodular BCCs. Marks and colleagues performed a multicenter, randomized, open-label, dose-response trial in 99 patients with solitary superficial BCCs who received imiquimod 5% cream for 6 weeks.7 The results showed clinical and histopathologic regression in the majority of patients in each of the four treatment groups,
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ranging from 69.7% of patients (23 of 33) treated with once-daily application three times a week to 100% of patients (3 of 3) treated with twice-daily applications of imiquimod 5% cream. In another multicenter, openlabel, randomized, 6-week study conducted in Europe, patients with superficial BCC received once-daily application of imiquimod 2 or 3 days per week either with or without occlusion.25 Response rates of 87% and 76% were found when imiquimod was applied 3 days per week with or without occlusion, respectively. When imiquimod was applied 2 days per week with or without occlusion, response rates were 43% and 50%, respectively. Notably, occlusion did not significantly affect the response rate at either dosing frequency. Geisse and colleagues did not find a significant difference between two regimens of once-daily application of imiquimod 5 or 7 days per week.26 Other reports also described single cases of solitary or multiple superficial BCCs successfully treated with imiquimod.38,39 In our series, complete regression of superficial BCC was achieved in 70 of 75 (93.3%) lesions after topical application of imiquimod without occlusion, once daily three times a week for 12 weeks. The higher response rate we observed compared with those reported in previous studies25 appears to be directly related to the longer duration of therapy in our study—12 weeks instead of 6 weeks. We could not establish an optimal treatment schedule, and we suggest that imiquimod treatment for superficial BCCs should be tailored for each patient according to clinical response. If a good clinical response is observed during the first 6 weeks, treatment can be continued for an additional 6 weeks. Imiquimod treatment has also shown promising results in patients with multiple BCCs, who might represent a specific target for this therapeutic approach. Kagy and Amonette first described clearing of two superficial nonfacial BCCs in a 49-year-old man with NBCCS after 18 weeks of imiquimod treatment.40 More recently, a complete response was shown in 18 superficial BCCs of three patients with NBCCS treated with imiquimod 3 times per week for 6 to 8 weeks, with no recurrence observed after 12 months.28 In our two patients with NBCCS syndrome, 11 and 13 superficial BCCs, respectively, completely regressed after 4 to 12 weeks of imiquimod treatment, and no recurrence was observed after a follow-up period of 12 and 15 months. In addition, topical treatment with imiquimod for 12 weeks showed a 100% response rate in one of our patients who had developed 10 superficial BCCs at the site of previous radiotherapy. Several open-label studies evaluated the efficacy and tolerability of imiquimod in the treatment of nodular BCCs.23,25,27 A 6-week, randomized, vehicle-con-
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trolled study in Australia and New Zealand and a similar 12-week study in the United States compared four dosing regimens of imiquimod 5% (once daily for 3 or 7 days per week or twice daily for 3 or 7 days per week).23 The complete response rates in the once-daily 3 times a week dosing regimen were 59% and 60% in the 6- and 12-week studies, respectively. Sterry and colleagues reported 65% and 50% response rates at the 3 days per week dosing regimen with and without occlusion, respectively.25 Our findings of 52.6% complete response in nodular BCCs are comparable to those previously reported.23,25 In contrast to the results seen in the treatment of superficial BCCs, no further clinical improvement of nodular BCCs was observed with treatment continuation. Huber and colleagues, however, recently reported a 100% response rate in nodular BCCs using imiquimod 3 times a week for 12 weeks.27 Further studies on nodular BCC would be recommended to confirm the efficacy and the appropriate treatment schedule. Recurrences have not been extensively assessed after imiquimod treatment because most studies confirmed the efficacy of such therapy by post-treatment histopathologic examination.6,23,25–29 Recently, few studies described an absence of recurrence in successfully treated BCCs after a follow-up period of 5 to 13 months.24,28 In our patients, recurrence has been observed in 2 of 70 (2.9%) successfully treated superficial BCCs 6 and 8 months after treatment discontinuation. No recurrence was detected in the remaining 68 superficial BCC lesions and in all 10 successfully treated nodular BCCs after a follow-up period of 12 to 34 months (mean 23 months). In our study, mild to moderate local skin reactions occurred in most patients (67.3%), and no systemic side effects were observed. The presence of at least one local side effect was reported in 59 to 100% of patients.6,7,23–26 This has been shown to be closely related to the frequency of applications and only rarely requires discontinuation of treatment. Systemic adverse events such as fever, fatigue, headache, pain, nausea, arthralgia, and myalgia have been described in a very low percentage of patients as probably or possibly related to treatment.6,7,23–26 In conclusion, topical application of imiquimod 5% given once daily 3 days per week for 12 weeks appears to be effective and well tolerated for treatment of BCCs, particularly for the superficial type. This treatment has several advantages compared with a surgical approach, including patient self-administration and excellent cosmetic results. Topical application of imiquimod 5% should be considered in patients with multiple or recurrent lesions and in patients who are unsuitable candidates for surgery.
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