Imiquimod 5% is a toll-like receptor agonist approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of primary superficial BCCs with a diameter of less than 2cm. It is believed to induce IFN-α, tumor necrosis factor-α, and other cytokines that activate T helper 1 cells, which, in turn, induce an antitumor immune response.18

The first study to evaluate imiquimod in the treatment of superficial BCC was published in 1999.19 It was a clinical trial that compared 3 treatment regimens: imiquimod twice a day, imiquimod once a day, and imiquimod 3 times a week. Histologically confirmed complete response was observed in the 3 groups on completion of treatment. The complete response rate was 60% in the group of patients who received 2 doses a week, and 50% in the group that received treatment once a week.

A systematic review of treatment success in primary superficial BCC published in 2012 by Roozeboom et al.20 reported an estimated complete response rate of 86.2% (95% CI, 82%-90%) for imiquimod after a follow-up period of 6 to 19 weeks. The 1-year tumor-free survival rate based on pooled estimates from 23 studies was 87.3% (95% CI, 84%-91%). The authors concluded that imiquimod was an effective treatment for superficial BCC with a maximum diameter of 2cm.

The British Association of Dermatologists guidelines for the management of BCC rate the use of topical imiquimod with a quality of evidence I and a strength of recommendation A.21 The use of histologic verification22–26 and follow-up periods of up to 5 years27–29 in the studies reviewed to draw up these guidelines adds strength to the effectiveness of imiquimod in the treatment of superficial BCC. The final study reports drawn up by Gollnick et al.27,28 showed 5-year histologic clearance rates of 85.4% and 86.9% for patients with superficial BCC treated with imiquimod 5 times and 7 times a week for a period of 6 weeks, respectively.

In 2014, the results of a multicenter clinical trial involving 501 patients with superficial or nodular BCC (not including BCC of the nose, forehead, eyelids, or ears) randomly assigned to daily treatment with imiquimod for 6 weeks (n=254) or surgical excision (n=247) were published.30 After 3 years of clinical follow-up, 84% of patients in the imiquimod group and 98% of those in the surgery group had no signs of recurrence.

In brief, imiquimod can be considered an effective treatment alternative for patients with small, primary superficial BCCs at low-risk anatomic sites and for patients in whom surgery is contraindicated or who choose not to undergo surgery.31

Although topical 5-FU was the first topical treatment to receive approval from the FDA for the treatment of superficial BCC, the drug has not been widely studied in this cancer. 5-FU interferes with DNA synthesis by blocking the methylation of deoxyuridylic acid, thereby inhibiting thymidylate synthetase and consequently cell proliferation. The study that led to the approval of 5-FU by the FDA reported a success rate of 93% for the use of imiquimod in 113 superficial BCC lesions in 54 patients.32

A Dutch multicenter study published in 2013 evaluated the efficacy of 3 treatments for superficial BCC with a follow-up period of 12 months: topical 5-FU (twice daily for 4 weeks), imiquimod (once daily 5 times a week for 6 weeks), and PDT with methyl aminolevulinate (2 sessions separated by 1 week).33 The estimated overall success rates, assessed by the proportion of patients free of tumor recurrence at 3 months and 12 months, were 80.1% for 5-FU, 83.4% for imiquimod, and 72.1% for PDT.

In brief, topical 5-FU is an effective topical treatment for patients with primary superficial BCC at low- or medium-risk sites or for patients who are not candidates for surgery or who have high cosmetic expectations.32

PDT is another medical treatment used in BCC. It uses visible light to activate a photosensitizing agent, which can be aminolevulinic acid or methyl aminolevulinate (MAL), to produce reactive oxygen species that destroy tumor cells through an intracellular product known as protoporphyrin IX.34 Success rates of around 75% have been reported for PDT with MAL in studies that have compared efficacy and cosmetic outcomes over 1 year with that of conventional surgical excision for superficial BCCs.31,35

A systematic review from 2012 that analyzed 1583 patients with superficial BCC reported that the efficacy of PDT may depend to a large extent on the number of cycles used. The pooled estimate of complete response, for instance, increased from 76.6% to 79% (95% CI, 62%-90%) when repeated cycles were used. Tumor-free survival also increased from 76.2% to 84%.20

A comparison of the efficacy of PDT in terms of cosmetic outcome and safety with that of other treatments for primary BCC showed that compared with surgery, PDT was associated with a lower complete clearance rate (risk ratio [RR], 0.93; 95% CI, 0.89-0.98) and a higher probability of recurrence at 1 year (RR, 12.42; 95% CI, 2.34-66.02) and 5 years (RR, 6.79; 95% CI, 2.43-18.96).36

The study also showed that PDT has a higher complete clearance rate than placebo. No significant differences were observed with pharmacologic treatment (imiquimod and topical 5-FU) for complete clearance or 1-year recurrence, although PDT performed worse in the second case. One-year recurrence rates for PDT ranged between 6% and 44%, although lower rates were seen with multiple treatments (≥ 2 cycles on days 1 and 8). Clearance rates of between 76% and 79% were reported.36

PDT can be considered a treatment option for low-risk BCC (mainly small tumors, superficial tumors, tumors in low-risk locations) or for patients who are willing to trade a higher risk of recurrence for a better cosmetic outcome, or in whom surgery is contraindicated for medical reasons.36

IFN is one of several intralesional chemotherapy agents currently used in the management of BCC. It stimulates macrophages, natural killer cells, and lymphocyte-mediated cytotoxicity to induce an antitumor immune response.37

The first clinical trial with this drug included 172 patients with histologically confirmed noduloulcerative or superficial BCC who were treated with either intralesional IFN-α2b or placebo.38 The patients in the IFN group received 1.5 million international units (IU) 3 times a week for 3 weeks, resulting in a cumulative dose of 13.5 million IU. The cure rate was 86%.

A systematic review designed to analyze the evidence currently available for the treatment of BCC published in 2014 reported a histologic clearance rate of 85% for INF-α2b and excellent cosmetic outcomes in 83% of cases. The most common adverse effects reported by all patients were flu-like symptoms consisting of headache, myalgia, and nausea.12,37

Intralesional IFN can offer advantages over traditional techniques in the treatment of BCC, particularly when surgery is not an option or when the tumor is in a cosmetically delicate area.39

Radiation therapy is a classic technique that was used as a first-line treatment for BCC for several years. It is now, however, used frequently for a number of reasons.7,31 It is currently indicated as a second-line treatment for high-risk tumors or for patients in whom surgery is contraindicated.40,41

A retrospective analysis of 712 BCCs (631 nodular and 81 superficial tumors) treated with 5 sessions of superficial x-ray therapy at a total dose of 35Gy showed recurrence rates of 2% at 2 years and 4.2% at 5 years.42 In another study, a randomized clinical trial, comparison of surgical excision of 174 BCCs (primary facial tumors <4cm in diameter with a nonaggressive histologic subtype) and radiation therapy of 173 BCCs with similar characteristics showed a 4-year recurrence rate of 0.7% in the surgery group and 7.5% in the radiation therapy group.43

The results for the use of radiation therapy in BCC vary considerably in the literature, possibly because of differences in treatment regimens and the lack of an optimal regimen.44

Radiation therapy, however, has several disadvantages, including absence of histologic verification, long treatment times requiring multiple visits, cosmetic outcomes that tend to worsen with time (cutaneous atrophy and telangiectasias), and a risk of new radiation-induced BCCs.31

In short, radiation therapy is a valuable treatment option for patients with BCCs with a high risk of recurrence who are not candidates for surgery, patients aged over 60 years (due to the likelihood of long-term complications), and patients with primary or recurrent tumors. It can also be used as adjuvant therapy after surgery or in cases with perineural invasion or involvement of margins.

The authors declare that no tests were carried out in humans or animals for the purpose of this study.

The authors declare that no private patient data appear in this article.

The authors declare that no private patient data appear in this article.