Therapy With Hedgehog Inhibitors for Locally Advanced or Metastatic Basal Cell Carcinoma
Rogerio I. Neves, MD, PhD, Bryan Anderson, MD, Joseph Drabick, MD, Donald R. Mackay, MD.
Penn State Hershey, Hershey, PA, USA.
PURPOSE: Basal cell carcinoma (BCC) may occasionally progress to an advanced state that is no longer amenable to surgery, radiation therapy or, more rarely, may spread to distant sites. Genetic studies have shown that almost all BCC's contain aberrant Hedgehog signaling pathway activation and uncontrolled proliferation of basal cells. Most commonly, these alterations cause loss of function of patched homologue 1 (PTCH1), which normally acts to inhibit the signaling activity of smoothened homologue (SMO). Vismodegib is an inhibitor of the Hedgehog pathway that binds to and inhibits SMO, a transmembrane protein involved in Hedgehog signal transduction. We present a series of patients from a single institution with locally advanced BCC (LABCC) or metastatic BCC (MBCC) that were treated with Vismodegib in a 16-month period.
METHODS: From April 2012 to June 2013 twenty adult patients with LABCC, recurring or MBCC that were not candidates for surgery or radiation therapy, received Vismodegib 150 mg once daily until disease progression, unacceptable side effects or discontinuation of the treatment at patients request. Objective response rate was assessed by RECIST guidelines version 1.0. When applicable, response was defined as a decrease of 30% or more in the externally visible or radiographic dimension or complete resolution of ulceration if present at baseline. Progressive disease was defined as an increase of 20% or more in the externally visible or radiographic dimension, new ulceration, or a new lesion. For patients with multiple lesions, the sum of the longest diameters was used to determine response and progression. Photographs were taken for all patients with LABCC, and radiographic scans for all patients with MBCC and for patients with LABCC who had radiographically measurable disease. Some patients with LABCC who had a response underwent tumor biopsy during the treatment and pathological evaluation was used to determine whether the response was partial or complete based on the presence or absence of residual BCC in the biopsy specimen. Photographs of the lesions were performed before and during treatment.
RESULTS: The most common side effects were loss of taste (100%), cramps (80%), hair loss (50%), weight loss (30%) and fatigue (10%). Patients with LABCC (n=19), objective response rate was above 80%. One patient was excluded from treatment on his request due to unacceptable side effects. As of the data-cutoff point 13 patients had complete response (defined as the absence of residual BCC on assessment of a biopsy specimen) and 7 patients had partial response. One patient with MBCC to the axillary lymph nodes (n=1) had only clinical objective response by assessment of cessation of pain, weeping and shrinkage of axillary wound with only 4 months of treatment. As of the data-cutoff point, 13 of the 13 patients who had a complete response had not had disease recurrence. The totality of patients with LABCC had visible reductions in tumor size and improvement in cosmetic appearance.
CONCLUSION: Vismodegib is a new treatment alternative and associated with tumor responses in patients with LABCC or MBCC.
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