The Impact of Inoperable Advanced Basal Cell Carcinoma: the Economic, Physical, and Psychological Burden of the Disease

(NMSC) is also significant. As the prevalence of NMSC has globally increased over the past 3 decades, the costs involved in treatment and management have also risen.⁵ Between 1992 and 2006, the number of procedures performed for NMSC in the United States rose by 76.9%.⁶Although treatment for an individual case of BCC is low compared with other malignancies (approximately $492 in a physician’s office setting), NMSC ranks fifth for cancer cost in the Medicare population.^6,7 This equates to 4.5% of all Medicare cancer costs.^6,8 The cost of treatment for an episode of BCC is positively correlated with tumor size and anatomical site. Lesions on the head and neck or feet are associated with a higher cost.⁶ In 2004, the total direct cost associated with treatment for NMSC was $1.5 billion.⁹

For patients with multiple BCCs requiring frequent and recurrent treatment, preventative management with a targeted molecular therapy offers promise. Genentech offers a one-month supply of once-daily capsules of vismodegib for $7,500, which comes out to $250 per capsule.⁹ While the length of treatment may vary by patient, the expected length of therapy is 10 months. This is a conservative estimate since the endpoint for BCC treatment remains undefined. Thereby, the total average cost is $75,000.⁹ This represents a cost increase of 150-fold over the current modalities.The sales projections in Europe are predicted to reach $401 million by 2015, and peak at $533 million in 2022.⁹

While the majority of BCC cases are found early and effectively cured by surgery and other treatment modalities, the minority that present late can progress to life-threatening, unresectable, advanced BCC, either in the form of locally advanced BCC or metastatic BCC tumors.^2,8 Late presentations and progression to advanced disease can occur due to a variety of factors. The patient may not have sought out timely treatment due to denial or neglect, or perhaps due to lack of finances or access to health care.⁵ Psychiatric comorbidities can also play a role in the progression of BCC to advanced disease.⁵ The point at which BCC becomes “advanced” or “inoperable” is somewhat subjective, as some physicians may be more willing than others to attempt surgical treatment, based on experience and expertise. Additionally, surgery may be precluded as a treatment modality secondary to patient age or comorbidities. In these situations, a multidisciplinary team comprised of experts in dermatologic surgery, surgical oncology, head and neck oncologic surgery, radiology, medical oncology, and radiation oncology should be considered.¹⁰

The instances when advanced BCC tumors develop despite aggressive treatment are known as “high risk BCC.” These lesions are characterized by several markers hypothesized to be related to a more aggressive BCC tumor phenotype.⁵ Characteristics include long duration, location on central face or ears, diameter greater than 2 cm in size, aggressive histologic subtype, perivascular or perineural spread, a history of radiation exposure, incomplete treatment, or previous treatment failure.^5,11,12 Other reasons, however, for this high risk phenotype are not fully understood at this time.⁸

While large BCCs are difficult to manage, the size itself does not necessarily deem a BCC “inoperable” or metastatic. In fact, certain BCCs that appear “typical” may very well be recurrences requiring multiple procedures, which, in turn, become inoperable or metastatic. In the past, radiation was the only alternative for these patients. However, there are certain skin conditions in which radiation is contraindicated, such as basal cell nevus syndrome (BCNS) or xeroderma pigmentosum.⁸

Basal cell nevus syndrome is an autosomal dominant disorder characterized by multiple basal cell carcinomas with onset occurring between puberty and 35 years of age.¹³ The current prevalence is estimated to be 1/57,000 to 1/256,000.¹³ Males and females are equally affected, and the syndrome has been found across multiple ethnicities and geographic locations.¹³ The classical clinical triad of BCNS is multiple BCCs, jaw keratocysts, and bifid ribs. Additional clinical features may include craniofacial defects such as macrocephaly, frontal bossing, and coarse facial features, facial milia, downward sloping shoulders, palmar-planar pits, ectopic intracranial calcifications, and central nervous system defects.^12,13 As the syndrome may manifest in a variety of ways, the diagnosis of BCNS is fulfilled with 2 major criteria and 1 minor criterion, or 1 major criterion and 3 minor criteria.

Basal cell nevus syndrome is caused by mutations in the sonic hedgehog (SHh) pathway, with the most common mutation located in the patched homologue 1 (PTCH1) gene, a tumor suppressor gene mapped to chromosome 9q22.3.¹³ The SHh pathway, while essential during embryogenesis for cell proliferation and growth, typically becomes inactive during adulthood.¹⁰ Patched homologue 1 is a SHh receptor on the cell membrane that suppresses the activation of another transmembrane protein, smoothened (SMO), a SHh pathway activator.¹³ When the