Advanced BCC: Rare but challenging

Higher risk cancers tend to be found on the face or genitalia, with poorly defined borders and perineural involvement.

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Basal cell carcinoma is one of the most common cancers known, and around half of Australians of European ancestry can expect to have one diagnosed by the time they are in their seventies.

The slow-growing nature of this keratinocyte cancer – and the high rates of treatment for it – mean doctors will rarely see an advanced or metastatic case. One estimate, published in the Australasian Journal of Dermatology suggested that fewer than 0.1% of BCC metastasise.

However basal cell carcinomas are still responsible for just under two deaths per 100,000 person–years in Australia.

Two reviews published in the Journal of the American Academy of Dermatology outline some of key messages around the diagnosis and treatment of this rare, serious but usually treatable advanced malignancy.

Between 1% and 10% of local BCCs cannot be managed with surgery or radiotherapy, and these locally advanced tumours are generally large and infiltrate deep into the skin and surrounding tissues.

“In many cases, patient neglect and denial often lead to delays in seeking care for skin lesions that may initially be local but develop with time into more advanced tumors,” the review authors wrote.

However diagnostic delays could also occur in people of colour because of the challenges of picking up BCCs in pigmented skin. BCC is less common in people with darker skin, but unfortunately that has led to a perception that there is no risk, and therefore less awareness among both patients and dermatologists, as well as less prevention such as sunscreen.

Higher risk BCCs tend to be those found on the face or genitalia, with poorly defined borders and perineural involvement. Patients with a history of immunosuppression or radiation are more at risk, as are those with more aggressive histologies such as micronodular, infiltrative, sclerosing and desmoplastic.

For those BCCs that cannot be treated with conventional surgery or radiotherapy, or which have recurred, one option is Mohs micrographic surgery.

Associate Professor Stephen Shumack, a clinical dermatologist at St George Dermatology and senior staff specialist at the Royal North Shore Hospital in Sydney, says Mohs surgery is certainly an option although the relatively low number of Mohs surgeons in Australia compared to the US means access is lower.

“Because it’s more restricted, it tends to be for the more difficult to treat basal cell carcinomas; those that are recurrent, the difficult subtypes – particularly sclerosing BCCs –or the ones that are in difficult-to-treat areas like around the nose or around the eyelids,” Professor Shumack says.

Beyond surgery, the mainstay of treatment for advanced BCC is with the hedgehog inhibitors vismodegib and sonidegib. Disruptions to the hedgehog signalling pathway is linked to uncontrolled cell proliferations, and all sporadic BCCs have mutations in some part of this pathway.

Vismodegib and sonidegib are both approved in Australia for the treatment of metastatic or locally advanced basal cell carcinoma that cannot be treated with surgery or radiation.

However, Professor Shumack said these medications came with side effects including hair loss and loss of appetite, which meant a significant number of patients stop taking their medication. The review suggested that around one in four patients experienced severe side effects, and a small number died from the toxicity.

The authors noted that there had not been any head-to-head studies comparing the two drugs. While the evidence suggested a slight advantage with vismodegib, the studies of each involved different patient populations, treatment histories and length of follow-up, “which can impact direct comparisons of the response rates between the studies.”

Another issue with hedgehog inhibitors was that tumours could become treatment-resistant and recur.

The review authors said there were efforts underway to design drugs that could overcome the resistance issues of hedgehog inhibitors, and there were also trials looking at their use as neoadjuvant therapy to reduce the extent of surgery.

Patients taking hedgehog inhibitors needed to be closely monitored for adherence and progression, the authors advised.

They recommended MRI or CT imaging every three months to assess the tumour response, as well as measurement of externally visible lesions.

They also recommended three-monthly testing of blood counts, liver and renal function, electrolytes and creatine kinase for the first year of treatment, then every three to six months after that.

The immune checkpoint inhibitor cemiplimab – a PD1 inhibitor – has also been approved in the US for treatment of advanced BCC, but Professor Shumack says for the moment in Australia it is only approved for treatment of SCC. He suggested that the drug would likely be used for compassionate treatment.

While clinicians were unlikely to encounter an advanced BCC very often, Professor Shumack advocated for a multi-disciplinary approach to managing a patient with the disease whose disease was not responding to conventional therapies.

“When we get into the locally advanced stage or the metastatic stage, the advantage of having a multidisciplinary clinic is going to be really very worthwhile because dermatologists themselves are not going to be the group of people dealing with PD1 inhibitor,” he said.

“Most of the larger teaching hospitals and centres will have multidisciplinary clinics, where you get medical oncologists, radiation oncologists, surgeons, dermatologists involved in treating a lot of head and neck, BCC and SCC.