Monitoring Safety with Hedgehog Inhibitors in BCC

In "Monitoring Safety with Hedgehog Inhibitors in BCC," the focus shifts to tolerability, laboratory monitoring, and the limits of smoothened inhibition.

Dr. Singh stresses that tolerability is key to achieving good outcomes with hedgehog inhibitors. Baseline and periodic creatine kinase and creatinine testing are required for both agents in the class. He notes that longtime clinicians may not recall this was not originally required for vismodegib. A citizen's petition, prompted by emerging real-world data, led to routine monitoring for both medications. Embryo-fetal toxicity is also a class-wide risk.

In his own practice, Dr. Singh adds a complete blood count and comprehensive metabolic panel, since liver abnormalities, anemias, and lymphopenias have been reported. Muscle spasms and alopecia each occur in more than half of patients. Dysgeusia affects somewhat under half, while fatigue and nausea each occur in more than a third. Musculoskeletal pain and diarrhea occur in about a third, and slightly fewer patients experience weight loss and decreased appetite.

Timing matters, particularly in the neoadjuvant setting. Fatigue, muscle spasms, nausea, and dysgeusia tend to appear within the first 4 months. Alopecia typically emerges around month 5, and weight loss generally begins at 6 months or later. Dr. Singh uses this timeline to plan therapy duration around anticipated adverse effects.

For muscle spasms, his team uses L-carnitine, which has limited supporting evidence, alongside naturopathic colleagues. Studies suggest possible benefit at up to 2 g per day. He prescribes 400 mg three times daily, because adherence drops significantly when a fourth daily dose is added.

He closes on resistance. Because these drugs inhibit smoothened, tumors can develop resistance, and response duration is finite. Downstream GLI antagonists are in development, though he notes a plausible mechanism does not guarantee real-world efficacy. Topical patidegib gel is being studied in Gorlin syndrome. Topical itraconazole and HDAC inhibitors, which suppresses GLI expression, also show early promise.

Coming up in "Case 1: Assessing a Surgery-Refractory Patient with Recurrent Temple BCC," Dr. Singh presents the first of three patient cases and makes the argument for looking beyond another excision.