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Objective: To review vismodegib, the first Food and Drug Administration (FDA)-approved Hedgehog (Hh) signaling pathway inhibitor, in the treatment of advanced basal cell carcinoma (BCC)., Data Sources: MEDLINE and PubMed were searched using the terms vismodegib, GDC-0449, RG3616, and basal cell carcinoma for relevant clinical trials through September 2013. The FDA Web site, the National Clinical Trials registry, and abstracts from the American Society of Clinical Oncology (ASCO) were also evaluated to identify unpublished data and future clinical trials., Study Selection/data Extraction: All identified clinical and preclinical studies published in the English language were assessed, including selected references from the bibliographies of articles., Data Synthesis: Activation of the Hh signaling pathway is well documented in BCC. Vismodegib is a small-molecule inhibitor of Hh signaling that acts by antagonizing the protein Smoothened (SMO), thereby preventing downstream transcriptional activation of genes involved in cell proliferation and survival. Vismodegib was approved by the FDA in January 2012 for the treatment of recurrent, locally advanced BCC (laBCC), or metastatic BCC (mBCC) for which surgery or radiation cannot be utilized. A pivotal phase 2 trial evaluating 104 patients demonstrated that treatment with vismodegib, 150 mg orally once daily, resulted in a 30% and 43% objective response rate in patients with mBCC and laBCC, respectively. The most common adverse effects from vismodegib were mild to moderate and included muscle spasms, dysgeusia, decreased weight, fatigue, alopecia, and diarrhea. However, clinical studies noted a high incidence of discontinuation of therapy by patients for reasons other than disease progression., Conclusions: The approval of vismodegib represents the only targeted, prospectively studied treatment option for patients with advanced BCC. Further research assessing the utility of vismodegib in the treatment of other malignancies and the development of resistance patterns will more clearly define the role of Hedgehog inhibition in the broader scheme of oncological disorders.

Abstract Bicalutamide is a nonsteroidal antiandrogen used extensively during the start of androgen deprivation therapy with a luteinizing hormone-releasing hormone agonist to reduce occurrence of the symptoms of tumor flare in patients with metastatic prostate carcinoma. The most common adverse effects of bicalutamide are induced by its pharmacologic property of competitive androgen receptor blockade and include gynecomastia, hot flashes, fatigue, and decreased libido. Although not as common, increases in liver function test results are also seen with bicalutamide therapy. These elevations are typically transient, and patients remain asymptomatic. We describe a 59-year-old man with metastatic prostate carcinoma treated with bicalutamide as part of androgen deprivation therapy before starting chemotherapy. At baseline, his liver function test results and serum creatinine concentration were within normal limits, and an abdominal computed tomographic scan did not demonstrate liver metastasis. After 4 days of bicalutamide therapy, the patient came to the emergency department with complaints of abdominal pain, distension, and tenderness. His liver function tests were abnormal, and bicalutamide was discontinued. After 2 days of increasing liver function tests and symptoms of hepatotoxicity, the patient developed tachycardia and hypotension that was resistant to fluid resuscitation. Multiorgan damage was manifested by an alanine aminotransferase level greater than 40 times the upper limit of normal, serum creatinine concentration of 4.2 mg/dl, and troponin I level of 18 ng/ml. The patient died 8 days after bicalutamide therapy was begun secondary to multiorgan failure, most likely as a result of fulminant hepatotoxicity. The Naranjo adverse drug reaction probability scale showed a probable (score of 5) causal relationship between bicalutamide and fulminant hepatotoxicity. Fulminant hepatotoxicity is a rare but potentially fatal adverse effect of bicalutamide. Liver function tests should be monitored before and during bicalutamide therapy, even for patients who have previously completed a course of this therapy with no signs or symptoms of toxicity.