Case study 101.1
1. A 45-year-old woman with a history of multiple basal cell carcinomas is seen in clinic. She is noted to have an eroded 5 cm basal cell carcinoma on her nasal bridge extending onto her left medial canthus. Physical exam also demonstrates palmar pits. Further history reveals that her mother and brother have been treated for multiple basal cell carcinomas and odontogenic cysts in the past. The patient is diagnosed with Gorlin’s syndrome. In addition to surgery and radiation, what medication might be useful for treating this patient?
- Ipilimumab
- Acitretin
- Ustekinumab
- Vismodegib
Basal cell carcinomas (BCCs) are the most common malignancy in the world, with an estimated incidence of more than 800,000 cases per year in the United States alone. They account for roughly 75–80% of all nonmelanoma skin cancers and may result in significant patient morbidity. The economic impact of these malignancies is staggering, with an estimated cost of $650 million per year in the United States.
The majority of BCCs are treated with either surgical or destructive methods. Surgical options vary based on tumor location and include the use of Mohs surgery or routine excision. Destructive modalities include the use of electrodessication and curettage, photodynamic therapy, or radiation therapy. Topical medications, such as imiquimod and 5-fluorouracil, are also sometimes employed to treat superficial malignancies.
In 2012 a new oral medication, vismodegib, was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic BCC and locally advanced BCCs in patients who are not candidates for surgery or have experienced recurrent tumors after surgery, nonamenable to radiation. It is a small-molecule inhibitor of Smoothened that acts on the Sonic Hedgehog pathway, which is mutated in a large percentage of sporadic BCCs. Increased Hedgehog activity has also been demonstrated in colon, ovarian, prostate, and pancreatic adenocarcinomas, representing possible future therapeutic targets for this novel medication.
This patient has a rare autosomal dominant syndrome classified as nevoid basal cell carcinoma syndrome, aka Gorlin’s syndrome. This syndrome results from a mutation in the PTCH1 (“Patched”) gene on chromosome 9q22–31 that also causes constitutive activation of the Sonic Hedgehog pathway. Affected individuals tend to develop palmar pits and odontogenic cysts at a young age. BCCs tend to occur frequently after puberty, with a median age of 20 years old in Caucasians. Patients may become severely disfigured due to the sheer size, number, and overall frequency of these skin cancers. Frequent skin exams and treatment of rapidly growing lesions are needed to minimize the overall morbidity and mortality associated with this disease.
Vismodegib has shown promise in this patient population to decrease the size of some BCCs and result in complete clearance of others. The main limiting factors for this medication are side effects and overall cost. Patients tend to develop ageusia, hair loss, and debilitating cramps. Management of these side effects is often difficult, and patients may require drug holidays or reduced dosages to tolerate the medication. The cost, currently estimated at $7500 monthly, is also a major drawback of this medication.
2. If this patient were to develop metastatic squamous cell carcinomas nonamenable to surgery, what chemotherapeutic agent should not be considered for treatment?
- Carboplatin
- Cisplatin
- Cyclophosphamide
- Capecitabine
- Cetuximab
Aggressive and/or metastatic cutaneous squamous cell carcinomas are most frequently treated with platinum-based chemotherapy, including carboplatin and cisplatin. Additional chemotherapeutic options include the use of capecitabine, a purine analog derivative of 5-fluorouracil, and cetuximab, an epidermal growth factor inhibitor. Cyclophosphamide, an alkylating agent, has been shown to promote development of cSCC when used for the treatment of Wegener’s granulomatosis and would make a poor choice to treat this malignancy.
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