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9 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
Locally advanced basal cell carcinoma is a skin cancer that has grown so large or deep, usually on the face, that surgery or radiotherapy can no longer remove it without unacceptable damage. Almost all these tumours depend on the hedgehog growth pathway, and the pills vismodegib and sonidegib shrink about four in ten of them; cemiplimab is used when the pills fail or cannot be tolerated.
Nearly every basal cell carcinoma is driven by the hedgehog pathway, through loss of the receptor PTCH1 in most tumours or activating mutations of SMO in about one in ten; germline PTCH1 mutations cause Gorlin syndrome with dozens to hundreds of tumours. Locally advanced disease means a tumour that is not amenable to surgery or radiotherapy because of size, depth, invasion of bone, orbit or nerves, or because repeated recurrence has exhausted local options; metastatic disease, to nodes, lung or bone, is very rare. Surgery with margin control, radiotherapy and, for superficial tumours, topical or photodynamic therapy cure the vast majority before this point.
Vismodegib, the first inhibitor of SMO, produced responses in 43 percent of locally advanced and 30 percent of metastatic tumours in ERIVANCE (2012) and was approved in January 2012 as the first systemic drug for the disease; sonidegib produced responses in 43 percent of locally advanced tumours at 200 mg in BOLT (2015). Responses are often deep and durable, but muscle cramps, hair loss, loss of taste and weight loss affect nearly everyone and lead many to stop within a year; intermittent dosing (MIKIE) keeps much of the benefit with fewer side effects, and neoadjuvant use to shrink tumours before surgery is established. Both drugs are teratogenic. Resistance arises through SMO mutations that block drug binding.
| Setting | Approach | Guideline |
|---|---|---|
| Locally advanced, first line | Vismodegib (ERIVANCE) or sonidegib (BOLT); intermittent dosing to limit cramps, hair loss and taste loss; surgery or radiotherapy after response where feasible. | not mapped |
| Neoadjuvant | Vismodegib for several months to shrink large facial tumours before surgery and reduce the defect. | not mapped |
| After hedgehog inhibitor failure or intolerance | Cemiplimab (approved 2021); clinical trials of intratumoural agents and immunotherapy combinations. | not mapped |
| Metastatic disease | Vismodegib or sonidegib; cemiplimab after progression; platinum chemotherapy has only case-series support. | not mapped |
| Radiotherapy and local options | Radiotherapy for tumours not resectable but still confined; electron beam and superficial radiotherapy for suitable sites; multidisciplinary review of all advanced cases. | not mapped |
| Gorlin syndrome | Surveillance and surgery, avoidance of radiotherapy, hedgehog inhibitors for multiple advanced tumours, topical patidegib in trials. | not mapped |