Swiss Recommendations for Cutaneous Basal Cell Carcinoma

Basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer in Switzerland and worldwide. Most BCCs can be treated in a curative setting. However, patients can develop locally destructive and, rarely, metastatic tumors that require a different treatment approach. The clinical subtype of individual lesions provides prognostic information and influences management decisions. Surgical excision, topical therapies, and radiotherapy are highly effective in the majority of subtypes as well as in low-and high-risk diseases. For patients with low-risk diseases and superficial tumors not amenable to surgery, several nonsurgical alternatives are available. Systemic therapy is indicated for high-risk BCCs, which are not amenable to either surgery or radiotherapy. Hedgehog pathway inhibitors (HHI) are currently approved. Other therapeutic options such as immune checkpoint inhibitors show promising results in clinical trials. This first version of Swiss recommendations for diagnosis and management of BCC was prepared through extensive litera-ture review and an advisory board consensus of expert dermatologists and oncologists in Switzerland. The present guidelines recommend therapies based on a multidisciplinary team approach and rate of recurrence for individual lesions. Based on the risk of recurrence, two distinct groups have been identified: low-risk (easy-to-treat) and high-risk (difficult-to-treat) tumors. Based on these classifications, evidence-based recommendations of available therapies are presented herein.

# Introduction

## Definition and epidemiology
Basal cell carcinoma (BCC) is a type of epithelial skin cancer, which usually follows a slow, progressive course [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref]. It is the most frequently diagnosed cancer in Caucasian populations [bib_ref] Epidemiology of basal cell carcinoma: a scholarly review, Verkouteren [/bib_ref] , accounting for about 80% of all nonmelanoma skin cancers (NMSC) [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref] [bib_ref] Epidemiology of skin cancer, Leiter [/bib_ref] [bib_ref] Metastatic basal cell carcinoma: a biological continuum of basal cell carcinoma?, Mehta [/bib_ref]. However, this number may be greater as not every individual lesion is registered due to its high incidence. Incidence increases with age and typically peaks during the eighth decade of life [bib_ref] The incidence and clinical analysis of nonmelanoma skin cancer, Ciazynska [/bib_ref]. In Switzerland, the prevalence of BCC is estimated at 75.1 per 10,000 population, which is one of the highest rates in Europe. This may be attributable to a better reporting system in Switzerland compared to other European countries [bib_ref] Evaluation of the National Skin Cancer Campaign: a Swiss experience of Euromelanoma, Lieberherr [/bib_ref] or other, not yet identified, factors. BCC rarely exhibits a propensity for metastasis, with a less than 0.6% reported incidence [bib_ref] Skin cancer: epidemiology, disease burden, pathophysiology, diagnosis, and therapeutic approaches, Apalla [/bib_ref] [bib_ref] Basal cell carcinoma metastatic to the parotid: report of a new case..., Malone [/bib_ref] [bib_ref] Report of five cases and review of 170 cases in the literature, Von Domarus [/bib_ref]. Although this type of skin cancer is typically not life-threatening, the disease can cause considerable morbidity due to local tissue destruction and disfigurement if untreated [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref] [bib_ref] Basal cell carcinoma, Mcdaniel [/bib_ref].

## Etiology
The etiology of BCC is multifactorial, involving environmental and genetic factors [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref]. Solar ultraviolet radiation is by far the most significant environmental risk factor, which is why most BCCs occur on sun-exposed areas of the body, such as the head and neck [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref] [bib_ref] Basal cell carcinoma: epidemiology; pathophysiology; clinical and histological subtypes; and disease associations, Cameron [/bib_ref]. Seconddegree sunburn, chemical carcinogens such as arsenic, ionizing radiation, male gender, increasing age, and immunosuppression are also associated with a higher risk to develop BCC [bib_ref] The epidemiology of skin cancer, Diepgen [/bib_ref] [bib_ref] Understanding the molecular genetics of basal cell carcinoma, Pellegrini [/bib_ref]. Genomic studies discovered that aberrant activation of various signaling pathways is linked to the development of BCCs. Somatic or inherited mutations in the Patched 1 (PTCH1), Patched 2 (PTCH2), smoothened (SMO), suppressor of fused (SUFU), and glioma-associated (GLI) genes, among others, are typically associated with BCC [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref] [bib_ref] Understanding the molecular genetics of basal cell carcinoma, Pellegrini [/bib_ref] [bib_ref] Gene-related response of basal cell carcinoma to biologic treatment with vismodegib, Sternfeld [/bib_ref]. PTCH1 is a transmembrane receptor that acts negatively in the hedgehog (HH) signaling pathway [bib_ref] Understanding the molecular genetics of basal cell carcinoma, Pellegrini [/bib_ref]. The pathway is active during fetal development but is strongly regulated after birth. Loss-of-function mutations of PTCH1 have been implicated in the pathogenesis of BCC [bib_ref] Understanding the molecular genetics of basal cell carcinoma, Pellegrini [/bib_ref]. Approximately, 75% of BCCs harbor somatic PTCH1 gene mutations [bib_ref] Basal cell carcinoma: a comprehensive review, Dika [/bib_ref]. In contrast, alterations in SMO genes are detected in up to 20% of BCCs [bib_ref] Basal cell carcinoma: a comprehensive review, Dika [/bib_ref]. Moreover, BCC has the highest tumor mutational burden (TMB) among the analyzed cancer types [bib_ref] Genomic analysis identifies new drivers and progression pathways in skin basal cell..., Bonilla [/bib_ref].
Specific genetic syndromes are also characterized by a tendency for early or increased development of BCCs. Aberrant HH signaling activation is a known prerequisite for developing Gorlin-Goltz's syndrome (OMIM 109400), a rare inherited genetic disease characterized by multiple BCCs at a young age [bib_ref] Understanding the molecular genetics of basal cell carcinoma, Pellegrini [/bib_ref]. Multiple face, neck, and head BCCs are a hallmark of another rare genetic condition, xeroderma pigmentosum (XP). BCC is also a prominent feature of other specific genetic conditions, including Bazex-Dupre-Christol and Rombo syndromes [bib_ref] Grammatico P. Genetic skin diseases predisposing to basal cell carcinoma, Castori [/bib_ref] [bib_ref] Immunotherapy in Xeroderma Pigmentosum: a case of advanced cutaneous squamous cell carcinoma..., Rubatto [/bib_ref].

## Clinical and histological features
Several clinical and histological subtypes of BCC have been defined. The most common clinical types are nodular (micronodular), superficial and morphoeic (infiltrative and sclerosing) [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref]. Ulcerated (ulcus rodens), destructive (ulcus terebrans), pigmented, and mixed variants may also be observed [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref] [bib_ref] British Association of Dermatologists. Guidelines for the management of basal cell carcinoma, Telfer [/bib_ref]. Nodular is the most frequent subtype, accounting for approximately 50-79% of all BCCs, followed by superficial BCC (15%) [bib_ref] Skin cancer: epidemiology, disease burden, pathophysiology, diagnosis, and therapeutic approaches, Apalla [/bib_ref] [bib_ref] Different anatomical distribution of basal cell carcinoma subtypes in Iranian population: association..., Ghanadan [/bib_ref]. Nodular subtypes are well-demarcated reddish to skincolored nodules or plaques that can be translucent and have a lowering in the middle [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref]. Superficial BCCs appear as scaly erythematous patches or plaques that are also typically well-demarcated, while morpheaformic BCCs present as slightly erythematous or skin-colored, scar-looking lesions with poorly defined margins [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref]. The more common histological subtypes of BCCs include nodular, superficial, sclerosing/morphoeic, pigmented, infundibulocystic, basosquamous, infiltrating, BCC with sarcomatoid differentiation, and micronodular. Less common variants include adenoid, trabecular, cystic, and fibroepithelial BCCs (Pinkus tumor) [bib_ref] S2k guidelines for cutaneous basal cell carcinoma -part 2: treatment, prevention and..., Lang [/bib_ref].

## Recurrence risk and stratification
The risk of recurrence is dependent on the clinical and histopathological subtype as well as on BCC location, tumor diameter, age, immune status, gender of the patient, and the used treatment modality [fig_ref] Table 1: Classification of the level of recurrence risk a in BCC [/fig_ref] [bib_ref] S2k guidelines for cutaneous basal cell carcinoma -part 2: treatment, prevention and..., Lang [/bib_ref] [bib_ref] Tumor recurrence 5 years after treatment of cutaneous basal cell carcinoma and..., Chren [/bib_ref] [bib_ref] Update of the European guidelines for basal cell carcinoma management, Trakatelli [/bib_ref]. Recurrence is generally low after standard treatments such as surgery, with an estimated 5-year recurrence probability of 2-8% for most primary BCCs [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref] [bib_ref] S2k guidelines for cutaneous basal cell carcinoma -part 2: treatment, prevention and..., Lang [/bib_ref] [bib_ref] Tumor recurrence 5 years after treatment of cutaneous basal cell carcinoma and..., Chren [/bib_ref] [bib_ref] Low recurrence rate of head and neck basal cell carcinoma treated with..., Kuiper [/bib_ref]. A small proportion (5%) of patients develop BCC with a higher risk of recurrence, which can be challenging to manage [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref] [bib_ref] Update of the European guidelines for basal cell carcinoma management, Trakatelli [/bib_ref] [bib_ref] Lack of efficacy of imiquimod in patients with basal cell carcinoma previously..., Campione [/bib_ref]. BCC classification based on high-and low-risk is endorsed in the National Comprehensive Cancer Network (NCCN) 2021 guidelines [fig_ref] Table 1: Classification of the level of recurrence risk a in BCC [/fig_ref].

## Diagnostic workup
Diagnosis is based on clinical, dermatoscopic, and/or histological features. A biopsy may be used to confirm a diagnosis when clinical and dermoscopic-based diagnosis is not possible. Biopsy is mandatory in ambiguous lesions, large BCCs, and high-risk areas [fig_ref] Table 2: Requirements for histopathological examination of BCC based on EADO 2019 guidelines Adapted... [/fig_ref]. Other noninvasive diagnostic approaches such as confocal microscopy and optical coherence tomography can also be used if available. In addition to confirming a diagnosis, a histopathological examination should identify histopathological subtypes as low-or high-risk tumors.
[formula] DOI: 10.1159/000526478 [/formula]
For suspected metastatic BCC (mBCC), diagnostic workup should include baseline imaging with ultrasonography or positron emission tomography and computed tomography or magnetic resonance imaging for suspected locally advanced BCC (laBCC).

## Disease management
An algorithm for the treatment of primary BCC, stratified by recurrence risk, is shown in .

## Management of low recurrence risk bcc surgery
The primary treatment of low-risk BCCs is complete excision by surgery, either using conventional (2D) surgery with safety margins (5-10 mm) to prevent recurrence or microscopically controlled (3D), stepwise surgery. The latter is especially appropriate for moderaterisk (M) zone (cheeks, forehead, chin, lower lip, capillitium, neck, pretibial) and low-risk (L) zone (torso, limbs) tumors [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref] [bib_ref] S2k guidelines for cutaneous basal cell carcinoma -part 2: treatment, prevention and..., Lang [/bib_ref] [bib_ref] Recurrence of periocular basal cell carcinoma and squamous cell carcinoma after Mohs..., Weesie [/bib_ref]. More than 95% of all BCCs can be treated by this standard method, which concurrently allows for histological confirmation [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref]. Adapted from the NCCN 2021 guidelines. CCPDMA, Complete Circumferential Peripheral and Deep Margin Assessment; H zone, high-risk zone; L zone, low-risk zone; M zone, moderate-risk zone; RT, radiotherapy. a Any high-risk factor places the patient in the high-risk category. b "Mask areas" of the face: central face, eyelids, eyebrows, periorbital, nose, lips (cutaneous and vermilion), chin, mandible, preauricular, and postauricular skin/sulci, temple, and ear. c This area is a high-risk location, independent of size. d Having (mixed) infiltrative, micronodular, morpheaform, basosquamous, sclerosing, or carcinosarcomatous differentiation features in any portion of the tumor. In some cases, basosquamous tumors may be prognostically similar to SCC; clinicopathologic correlation is recommended in these cases. e Low-risk histologic subtypes include nodular, superficial, and other nonaggressive growth patterns such as keratotic, infundibulocystic, and fibroepithelioma of Pinkus. RT provides an effective alternative to surgery in select cases, e.g., for nonsurgical candidates or elderly patients. For small BCCs without high-risk features, rates of disease control are high (75-100%) in early-stage BCC [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref] [bib_ref] Updates on the management of Non-Melanoma Skin Cancer (NMSC), Fahradyan [/bib_ref]. However, in the treatment of BCC of the face, radiotherapy (RT) is associated with inferior oncologic and cosmetic outcomes compared to surgery [bib_ref] Basal cell carcinoma of the face: surgery or radiotherapy? Results of a..., Avril [/bib_ref]. RT or other local less aggressive treatments described below can be considered as a nonsurgical approach for patients who refuse surgery [bib_ref] Management of high-risk and advanced basal cell carcinoma, Puig [/bib_ref].
Topical Therapies When surgical excision or other better established treatments are not possible or contraindicated, 5% imiquimod and topical 5% 5-fluorouracil (5-FU) therapies are recommended as a treatment option for small, superficial lesions in low-risk locations [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref] [bib_ref] Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: a..., Love [/bib_ref]. Five-year follow-up data demonstrated a probability of tumor-free survival of 80.5% for imiquimod (95% CI: 74.0-85.6) and 70.0% for 5-FU (95% CI: 62.9-76.0) in patients with superficial BCC [bib_ref] Five-year results of a randomized controlled trial comparing effectiveness of photodynamic therapy,..., Jansen [/bib_ref]. For nodular or infiltrative BCCs, topical 5-FU or imiquimod are not recommended as primary monotherapy [bib_ref] Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: a..., Love [/bib_ref].

## Physical modalities
Conventional red-light photodynamic therapy (PDT) with 5-aminolevulinic acid (5-ALA) and its ester methyl aminolevulinate (MAL) may be used for small, thin (less than 2 mm) low-risk BCCs when surgery is contraindicated or unsuitable [bib_ref] S2k guidelines for cutaneous basal cell carcinoma -part 2: treatment, prevention and..., Lang [/bib_ref]. Using conventional red-light PDT, very good esthetic results can be achieved with clearance rates over 90% at 12 months in small superficial or nodular BCCs; however, recurrences are higher at 5 years than with surgery (14% vs. 4%) [bib_ref] S2k guidelines for cutaneous basal cell carcinoma -part 2: treatment, prevention and..., Lang [/bib_ref] [bib_ref] A clinical study comparing methyl aminolevulinate photodynamic therapy and surgery in small..., Szeimies [/bib_ref] [bib_ref] Five-year follow-up of a randomized, prospective trial of topical methyl aminolevulinate photodynamic..., Rhodes [/bib_ref]. Other destructive approaches, including cryotherapy and laser therapy (ablative and non-ablative), should be considered in patients with low-risk superficial or small nodular BCC, primarily if surgery or topical therapies are contraindicated [bib_ref] S2k guidelines for cutaneous basal cell carcinoma -part 2: treatment, prevention and..., Lang [/bib_ref]. Notably, cryotherapy may be considered in patients with superficial BCC on the trunk or extremities [bib_ref] S2k guidelines for cutaneous basal cell carcinoma -part 2: treatment, prevention and..., Lang [/bib_ref].
RT provides an effective alternative to surgery in select cases, e.g., for nonsurgical candidates, elderly patients, or patients with tumors in anatomically or aesthetically important areas where surgery would lead to loss of function, such as the periocular area. After superficial RT as first-line therapy, relapses at 5-, 10-, and 15 years were 4.2%, 5.7%, and 5.7%, respectively [bib_ref] Updates on the management of Non-Melanoma Skin Cancer (NMSC), Fahradyan [/bib_ref] [bib_ref] Soft x-ray therapy for cutaneous basal cell and squamous cell carcinomas, Schulte [/bib_ref]. However, Low risk BCC 2D excision with surgical margins 5-10 mm or MMS (3D) excision (especially in the M zone and surgical margins 3-5 mm in L-zone) OR RT in select cases (e.g., non-surgical candidates or elderly patients) MMD (3D) excision for difficult-to-treat lesions OR RT in select cases (e.g., locally advanced BCC, elderly patients, facial lesions including periorbital regions) with recurrent BCCs, response rates are considerably lower; hence if not contraindicated, surgery should be considered [bib_ref] Soft x-ray therapy for cutaneous basal cell and squamous cell carcinomas, Schulte [/bib_ref].

## First-line

## Management of high-risk bcc
Several RT methods are available, including superficial RT, external beam RT, and interstitial brachytherapy [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref]. The most commonly used technique is external beam RT, which penetrates deeper tissues and can be used in the case of thick tumors [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref] [bib_ref] British Association of Dermatologists. Guidelines for the management of basal cell carcinoma, Telfer [/bib_ref]. Superficial RT is an alternative for lesions up to approximately 6 mm in depth [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref] [bib_ref] British Association of Dermatologists. Guidelines for the management of basal cell carcinoma, Telfer [/bib_ref]. Brachytherapy is useful for lesions arising on curved surfaces. Recommended doses of RT range between 60 and 70 Gy (using 2 Gy fractions) using megavoltage photons for larger, more advanced lesions, and 45 Gy or 51 Gy (in 10 and 17 fractions, respectively) using orthovoltage photons for smaller lesions [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref]. Compared to surgery, local control rates after RT are lower (approximately, 70-90%) [bib_ref] Radiotherapy for locally advanced basal cell and squamous cell carcinomas of the..., Kwan [/bib_ref] [bib_ref] Radiotherapy for epithelial skin cancer, Locke [/bib_ref].
For XP patients, and other genetic disorders, RT should be avoided because late side effects and complications have been described but are not well known. Therefore, before considering RT, knowledge of the XP complementation group and cellular sensitivity to ionizing radiation may be reasonable due to the different frequency and age of onset of cutaneous tumors [bib_ref] Radiation therapy for patients with xeroderma pigmentosum, Sakata [/bib_ref] [bib_ref] Radiotherapy for cutaneous cancers with xeroderma pigmentosum, Salah [/bib_ref] [bib_ref] Squamous cell carcinoma in African children with xeroderma pigmentosum: three case reports, Kaloga [/bib_ref] [bib_ref] Invasive basal cell carcinoma in a xeroderma pigmentosum patient: facing secondary and..., Lasso [/bib_ref].

## Hh pathway inhibitors
In high-risk BCC patients who are not surgical candidates or refuse surgery and where RT alone would offer insufficient control rates, alternative treatment options have been limited in the past. However, following the identification of the role of the HH signaling in the pathogenesis of BCC, a new class of systemic medications known as HH pathway inhibitors (HHIs) have been developed. In particular, vismodegib and sonidegib are now considered standard treatments in locally advanced (laBCC) and metastatic BCC (mBCC) [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref]. Both HHIs are approved in Switzerland based on their clinical efficacy as demonstrated in their respective phase 2 trials, ERIV-ANCE [bib_ref] Pivotal ERIV-ANCE basal cell carcinoma (BCC) study: 12-month update of efficacy and..., Sekulic [/bib_ref] [bib_ref] Efficacy and safety of vismodegib in advanced basal-cell carcinoma, Sekulic [/bib_ref] and BOLT [bib_ref] Treatment with two different doses of sonidegib in patients with locally advanced..., Migden [/bib_ref] [bib_ref] The 12-month analysis from basal cell carcinoma outcomes with LDE225 treatment (BOLT):..., Dummer [/bib_ref] [bib_ref] Long-term efficacy and safety of sonidegib in patients with locally advanced and..., Lear [/bib_ref] [bib_ref] Long-term efficacy and safety of sonidegib in patients with advanced basal cell..., Dummer [/bib_ref].
In the pivotal, single-arm, 2-cohort ERIVANCE study (NCT00833417), vismodegib met its primary endpoint at 9 months, with overall response rates (ORRs) of 30% (95% CI: 16-48; p = 0.001) among 33 patients with mBCC and 43% (95% CI: 31-56; p = 0.001) among 63 patients with laBCC [bib_ref] Efficacy and safety of vismodegib in advanced basal-cell carcinoma, Sekulic [/bib_ref]. All 104 patients had at least one adverse event (AE), and in 12% of patients, AEs led to discontinuation of vismodegib [bib_ref] Efficacy and safety of vismodegib in advanced basal-cell carcinoma, Sekulic [/bib_ref]. The safety of vismodegib was confirmed in the single-arm, open-label, multicenter SafeTy Events in VIsmodEgib (STEVIE) study in 1,215 adult patients with laBCC (n = 1,119) or mBCC (n = 96) [bib_ref] Vismodegib in patients with advanced basal cell carcinoma: primary analysis of STEVIE,..., Basset-Seguin [/bib_ref]. Median duration of response (DOR) was 23.0 months for laBCC and 13.9 months for mBCC, and median progression-free survival (PFS) was 23.2 and 13.1 months for laBCC and mBCC, respectively [bib_ref] Vismodegib in patients with advanced basal cell carcinoma: primary analysis of STEVIE,..., Basset-Seguin [/bib_ref]. ORRs were observed in 68.5% of patients with laBCC and 36.9% of those with mBCC disease due to longer treatment duration [bib_ref] Vismodegib in patients with advanced basal cell carcinoma: primary analysis of STEVIE,..., Basset-Seguin [/bib_ref]. All-grade treatment-related AEs occurred in 98% (n = 1,192) of patients [bib_ref] Vismodegib in patients with advanced basal cell carcinoma: primary analysis of STEVIE,..., Basset-Seguin [/bib_ref]. The most common allgrade AEs were muscle spasm (66.4%), alopecia (61.5%), dysgeusia (54.6%), weight decrease (40.6%), and decreased appetite (24.9%). Approximately 50% of the AEs were mild to moderate [bib_ref] Vismodegib in patients with advanced basal cell carcinoma: primary analysis of STEVIE,..., Basset-Seguin [/bib_ref]. Different dose reduction strategies have been suggested to reduce the severity of AEs associated with long-term vismodegib treatment [bib_ref] Managing adverse effects by dose reduction during routine treatment of locally advanced..., Woltsche [/bib_ref] [bib_ref] Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE):..., Dreno [/bib_ref] [bib_ref] Vismodegib efficacy in advanced basal cell carcinoma maintained with 8-week dose interruptions:..., Chanu [/bib_ref]. Treatment interruptions of up to 8 weeks are recommended to manage intolerable AEs. The MIKIE study (NCT01815840) evaluated the efficacy and safety of two intermittent vismodegib dosing regimens in 229 patients with multiple BCCs [bib_ref] Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE):..., Dreno [/bib_ref]. This study provided evidence that intermittent dosing of vismodegib (i.e., 8 or 12 weeks of treatment followed by an 8-week interruption) is effective and tolerable in patients with multiple lowrisk BCC [bib_ref] Two intermittent vismodegib dosing regimens in patients with multiple basal-cell carcinomas (MIKIE):..., Dreno [/bib_ref]. Notably, multiple BCCs of nodular subtype should be considered as high-risk BCC and treated accordingly [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref]. Evidence from a small cohort of 15 nonrecurrent BCC patients suggests that neoadjuvant vismodegib treatment for 3 months reduces surgical defect areas [bib_ref] An investigatorinitiated open-label clinical trial of vismodegib as a neoadjuvant to surgery..., Ally [/bib_ref]. The effectiveness of vismodegib as a neoadjuvant to surgery for high-risk BCC is currently investigated in two ongoing clinical trials (NCT02667574 and NCT03035188; https://clinicaltrials.gov/).
BOLT was a randomized, double-blind, multicenter phase 2 study of sonidegib for the treatment of laBCC or mBCC (NCT01327053). Patients were randomized 1:2 to receive a daily dose of sonidegib 200 mg or 800 mg until disease progression or unacceptable toxicity. Overall, 230 patients with high-risk BCC were included in the trial. At the initial 6-month analysis, treatment with sonidegib demonstrated objective response rates by central review of 43% in patients with laBCC and 15% in patients with mBCC [bib_ref] Treatment with two different doses of sonidegib in patients with locally advanced..., Migden [/bib_ref]. According to the final analysis at 42 months in the sonidegib 200-mg arm, by central review, 56% (95% CI: 43-68) and 8% (95% CI: 0.2-36) of patients with laBCC and mBCC had an objective response, respectively [bib_ref] Long-term efficacy and safety of sonidegib in patients with advanced basal cell..., Dummer [/bib_ref]. In the 800-mg arm, 46.1% (95% CI: 37-55) and 17% (95% CI: 5-39) of patients with laBCC and mBCC had an objective response, respectively [bib_ref] Long-term efficacy and safety of sonidegib in patients with advanced basal cell..., Dummer [/bib_ref]. The median DOR for responders was 26.1 months. Median PFS was Dermatology 2023;239:122-131 DOI: 10.1159/000526478 22.1 (not estimable) and 13.1 (95% CI: 5.6-33.1) months, respectively, in the 200-mg sonidegib laBCC and mBCC arms [bib_ref] Long-term efficacy and safety of sonidegib in patients with advanced basal cell..., Dummer [/bib_ref]. The mean time until tumor response was 4 months. Grade 3 and 4 AEs were infrequent and deemed treatment-related in 25 (32%) patients in the 200-mg sonidegib group, leading to treatment discontinuation in 11 (14%) of patients in this group. The most common AE by the preferred term was muscle spasms, reported in 43 (54%) patients in the 200-mg group [bib_ref] Long-term efficacy and safety of sonidegib in patients with advanced basal cell..., Dummer [/bib_ref]. With data at 42 months, the BOLT study is the longest follow-up published to date for an HHI [bib_ref] Long-term efficacy and safety of sonidegib in patients with advanced basal cell..., Dummer [/bib_ref].
A meta-analysis that compared the efficacy and safety of vismodegib and sonidegib reported similar ORRs but lower complete responses with sonidegib (31% vs. 3%, respectively) [bib_ref] Efficacy, safety, and comparison of sonic hedgehog inhibitors in basal cell carcinomas:..., Xie [/bib_ref]. Similar AEs were also observed for the two HHIs [bib_ref] Efficacy, safety, and comparison of sonic hedgehog inhibitors in basal cell carcinomas:..., Xie [/bib_ref]. Recently, 90% of a European Delphi panel consensus of 11 experts agreed that HHIs should be the first-line standard of care for high-risk BCC patients, with vismodegib being the most commonly used in Europe. Moreover, 70% of the Delphi panel agreed that continuing with the same HHI is the most used therapeutic strategy for patients with stable disease after 9 months of HHI treatment, given the lack of alternatives. Both HHIs are also approved in the treatment of Gorlin-Goltz patients, where they affect basal carcinoma and odontogenic keratocysts. NIELS, a noninterventional, real-world study conducted across 26 centers in Germany, confirmed the effectiveness and safety of vismodegib in 66 patients with laBCC, with an ORR of 74.2% and disease control rate of 90.9% [bib_ref] Effectiveness, safety and utilization of vismodegib in locally advanced basal cell carcinoma..., Gutzmer [/bib_ref].

## Pd-1 inhibitors
As BCC is characterized by a high TMB, immunotherapy with checkpoint inhibitors could be a viable treatment option in patients with BCC [bib_ref] Genomic analysis identifies new drivers and progression pathways in skin basal cell..., Bonilla [/bib_ref]. Data on TMB of BCCs from patients with Gorlin-Goltz are limited; hence, efficacy of immunotherapy may be different in this patient population [bib_ref] Genomic analysis identifies new drivers and progression pathways in skin basal cell..., Bonilla [/bib_ref].
In an open-label study investigating the anti-programmed death-1 (PD-1) inhibitor cemipilimab in patients with laBCC or mBCC, patients received 350 mg cemiplimab intravenously every 3 weeks for up to 93 weeks. Among 84 patients with laBCC, cemiplimab showed a centrally confirmed ORR of 31% (95% CI: 21-42), with 6% complete responses and 25% partial responses [bib_ref] Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an..., Stratigos [/bib_ref]. Median DOR was not reached [bib_ref] Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an..., Stratigos [/bib_ref]. The estimated Kaplan-Meier probability of DOR at 6 and 12 months was 91% (95% CI: 68-98) and 85% (95% CI: 61-95), respectively [bib_ref] Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an..., Stratigos [/bib_ref]. The median PFS was 19 months (95% CI: 9 to not estimable), with a 12-month PFS rate of 57% (95% CI: 44-67) and a 24-month overall survival rate of 80% [bib_ref] Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an..., Stratigos [/bib_ref]. The median overall survival was not reached [bib_ref] Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an..., Stratigos [/bib_ref]. No considerable differences in efficacy were observed in patients stratified by the baseline programmed death-ligand 1 (PD-L1) expression status (PD-L1 <1% vs. PD-L1 1%) [bib_ref] Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an..., Stratigos [/bib_ref]. The safety profile was manageable and consistent with previous reports on cemiplimab and other anti-PD-1 antibodies [bib_ref] Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an..., Stratigos [/bib_ref]. Grade 3-4 treatment-emergent AEs occurred in 40 (48%) of 84 patients, leading to study discontinuation in 9 patients (11%); the most common were hypertension (5%), colitis (5%), fatigue (4%), urinary tract infection (4%), and visual impairment (4%) [bib_ref] Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an..., Stratigos [/bib_ref]. Immune-related AEs occurred in 21 (25%) of 84 patients, most commonly hypothyroidism (10%) and immune-related colitis (4%) [bib_ref] Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an..., Stratigos [/bib_ref].
A recent phase 2, open-label health-related quality-oflife study in laBCC patients treated with cemiplimab demonstrated that for the majority of patients, overall health-related quality of life and functioning improved or was maintained across the SKINDEX-16 [bib_ref] Measurement properties of Skindex-16: a brief quality-of-life measure for patients with skin..., Chren [/bib_ref] subscales (e.g., on the key symptom of pain, 31% of patients reported a clinically meaningful improvement and 44% reported maintenance). On the SKINDEX-16 emotional scale, in particular, nearly 60% of patients reported clinically meaningful improvement with cemiplimab.
Prespecified interim data from a pivotal phase 2 study (NCT03132636) of cemiplimab-treated patients with mBCC who progressed on or were intolerant to HHIs demonstrated clinically meaningful anti-tumor activity, including durable response (median DoR not reached). Notably, the disease control rate was 67.9% (95% CI, 47.6-84.1). The safety profile of cemiplimab is consistent with previous reports on other tumor types.
Cemiplimab is approved in the USA and Europe for the treatment of adult patients with laBCC or mBCC who have progressed on or are intolerant to an HHI. Treatment of laBCC and mBCC with cemiplimab is offlabel in Switzerland.

## Chemotherapy
Chemotherapy for advanced BCC has not yet been evaluated in clinical trials, and recommendations are based on responses observed in case reports. The reported response rate with platinum-based chemotherapy is 2030%, with a DOR of 23 months [bib_ref] Metastatic basal cell carcinoma: prognosis dependent on anatomic site and spread of..., Mccusker [/bib_ref]. Given the higher efficacy and good safety profile of modern therapies, chemotherapy is usually recommended once other treatment options are exhausted. DOI: 10.1159/000526478 Electrochemotherapy Electrochemotherapy (ECT) is used for the nonspecific treatment of advanced cancers and cutaneous metastases of a wide range of primary cancer types. Epithelial tumors such as BCCs may also be treated with this method, including patients with multiple lesions [bib_ref] Successful treatment of multiple basaliomas with bleomycin-based electrochemotherapy: a case series of..., Kis [/bib_ref]. A randomized controlled trial compared ECT to surgery in 117 patients with primary BCC [bib_ref] Electrochemotherapy for the treatment of primary basal cell carcinoma; a randomised control..., Clover [/bib_ref]. At 5 years follow-up, the recurrence rate with ECT (n = 69) was 10.4% compared to 2.5% of recurrence following surgical treatment [bib_ref] Electrochemotherapy for the treatment of primary basal cell carcinoma; a randomised control..., Clover [/bib_ref].

## Clinical trials
Patients, especially those with high-risk BCC, should be evaluated for participation in a clinical trial whenever suitable. Currently, local as well as systemic therapies are being investigated for patients with laBCC and mBCC.

## Prevention
All patients are recommended to protect themselves against excessive sun exposure [bib_ref] S2k guidelines for cutaneous basal cell carcinoma -part 2: treatment, prevention and..., Lang [/bib_ref]. However, there is limited evidence about whether sunscreen effectively reduces the incidence of BCC [bib_ref] Sun protection for preventing basal cell and squamous cell skin cancers. Cochrane, Sanchez [/bib_ref] [bib_ref] Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell..., Green [/bib_ref]. Nicotinamide has been shown to offer some protection against ultravioletinduced immunosuppression in a human skin model. As immunosuppression plays a bigger role in the development of squamous cell carcinoma (SCC) than BCC, evidence from clinical studies to date indicates that nicotinamide is less effective in preventing BCC than other NMSCs (relative risk reduction approx. 20% vs. 30%, respectively) [bib_ref] A Phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention, Chen [/bib_ref] , with no statistical difference compared to placebo. In a phase 3 double-blinded, placebo-con-trolled randomized study, the rate of new NMSC was 23% lower (95% CI: 4-38) with nicotinamide than placebo (p = 0.02) [bib_ref] A Phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention, Chen [/bib_ref].
Similarly, the rate of new BCC development was lower in the nicotinamide group than in the placebo group (20%, 95% CI: 6 to 39; p = 0.12) [bib_ref] A Phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention, Chen [/bib_ref]. Given these data, nicotinamide may be used in patients with cutaneous carcinogenesis.

## Follow-up
Follow-up recommendations vary according to the risk of recurrence of the BCC observed, but along with the follow-up visits, all patients should be encouraged to perform self-checks [fig_ref] Table 3: Follow-up recommendations for basal cell carcinoma [/fig_ref] [bib_ref] Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines, Peris [/bib_ref]. For the low-risk BCCs, patients should be followed up every 6 months for the first year after complete response of BCC [bib_ref] S2k guidelines for cutaneous basal cell carcinoma -part 2: treatment, prevention and..., Lang [/bib_ref]. If no new BCCs develop during the first year of follow-up, the option for follow-up every 12 months should be considered and discussed with the patient.
For high-risk BCCs, there is a high probability of recurrence and development of another BCC or other form of skin cancer [bib_ref] Risks of different skin tumour combinations after a first melanoma, squamous cell..., Van Egmond [/bib_ref]. These patients should be followed up every 6 months during the first 2 years post-excision [bib_ref] S2k guidelines for cutaneous basal cell carcinoma -part 2: treatment, prevention and..., Lang [/bib_ref]. Appropriate imaging (ultrasound, positron emission tomography and computed tomography, or magnetic resonance imaging) should be assessed on an individual basis. During the third year of follow-up, and provided no new BCCs develop in the first 2 years, follow-up options every 12 months should be considered/discussed with the patient.
During systemic treatment, patients receiving HHIs should be followed up every 4 weeks or at each treatment visit for other therapies (e.g., anti-PD-1, chemotherapy, ECT, etc.). In addition, in cases of laBCC and mBCC, appropriate imaging should be performed every 3 months to determine the extent of the tumor.

# Conclusions
In order to select the most appropriate treatment and follow-up modality, it is important to identify the risk of recurrence for the individual lesion. For low-risk lesions, effective treatments may include surgical excision, RT, topical therapy (e.g., imiquimod and 5-FU), and minimally invasive procedures (e.g., PDT). High-risk BCC is primarily managed with micrographic surgical excision. In addition, promising new systemic therapies have recently been added to the BCC treatment armamentarium in Switzerland for difficult-to-treat patients, including HHIs (e.g., vismodegib and sonidegib) and PD-1 checkpoint inhibitors (e.g., off-label cemiplimab).

## Key message
Identifying recurrence risk for individual lesions enables the selection of the most effective treatment modality.
[table] Table 1: Classification of the level of recurrence risk a in BCC [/table]
[table] Table 2: Requirements for histopathological examination of BCC based on EADO 2019 guidelines Adapted from Peris et al.[1] 2019. Grade of recommendation B: aided noninvasive diagnosis with dermatoscopy, reflectance confocal microscopy, and/or optical coherence tomography can improve the diagnostic accuracy in difficult-to-recognize BCCs[1]. BCC, basal cell carcinoma; EADO, European Association of Dermato-Oncology. [/table]
[table] Table 3: Follow-up recommendations for basal cell carcinoma (BCC) patients BCC type Follow-up recommendations (Note: All patients should be encouraged to perform self-checks) Low-risk BCC Every 6 months for the first 12 months after CR Every 12 months thereafter, if no BCC recurrence a High-/moderate-risk BCC b Every 6 months for the first 24 months post-excision Every 12 months thereafter, if no BCC recurrence a Locally destructive and metastatic BCC Every 3 months for the first 24 months post-excision Every 6 months thereafter, if no BCC recurrence a BCC, basal cell carcinoma; CR, complete response; MRI, magnetic resonance imaging; PET/CT, positron emission tomography and computed tomography. a Discussion with the patient is recommended. b Appropriate imaging may include ultrasound, PET/CT, and MRI, assessed on an individual basis. 2023;239:122-131 DOI: 10.1159/000526478 [/table]