Topical Fluorouracil Therapy for Basal Cell Carcinoma

Abstract

Basal cell carcinoma is a nonmelanoma skin cancer and is the commonest malignancy of the skin. It accounts for approximately 80% of all skin cancers and is encountered frequently in daily clinical practice. The nonsurgical methods in the treatment of basal cell carcinoma gain more and more attention due to the increasing incidence of the tumor and the aging population. The authors hereby summarize the therapeutic place of topical 5-fluorouracil in the treatment of basal cell carcinoma. They review the mechanism, effectiveness of the therapeutic agent, how it should be applied by the patient, and the possible side effects. The chapter is also illustrated with cases.

1. Introduction

Basal cell carcinoma (BCC) accounts for 80% of all nonmelanoma skin cancers and is the most common malignant tumor in the Caucasian population [1]. The treatment of basal cell carcinoma depends on the tumor, the individual risk factors (like age, comorbidities, performance status, and preference), the available treatment options, and the preference or expertise of the treating clinician/physician.

The goal of treatment is the complete removal of the tumor with the least cosmetic and functional impact [2]. Treatment modalities can be divided into surgical and nonsurgical methods. Surgical treatments are standard excision, microscopically controlled surgery or Mohs micrographic surgery, curettage, electrodessication, cryosurgery, and laser therapy. Nonsurgical therapies include topical treatments (5-fluorouracil, imiquimod), radiotherapy, photodynamic therapy, electrochemotherapy, and systemic therapy (vismodegib, sonidegib, cemiplimab, pembrolizumab). Several factors influence the choice of which treatment will be sufficient. A new classification proposed by European consensus-based interdisciplinary guidance divides the tumors into two groups based on their difficulty to treat (“easy-to-treat” (common) BCC vs. “difficult-to-treat” BCC). The first line treatment of BCCs, according to the international guidelines, is the complete surgical excision with histological confirmation of the subtype and margins of the tumor.

Microscopically controlled surgery should be chosen for high-risk BCC, recurrent BCC, and BCC in critical anatomical sites [3]. If the clinical-dermoscopic examination shows features of superficial BCC (sBCC) without any high-risk BCC features, then topical therapies and other destructive therapies can be considered, though the cure rate is lower than with surgical treatment.

Another important consideration of treatment choice is the risk of recurrence. sBCCs treated with nonsurgical methods show a higher risk of recurrence compared to surgical treatment with available histopathology.

Also, when choosing a nonsurgical method, the localization of sBCC should be taken into consideration as the recurrence of the tumor on the back has a better prognosis and is easier to manage than a recurrence of a high-risk BCC on the face [2, 3].

When deciding whether to treat a superficial basal cell carcinoma surgically or nonsurgically, our therapeutic decision is influenced by several factors of the patient such as age, comorbidities, medications, and social circumstances. Older people often refuse surgical interventions due to the inconvenience.

2. Superficial basal cell carcinoma clinical and dermoscopic features

Superficial BCC is the second most common clinical subtype, accounting for up to 15% of cases [4]. Superficial BCCs appear most commonly on the trunk and extremities, in contrast to the other subtypes, which favor head and neck localization. The mean age at diagnosis is 57 years, suggesting that this subtype occurs at a younger age compared to other subtypes [5]. sBCC typically appears as a well-circumscribed, scaly, pink-to-red macule, patch, thin papule, or thin plaque. It may show as a crust or a thin rolled border consisting of fine translucent small papules. Areas of spontaneous regression can occur, leaving behind atrophic, hypopigmented areas. Variable amounts of melanin pigment may be present [6].

Dermoscopic features of superficial basalioma are short-fine vessels, multiple small erosions, and shiny white structures. In addition, 79% of lesions present with the shiny white-red structureless background. When pigmentation is present, it most commonly appears as multiple brown dots and globules, spoke wheel, and leaf-like areas [7].

3. Topical therapies in the management of superficial basal cell carcinomas

The two most common topical treatments in the management of basal cell carcinoma are imiquimod and 5-fluorouracil-containing cream, and the combination of these therapies with other modalities.

Nowadays, other novel topical therapies are under investigation, for example, topical hedgehog pathway inhibitors (HPI) (sonidegib, patidegib) and histone deacetylase (HDAC) inhibitors (vorinostat, remetinostat). They are targeting the molecular inhibition of aberrantly overactivated hedgehog signaling. A phase II study of sporadic nodular BCC and superficial BCC treated with topical sonidegib was terminated early due to a lack of efficacy [8]. A phase I study for a novel topical HPI, CUR61414, also did not show efficacy [9]. Patidegib 2% or 4% gel was being evaluated in several clinical trials for patients with basal cell nevoid syndrome (BCNS, Gorlin-Goltz Syndrome) and in non-syndromic patients with high-frequency BCCs (NCT02762084, NCT02828111). The results of both trials demonstrated that patidegib 2% gel has a higher clinical (reduction of 51.29% in the number of tumors) and molecular (reduction of −56.3% in the GLI1mRNA levels) efficacy on BCC, with less AEs, than the 4% gel [10]. Remetinostat 1% gel applied three times daily for 6 weeks, was evaluated in phase II open trial of 25 patients with 33 BCCs. The pathological resolution was seen in 54.8% of tumors, but response varied by histological subtype with 100% of sBCCs, 68.2% of nBCCs, and 66.7% of iBCCs responding. No serious adverse events were reported. The most common side effect was treatment site dermatitis [11]. Topical HPIs and HDAC inhibitors are still being investigated even though they are not yet clinically available [12].

Imiquimod is an immunomodulator drug used topically against cutaneous viral infections and tumors. The United States Food and Drug Administration approved imiquimod under the brand name Aldara in 1997 for the treatment of genital and perianal warts, and the treatment of typical, nonhyperkeratotic, and nonhypertrophic actinic keratoses on the face or scalp in immunocompetent adults. The FDA approved imiquimod for the topical treatment of sBCC in 2004, specifically biopsy-proven primary sBCC in immunocompetent adults with largest diameter of 2.0 cm, located on the trunk (barring anogenital region), neck, or extremities (excluding hands and feet) in immunocompetent adults when surgical methods are not available or inappropriate [13, 14]. Imiquimod acts through the toll-like receptor (TLR) 7 and 8. It activates both the innate and the adaptive immune systems and enhances the production of cytokines and natural killer cells, the proliferation of B lymphocytes, and the activation of Langerhans cells. This treatment causes inflammation at the tumor site, due to stimulation of the immune response, resulting in erythema, edema, scaling, and erosions. In a prospective trial, superficial BCCs treated with imiquimod cream 5% once daily seven times per week for 6 weeks showed a 5-year cure rate of 85% [15]. In a phase III randomized controlled trial treating superficial BCC and nodular BCC with 5% imiquimod applied once daily 5 days a week for 6 weeks showed an 84% cure rate at 3 years [16].

3.1 Fluorouracil

5-fluorouracil (5-FU) is an antimetabolite that impairs DNA replication by blocking the synthesis of thymidylate. Systemic use of 5-FU is FDA/EMA-indicated for treating gastric adenocarcinoma, pancreatic adenocarcinoma, breast carcinoma, and colorectal adenocarcinoma. Topical 5-FU is commonly used as a first-line treatment for malignant and premalignant skin conditions [17]. 5-FU first appeared in 1957 as a new chemotherapeutic drug. In the early 1960s, topical use of 5-FU showed cytotoxic effects in some skin cancers and precursor lesions. In 1970, FDA approved 5-FU (in 1% and 5% formulations) for topical use [18]. The indication for therapy by 5-FU is the nonmelanoma skin cancers and their precursor lesions. We have good evidence-based data in the treatment of actinic keratosis, especially in the field treatment [19], but the evidence in the treatment of keratoacanthomas and squamous cell carcinoma in situ is limited [20]. Later in this chapter, the studies with 5-FU in the treatment of sBCCs will be mentioned.

3.1.1 5-Fluorouracil mechanism of action

As mentioned earlier, 5-fluorouracil belongs to the antimetabolite chemotherapeutic drugs. 5-FU is a heterocyclic aromatic organic compound with a structure similar to that of the pyrimidine molecules of DNA and RNA; it is an analog of uracil with a fluorine atom at the C-5 position in place of hydrogen [18]. It has three main methods of action:

1. 5-FU is a thymidylate synthase inhibitor. Thymidylate synthase (TS) catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythimidine monophosphate (dTMP). 5-FU is transported into the cell, where 5-FU is converted to fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine triphosphate (FdUTP), and fluorouridine triphosphate (FUTP). The normal synthesis and functioning of DNA and RNA are affected by these abnormal metabolites by forming a stable complex with thymidylate synthase, leading to the inhibition of deoxythymidine monophosphate (dTMP) production. The cytotoxicity is due to the impairment of DNA replication and repair because of the depletion of dTMP, so the rapidly dividing tumor cells undergo death owing to the lack of dTMP [21].

2. 5-FU is a pyrimidine analog that can be misincorporated into RNA and DNA in place of uracil or thymine. The abnormal 5-FU antimetabolites are misincorporated into DNA, which demands excision and repair of DNA. The increased requirement of DNA repair leads to DNA strand breaks and ultimately cell death in mammalian cells [22]. 5-FU can also be misincorporated into RNA and interfere with many aspects of RNA function, inhibiting the processing of pre-rRNA into mature rRNA, modification of tRNAs, and the inhibition of the splicing of pre-mRNA [23].

3. Another hypothesized mechanism of action is the interference with p53. p53 induce cell-cycle arrest and apoptosis in cells with DNA damage. Topical administration of 5-FU may result in stimulation of p53-mediated apoptosis of the rapidly proliferating cells found in dermatological lesions with altered p53 expression like sBCC, actinic keratosis, and squamous cell carcinoma [24]. In a study gene and protein expression of various molecules were measured after topical fluorouracil treatment. They observed an increase in keratin 16, interleukin-1b, matrix metalloproteinase-1 and -3 mRNA levels. These latter molecules are also increased in the wound healing process, suggesting that after damage fluorouracil may be inducing a healing response as well [18, 25].

3.1.2 Topical formulations

In the case of topical application cytotoxicity with 5-FU occurs only in the rapidly proliferating cells of abnormal skin, leaving normal skin cell types relatively unaffected. A hypothetical method of action of topical 5-FU is the inhibition of TS activity completely in actinic/injured skin [20].

5-FU is available in the following forms: 0.5%, 1%, 2%, 4%, and 5% cream and there is a combination of 0.5% 5-FU + 10% salicylic acid.

In Europe, topical 5-fluorouracil is currently marketed in two different concentrations 0.5% and 5%. The 0.5% solution contains 10% salicylic acid and is indicated for the topical treatment of slightly palpable and/or moderately thick hyperkeratotic actinic keratosis in immunocompetent adult patients, as well as to treat warts. The 5% cream formula (Efudix®) is indicated for the topical treatment of superficial premalignant and malignant skin lesions; keratoses, including senile, actinic and arsenical forms, keratoacanthoma, Bowen’s disease, and superficial BCC [26].

In the USA, Efudex® Solution contains 2% or 5% fluorouracil. Efudex® cream contains 5% fluorouracil. They are approved for the treatment of actinic keratosis (AK) using the 5% fluorouracil cream in the treatment of sBCCs. The other available 5-FU-containing creams are administered in AK treatment, for example, Fluoroplex® 1% topical cream twice daily, for a treatment period of 2–6 weeks, Tolak® 4% cream once each day for 4 weeks, and Carac ® cream once daily for 4 weeks.

Among these preparations, only 5% 5-FU cream is registered to treat sBCCs [19].

3.1.3 Studies on efficacy of 5-FU in the treatment of superficial BCC

Topical 5-FU has been used in the treatment of basal cell carcinoma since the 1960s. In the early studies, the concentration of 5-FU varied between 1 and 30%, the application length was approximately 6 weeks or more. The reported clearance rate was 56–80% and only one study claimed 90% in which the concentration of 5-FU was 30% [27, 28, 29, 30]. The higher concentration was linked to more frequent and severe side effects. In 1970, 5% 5-FU was the first topical therapy approved by the U.S. Food and Drug Administration for the treatment of superficial BCCs. This approval was based on a study of 113 superficial BCC lesions in 54 patients, which demonstrated a 93% complete clearance rate [31]. The recommended mode of application is twice daily, at least for 3–6 weeks. Since then, few clinical trials have been conducted with 5-FU cream for sBCCs.

In 2007, a clinical study was performed where the authors evaluated, with a histologic endpoint, the efficacy, tolerability, cosmetic outcome, and patient satisfaction of 5% 5-FU therapy in superficial BCC. The 5-FU cream was applied twice daily for up to 12 weeks. The treated lesion was excised and histologically examined 3 weeks after the end of treatment. The histologic cure rate was 90% and the therapy was well tolerated with good cosmetic outcomes [32].

In a single-blinded, randomized controlled multicenter trial, conducted in Netherlands, patients were assigned for treatment with methyl aminolevulinate-photodynamic therapy (MAL-PDT, two sessions with an interval of 1 week), imiquimod cream (once daily, five times a week for 6 weeks), or fluorouracil cream (twice daily for 4 weeks). 601 patients were enrolled in the study. The proportion of patients, tumor-free at both 3- and 12-month follow-up was 72.8% (95% CI 66.8–79.4) for MAL-PDT, 83.4% (78.2–88.9) for imiquimod cream, and 80.1% (74.7–85.9) for fluorouracil cream. The authors concluded that topical fluorouracil was non-inferior and imiquimod was superior to MAL-PDT for the treatment of superficial basal-cell carcinoma [33].

The 5-year follow-up results of this study were presented in 2018. The authors found that the probability of tumor-free survival was 62.7% for MAL-PDT therapy (95% confidence interval [CI] = 55.3–69.2), 80.5% for imiquimod (95% CI = 74.0–85.6), and 70.0% for 5-fluorouracil (95% CI = 62.9–76.0) after 5 years of treatment. The hazard ratio for treatment failure of imiquimod and 5-fluorouracil were 0.48 (95% CI = 0.32–0.71, P < 0.001) and 0.74 (95% CI = 0.53–1.05, P = 0.09), respectively, when compared with MAL-PDT therapy. Compared with 5-fluorouracil, imiquimod showed a hazard ratio of 0.65 (95% CI 0.43–0.98, P = 0.04). In summary, 5 years after treatment, 5% imiquimod cream was proven to be superior to both MAL-PDT and topical 5-FU cream. Based on these findings, the authors recommend the use of 5% imiquimod cream as the first choice for noninvasive treatment in most primary superficial basal cell carcinomas [34].

In a recent retrospective study, 350 patients with sBCC and 411 in situ squamous cell carcinoma were enrolled. In the treatment of epidermal carcinomas surgical, destructive therapy or topical 5% FU was used. In a comparison of all methods, treatment with 5-FU had the most failures (12.5%) for sBCC, although compared with the failure rates of surgical (3.7%) and destructive (5.2%) modalities, differences did not reach statistical significance. Regarding this real-world data, the outcomes of topical 5-FU for both SCCIS and sBCC showed an overall success rate of greater than 90% (92.9% for SCCIS and 87.5% for sBCC) in a cohort with a mean clearance follow-up of 41 months. The authors concluded that 5-FU is an appropriate nonsurgical method for sBCC, although lesion and patient factors must be considered [35].

3.1.4 Combination therapies with 5-fluorouracil

By altering the skin barrier, there is a possibility to enhance the penetration of the chemotherapeutic drug. Different chemicals and physical tools can increase the efficacy of 5-FU like occlusion [36], microemulsions and liposomes [37, 38], microneedles [39], iontophoresis, electroporation [40], laser-assisted drug delivery [41, 42], salicylic acid, and cryotherapy [43].

In a case study series with two patients, 0.5% 5-fluorouracil and 10% salicylic acid (5-FU-SA) were used once a day at night for 6 weeks for multiple pigmented sBCCs. After 6 weeks of application, clinical and dermoscopical examination confirmed complete regression of the lesions, which was also confirmed by the histopathological findings. No recurrences were seen at 6 months of follow-up. The authors attributed the good result to the better penetration of 5-FU induced by the keratolytic effect of salicylic acid [44].

In a study, ablative fractional laser (AFL) was used followed by a single application of topical 5% 5-FU under occlusion for 7 days for 30 primary sBCC and SCCis lesions, measured less than 2 cm on the trunk and extremities. Histologic clearance was 87% overall, 100% (16/16) for SCCis vs. 71% for sBCC [41].

In another follow-up study, ablative fractional laser (AFL) assisted delivery of cisplatin and 5-FU in low-risk BCCs showed complete tumor clearance of 89% and 79% at 6 and 12 months, respectively. The clearance rate for sBCCs 1 year after treatment was 100% and lower for nodular BCC at 69% [42].

In a study by Soong et al., sBCCs and SCCis were treated with cryotherapy (liquid nitrogen, 10 s, 2 mm margins, distance of 1–2 cm). After a 1-month healing period patients completed a 3-week course of 5% 5-FU applied twice daily. Among the sBCCs, 30 lesions of the 34 that were assessed, demonstrated no evidence of recurrence at a mean follow-up time of 6.6 months [43].

3.1.5 Systemic absorption of topical 5-FU

The commercially available formulations show poor skin permeation and retention of 5-FU and cytotoxicity occurs only in the rapidly proliferating cells of abnormal skin.

Dillaha et al. found that the cutaneous absorption rate after topical application of 5-FU was approximately 6% in their study, a too small amount to cause systemic side effects [45]. According to the Efudix package insert, application on skin areas over 529 cm² (23 × 23 cm) is not recommended [46]. In affected skin, the rate of absorption was raised to about 15–75 times that of healthy skin but this quantity of 5-FU in a large area like 200 cm², could still be considered as unable to induce systemic toxicity [47]. In a comparison of the pharmacokinetics of 0.5% fluorouracil and 5% fluorouracil in actinic keratosis, it was found that the drug plasma concentration was detectable 60% more often in the 5% FU group and the cumulative amount excreted in the urine of the 0.5% fluorouracil group was approximately one-fortieth that of the 5% fluorouracil group. The side effects were less in the 0.5% group [48]. New drug formulations like nanostructured lipid carrier-based hydrogels can enhance the 5-FU penetration potential into the epidermis and dermis layers in in vivo studies and can possibly reduce systemic access and side effects compared to 5-FU conventional formulations such as cream, gel, and ointment [49]. Dihydropyrimidine dehydrogenase (DPD) is a key enzyme involved in metabolizing and eliminating fluorouracil. Systemic drug toxicity is increased in patients who have reduced activity of DPD, because they are unable to convert 5-FU to a biologically inactive metabolite. In these cases, DPD activity determination has to be considered, but the incidence of this is very low [50].

3.1.6 Side effects of topical 5-FU

Normal skin reactions to the treatment are redness, dryness, tenderness, and later crusts appear with erosions and minimal bleeding (Figures 1 and 2). The clinical manifestation of response usually occurs in the second week of 5-FU treatment.

Figure 1.

45-year-old female patient with multiple sBCCs treated with 5% 5FU cream. Lesion located on the chest clinical and dermoscopy picture (A). At 2 weeks of treatment, moderate inflammation and ulceration are depicted in the photos (B). Two weeks after cessation of therapy, complete healing of the lesion and no sign of malignancy on the dermoscopic image (C).

Figure 2.

89-year-old female patient with basal cell carcinoma on the left cheek. The lower part of the lesion was more infiltrative (A). Linear vessels and multiple erosions were seen with dermoscopy (B). Two weeks after the initiation of 5% 5-FU cream inflammation was already seen (C). Later, oozing and crusting occurred (D). Three weeks after cessation of 5-FU treatment, complete regression of BCC (E).

The most common side effects from topical 5-FU include irritant dermatitis with associated erythema, dryness, pain, burning, and itching (Figures 3 and 4). Other side effects are hyperpigmentation, hypopigmentation, onycholysis, photosensitivity, and telangiectasia. If the erosions become superinfected, secondary bacterial infections can occur. Applying it on the face can trigger the reactivation of previous diseases, such as herpes simplex virus, rosacea, or seborrheic dermatitis [51].

Figure 3.

Irritative contact dermatitis is caused by 5% 5-FU cream, when applied to more areas than recommended.

Figure 4.

Irritative contact dermatitis by 5% 5-FU cream (A), and 2 weeks after application of topical steroid (B).

More severe topical adverse events can be allergic contact dermatitis, with redness, swelling, papulation, vesiculation, oozing and weeping, and even blistering [52].

Extreme inflammatory skin reaction has been reported when it is applied under wraps, which increases the contact time and penetration of 5-FU into the skin [53].

A life-threatening case of toxicity has been reported after topical 5% 5-FU by Johnson in 1999 [54], and one with the lower-strength 0.5% 5-FU [55]. Both of these patients suffered from dihydropyrimidine dehydrogenase deficiency.

In the management of the side effects, the first step is the withdrawal of the 5-FU. Analgesics, moisturizers, and if there are severe erosions appropriate dressing can be given to the patients, in the case of superinfection antibiotics should be introduced. In severe irritant or allergic contact dermatitis topical steroids may be administered.

3.1.7 Administration of 5-fluorouracil

The adequate application of 5% 5-FU results in maximum efficacy and minimal side effects. Before applying the cream, the area to be treated should be washed with water and dried. Afterward the cream is applied thinly with a cotton ball or with the tip of the finger. If no gloves are worn, the hands should be washed immediately.

The cream should cover the area to be treated and can go max 2–3 mm beyond the visible border of the lesion. The area to be treated at a time cannot exceed 23 cm × 23 cm. Larger areas should be treated one section at a time. The cream should be used twice daily for 3–4 weeks, but this may be extended until there is a marked inflammatory response, preferably with some erosions. Exposure to UV radiation (e.g., natural sunlight, tanning salon) should be avoided.

4. Conclusions

Even though surgical treatment is the first choice of care for BCCs, 5-fluorouracil cream in 5% concentration is a good treatment option for sBCCs in certain circumstances. These include patients who wish to avoid procedures or are not good surgical candidates or have many sBCCs. Disadvantages of topical therapy are the lack of histological control and the relatively limited depth of action, therefore 5-FU generally is not recommended in other types of BCCs. Although there are some case study series of combination therapies to enhance the penetration of 5-FU, but further studies are needed.

Today, we have only one available study on long-term follow-up, where the tumor-free survival rate was 70% at 5 years. Comparing the efficacy of 5% 5-FU to imiquimod with the same indication, the latter was shown superior. The advantage of 5-FU over imiquimod is that it is less expensive. To choose the appropriate topical agent for the treatment of sBCC, these factors and patients’ preferences should be taken into account.

Acknowledgments

The research was financed by the Thematic Excellence Program 2021 Health Sub-programme of the Ministry for Innovation and Technology in Hungary, within the framework of the EGA-10 project of the University of Pécs.

Conflict of interest

The authors declare no conflict of interest.