Defining Locally Advanced Basal Cell Carcinoma

Basal cell carcinoma (BCC) is the most common human cancer.¹ When detected early the vast majority of cases are successfully managed surgically, with 5-year cure rates exceeding 90%.² Although rare, BCCs have the potential to progress to locally advanced and even metastatic disease. Collectively termed ‘advanced BCCs’, these cutaneous malignancies are often not amenable to surgery or radiation therapy and thus represent a major treatment challenge for dermatologists, surgeons, and oncologists. In January 2012, vismodegib became the first hedgehog signaling pathway inhibitor FDA-approved for the treatment of adults with metastatic BCC (mBCC) or with locally advanced BCC (laBCC) that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. The emergence of vismodegib as a new therapeutic option has subsequently forced dermatologists to accept a new diagnostic category of skin cancer (locally advanced BCC) that would have previously defaulted into an entirely different therapeutic realm.

Long before vismodegib or its newly defined FDA-approved indication, words such as ‘extreme’, ‘advanced’, ‘extremely advanced’, ‘locally advanced’, ‘complex’, and ‘inoperable’ were used to describe presumably similar entities. Use of the term ‘advanced BCC’ dates back to 1979, when Sakura et al. published a study comparing treatment modalities for recurrent BCCs in the Journal of Plastic and Reconstructive Surgery.³ ‘Locally advanced BCC’ first appeared in an authored publication that was not commercial advertising in October 1994. Here Goldberg et al. published their study on cisplatin-based chemotherapy in the journal Harefuah, though no definition is provided.⁴ Finally, a definition emerged as inclusion criteria for a radiotherapy treatment study conducted by Kwan et al in 2004. Patients were considered to have locally advanced disease by satisfying one of the following criteria: ‘1. T2 or above (tumor size 2 cm or deeply invasive disease) by International Union Against Cancer (UICC) 1997 TNM staging, or 2. Node-positive disease by clinical or radiologic examination’.⁵ To the best of our knowledge, this is the only formal definition provided in the literature prior to the advent of vismodegib. Indeed, no major dermatology textbooks to date have attempted to define this clinical entity. As an FDA-approved indication for targeted molecular therapy, locally advanced BCC has thus achieved a new level of significance, demanding that we as prescribers collectively consider how this term will be defined and utilized in patient care.

Clinical Trial Criteria
Several studies have demonstrated the efficacy of vismodegib, but few have attempted to adequately define 'locally advanced BCC’ as a clinical entity and indication for therapy. Despite this shortcoming, clinical trial eligibility criteria have been similar. Characteristics such as size (>10 mm), extent of local invasiveness, location, expected morbidity and mortality from surgery and/or radiation, low likelihood of curative resection, contraindications to surgery, and two or more recurrences in the same location have all been described as features of laBCC.^6-12 Importantly, several of these characteristics were used to select patients in the pivotal phase II, international, multicenter ERIVANCE BCC trial.¹³ While tumor features such as size remain objective in measurement, others are fundamentally subjective and dependent upon evaluator subspecialty, opinion, and clinical context.

Differing Perspectives
Both surgeons and medical dermatologists may diagnose laBCC and prescribe vismodegib, yet fundamental differences in delivery of care influence how this clinical entity is perceived. For example, tumor location in relation to critical anatomic structures is likely to be emphasized more by surgeons; a 1 cm lesion on the canthus of the eye or on the auricle extending into the external auditory canal is much more likely to reach a designation of locally advanced simply based on the complexity of and likely disfigurement caused by any surgical intervention. Furthermore, surgeons may emphasize involvement of cartilage, bone or nerve, the need for adjuvant therapy and/or recurrence after multiple operations as key features of laBCCs. Among Mohs micrographic, ENT, and plastic surgeons there are also subjective discrepancies in perceived inoperability, likelihood of curative resection and anticipated morbidity and mortality from surgery.

From a medical dermatologist’s perspective, the notion of laBCC arises when there is an experience-based feeling that something beyond the standard of care (eg, surgery) is necessary to provide definitive therapy. In this regard, the easiest way to define locally advanced BCC is the way United States Supreme Court Justice Potter Stewart described his threshold test for obscenity, famously stating “I know it when I see it.” This definition would work well for many dermatologists as the great majority of BCC diagnoses are made by clinical intuition, confirmed with a biopsy and histological analysis, and treated with a variety of familiar medical and surgical modalities. During this process, dermatologists guide patients to the best treatment option after consideration of several factors including anatomic location, clinical appearance, histological subtype, previous treatments, and individual patient factors such as medications, ability to tolerate surgery, and the patient’s specific treatment goals or restrictions. Because the overwhelming majority of BCCs are not locally advanced or metastatic, little time is usually spent