The common antifungal drug itraconazole may be useful in treating basal cell carcinoma (BCC), according a phase 2 study published online February 3 in the Journal of Clinical Oncology.
Itraconazole showed anti-BCC activity in a 29-patient study: 24% of the 19 patients treated for a month with common doses of the drug had a reduced tumor area. Also, itraconazole reduced cell proliferation by 45%.
In contrast, the tumors of the study's 10 untreated control patients showed no significant changes in tumor size or proliferation.
"Itraconazole can reduce basal cell carcinoma tumor size via inhibition of the hedgehog signaling pathway after 1 month of treatment," write the authors, including Jean Tang, MD, PhD, of Stanford University School of Medicine in Palo Alto, California.
All BCCs have malignant activation of the hedgehog signaling pathway, the authors point out.
Itraconazole is in the same class of drugs as vismodegib (Erivedge, Genentech), which was the first orally bioavailable small molecule inhibitor of the hedgehog pathway and was approved in 2012 for first-line treatment of advanced BCC by the US Food and Drug Administration (FDA).
The approval validated the effectiveness of hedgehog pathway inhibition in the treatment of BCC, the study authors say.
They also say that vismodegib is the more potent treatment, even though the 2 agents have not been compared head to head.
"Itraconazole may be effective as second-line therapy," the authors write, explaining itraconazole acts on the pathway at a site distinct from vismodegib.
Another expert agrees that itraconazole is the inferior agent here. The degree of hedgehog pathway inhibition is "clearly more profound with vismodegib," writes Luc Dirix, PhD, in an editorial that accompanies the new study. He is from the Sint-Augustinus Cancer Center, Antwerp University Hospital, in Belgium.
Itraconazole reduced hedgehog pathway activity by 65% in the new study, while vismodegib has been shown to reduce it by 90%, he points out.
But, on a positive note, there is a different spectrum of adverse events with itraconazole than with other drugs in this class including vismodegib.
The absence of these side effects, including hair loss, muscle cramps and weight loss, bodes well for itraconazole, the study authors suggest. They point out that vismodegib is not a "viable treatment" for a majority of nonadvanced BCCs because of such effects.
And BCC is mostly made up of nonadvanced disease. Only 2% of all BCC is advanced (inoperable or metastatic).
Most BCC can be treated by surgery, but that can lead to significant scarring and morbidity, Dr. Tang and her coauthors point out.
There is a great need for nonsurgical forms of treatment in BCC, say the authors.
"Given the rising incidence of BCC and its costly treatment — one of the highest among Medicare recipients — there is a large unmet clinical need for nonsurgical forms of treatment," they write.
Chemotherapeutic creams such as imiquimod and fluorouracil are FDA approved for BCC, but these topical options are effective only against the superficial subtype, which comprises only 30% of all BCCs. That leaves a lot of patients with surgery as their main treatment choice, the authors suggest.
Itraconazole is ready to be investigated in large clinical trials for BCC, the authors believe. Much is yet to be learned about the drug in this setting, they say, including the safety and efficacy in the longer term. In the current study, efficacy was assessed after only 1 month of treatment. Also, the study population did not include any patients with advanced basal cell carcinoma.
In their new paper, the researchers also tell a bit of the back story of how itraconazole, which is used in the treatment of fungi such as oral candidiasis and blastomycosis, came to be tested in skin cancer.
Members of the research team previously published a 2010 study identifying drugs that could block the hedgehog pathway but that were approved for or tested in diseases other than BCC.
They screened 2400 drugs. Itraconazole was the "most promising" because it blocked the hedgehog pathway at the normal dosage prescribed for fungal infections, according to a press statement.
Subsequent lab research indicated itraconazole suppressed BCC carcinogenesis in mice. It was time for early research in humans.
"New drugs cost about $800 million and an average of 10 years to develop," Dr. Tang said in a press statement. "We are shortcutting the process by using a drug that's already been around for 25 years and given to tens of thousands of people."
The study was funded by the Stanford SPARK program and the Damon Runyon Clinical Investigator Award.
Dr. Tang has a financial relationship with Genentech. The editorialist has disclosed no relevant financial relationships.
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Cite this: Common Antifungal Drug Works in Basal Cell Carcinoma - Medscape - Feb 10, 2014.