Surgical approaches represent the primary and most effective means of curative treatment and are the mainstay of treatment for localized BCC. Standard excision is typically utilized for lesions located in noncosmetically sensitive locations where tissue-sparing is not paramount. In low-risk locations such as the trunk and extremities, standard excision can achieve cure rates of over 95%.⁶,⁷ MMS, meanwhile, is the treatment of choice for tumors located in cosmetically sensitive or high-risk anatomic locations. It is also preferred for tumors that are recurrent or demonstrate high-risk, aggressive histology. MMS can achieve cure rates of up to 99% for primary tumors and 96% for recurrent tumors.⁸,⁹,¹⁰,¹¹ Figure 13.1.1 shows a BCC before and after MMS and reconstruction with a wedge excision and advancement flap, with an excellent cosmetic outcome.

ED&C is usually reserved for well-defined, low-risk primary lesions located in noncosmetically sensitive areas. For these tumors, cure rates upward of 95% have been demonstrated and comparable with primary excision.¹² ED&C should not be used for recurrent tumors or those with high-risk histologic growth pattern, for which cure rates as low as 40% have been observed.¹²,¹³ The technique should also be avoided for lesions that extend into the
subcutaneous fat, as this precludes the ability for proper tactile detection of a tumor-free dermal plane, as well as those that are located in areas with terminal hair growth, due to the potential risk of tumor extension down follicular structures.⁵ Figure 13.1.2 shows a typical hypopigmented atrophic scar from a superficial BCC after ED&C.

Nonsurgical treatment modalities are considered second-line treatment options. RT can achieve cure rates of over 90% for primary tumors but is generally reserved for patients who cannot tolerate surgery or for whom surgery is impractical, as it carries the drawback of poorer cosmetic outcomes compared with other treatments. RT is also used as an adjunctive modality postoperatively to reduce the risk of recurrence in high-risk patients. Importantly, RT should be avoided in patients with conditions predisposing to cutaneous malignancy and younger patients for whom long-term adverse effects are a consideration.⁵

Topical therapies, such as imiquimod and 5-FU cream, cryosurgery, and PDT, are reserved for nonsurgical candidates who cannot undergo RT as they offer inferior cure rates.⁵

Cryosurgery is not commonly used because of its association with unfavorable cosmetic outcomes, although it has the potential to penetrate more deeply into tumors than topical therapies.

Imiquimod and cryosurgery have only been demonstrated to be effective for superficial and nodular tumors, whereas the use of PDT and 5-FU is mainly limited to superficial tumors.

In general, the superficially acting topical therapies are associated with the most favorable cosmetic outcomes,¹⁷,¹⁸ with high patient satisfaction and little risk for scarring. In the only comparative trial of imiquimod, 5-FU, and PDT, all three modalities were found to yield similarly excellent cosmetic results.¹⁹ Given this advantage, topical modalities can prove to be a valuable therapeutic option for the aesthetically oriented patient. However, appropriate patient selection is critical, as all of these therapies are less effective than surgery and are reserved for BCCs with low-risk histology. The treatment of morpheaform or infiltrative tumors should be avoided due to the likelihood of insufficient depth of penetration of these medications.

Imiquimod. Imiquimod 5% cream is a topical immune response modifier that is Food and Drug Administration (FDA) approved for the treatment of primary superficial BCCs not larger than 2 cm in diameter located on the trunk, neck, or extremities excluding the hands and feet. Among the topical therapies, imiquimod has been demonstrated in a randomized controlled trial to have superior clinical efficacy compared with 5-FU and PDT for the treatment of superficial BCC.¹⁹,²⁰ The overall efficacy of imiquimod 5% cream has been well studied and substantiated for the treatment of superficial BCC. Initial large, randomized, double-blind, vehicle-controlled studies showed complete histologic clearance rates of 79% to 88% with an application regimen of once daily for 6 weeks, with rest periods as needed.²¹,²²,²³ Subsequent studies confirmed that a comparable clearance rate of 80% to 84% can be expected with the FDA-approved dosing regimen of five times weekly for 6 weeks.²⁴,²⁵ The efficacy of imiquimod 5% cream for nodular BCC has not been well established, however, and it is not FDA approved for this indication. There is some limited evidence that it may be effective with daily use for 12 weeks,²⁵ so a longer and more frequent treatment regimen is imperative if it is to be attempted for the treatment of nodular tumors.

Proper usage of imiquimod 5% cream entails application of the medication to the tumor as well as a 1 cm of normal skin surrounding it.²⁶ The most common adverse effects associated with imiquimod 5% cream are local application site reactions in the form of erythema, edema, itching, pain, erosion, crusting, scaling, and ulceration. These occur frequently but range in severity and are dose dependent. Skin inflammation resolves in the weeks following treatment, and treatment sites usually heal without scars. To prevent scarring, monitoring for side effects and decreasing application dosages to avoid excessive blistering are required. Occasionally, hypopigmented scarring is observed, but overall, cosmetic results are often perceived as excellent, making it an appealing treatment option for patients.²⁷ When used off-label for periocular tumors, conjunctivitis and ocular stinging are the most common ophthalmic side effects. Uncommonly, infection in the form of keratitis or preseptal cellulitis can also occur. To prevent these side effects, some advocate for the application of a lubricating or viscous gel in the conjunctival sac before treatment, frequent use of lubricating drops during treatment course, and copious irrigation with normal saline for any irritation.²⁸,²⁹

Photodynamic Therapy. PDT involves the application of a photosensitizing agent, usually aminolevulinic acid (ALA) or methyl aminolevulinate (MAL), to the skin followed by exposure to visible light for activation. Incubation times vary from 1 to 6 hours, and treatment of BCC requires a red light source operating in the 630-nm range for sufficient penetration. Numerous studies have investigated the efficacy of PDT for the treatment of primary and nodular BCC. Both ALA- and MAL-PDT have been shown to be effective and are able to achieve clearance rates of approximately 75% to 82% for superficial BCC.³⁰,³¹,³²,³³ Response rates for nodular tumors are lower, and infiltrative or recurrent tumors fare even more poorly, with cure rates as low as 40%.³⁴,³⁵,³⁶

A standardized protocol of two treatment sessions spaced 1 week apart is typically used for MAL-PDT, but treatment schedules with ALA-PDT are less well established.³⁷ A higher number of treatment cycles,³⁸ fractionated delivery of PDT,³⁹ and the practice of preprocedure deep curettage⁴⁰ may improve treatment response. Like imiquimod cream, PDT generally yields an excellent cosmetic outcome with little or no scarring. In randomized clinical trials, PDT has specifically been shown to have superior cosmetic outcomes compared with surgery³¹,⁴¹,⁴² or cryosurgery.¹⁷,³⁰ The most commonly observed adverse effects are erythema,
edema, erosion, and crust formation, which heal over 2 to 6 weeks following treatment. Postinflammatory hypopigmentation and hyperpigmentation are rarely observed.³⁷

PDT may be a particularly valuable treatment option for patients with basal cell nevus (Gorlin) syndrome, for whom multiple BCCs can cause overwhelming disease burden and render surgical modalities impractical and disfiguring. PDT has been shown to reduce tumor burden and may delay development of subsequent tumors in this these patients.⁴³,⁴⁴ European consensus recommendations regard MAL-PDT as safe and effective for superficial BCC of all sizes and nodular BCC <2 mm in thickness in these patients. Treatment algorithms should be tailored to the individual, and monthly treatments may be required in certain cases.⁴⁵

5-Fluorouracil. Like imiquimod cream, 5-FU 5% cream is another topical agent approved for the treatment of superficial BCC less than 2 cm in diameter, but data to substantiate its efficacy are lacking when compared with other treatment options. FDA approval was obtained based on an unpublished study of 113 superficial BCC lesions that demonstrated a 93% clearance rate. A subsequent study funded by the drug manufacturer showed a similarly promising histologic cure rate of 90% among 31 tumors on the trunk and limbs.⁴⁶ However, the mean time to clinical cure was 11 weeks, substantially longer than the FDA treatment recommendation of 3 to 6 weeks. The only study evaluating the long-term efficacy of 5-FU was a comparative prospective trial of 5-FU, PDT, and imiquimod. This study found a 3-year tumor-free survival of 68.2% for 5-FU, although this study used a shorter application regimen of twice weekly for 4 weeks²⁰ Adverse effects from 5-FU are generally mild and limited to erythema and erosion, with little risk of scarring.²⁰,⁴⁶