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Brief Report |

Effects of Combined Treatment With Arsenic Trioxide and Itraconazole in Patients With Refractory Metastatic Basal Cell Carcinoma

Mina S. Ally, MD1; Katherine Ransohoff, BA1,2; Kavita Sarin, MD, PhD1; Scott X. Atwood, PhD2; Melika Rezaee, BA1; Irene Bailey-Healy, MLS1; Jynho Kim, DVM, PhD2; Philip A. Beachy, PhD2; Anne Lynn S. Chang, MD1; Anthony Oro, MD, PhD1,2; Jean Y. Tang, MD, PhD1; A. Dimitrios Colevas, MD3
[+] Author Affiliations
1Department of Dermatology, Stanford University, Stanford, California
2Department of Dermatology, School of Medicine, Stanford University, Stanford, California
3Cancer Center, Stanford University, Stanford, California
JAMA Dermatol. 2016;152(4):452-456. doi:10.1001/jamadermatol.2015.5473.
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Importance  Tumor resistance is an emerging problem for Smoothened (SMO) inhibitor–treated metastatic basal cell carcinoma (BCC). Arsenic trioxide and itraconazole antagonize the hedgehog (HH) pathway at sites distinct from those treated by SMO inhibitors.

Objective  To determine whether administration of intravenous arsenic trioxide and oral itraconazole in patients with metastatic BCC is associated with a reduction in GLI1 messenger RNA expression in tumor and/or normal skin biopsy samples.

Design, Setting, and Participants  Five men with metastatic BCC who experienced relapse after SMO inhibitor treatment underwent intravenous arsenic trioxide treatment for 5 days, every 28 days, and oral itraconazole treatment on days 6 to 28. Data were collected from April 10 to November 14, 2013. Follow-up was completed on October 3, 2015, and data were analyzed from June 5 to October 6, 2015.

Main Outcomes and Measures  The primary outcome was the change in messenger RNA levels of the GLI family zinc finger 1 (GLI1) gene (HH-pathway target gene) in biopsy specimens of normal skin or BCC before and after treatment. Secondary objectives were evaluation of tumor response and tolerability.

Results  Of the 5 patients (mean [SD] age, 52 [9] years; age range, 43-62 years), 3 completed 3 cycles of treatment and 2 discontinued treatment early owing to disease progression or adverse events. Adverse effects included grade 2 transaminitis and grade 4 leukopenia with a grade 3 infection. Overall, arsenic trioxide and itraconazole reduced GLI1 messenger RNA levels by 75% from baseline (P < .001). The best overall response after 3 treatment cycles was stable disease in 3 patients.

Conclusions and Relevance  Targeting the HH pathway with sequential arsenic trioxide and itraconazole treatment is a feasible treatment for metastatic BCC. Although some patients experienced stable disease for 3 months, none had tumor shrinkage, which may be owing to transient GLI1 suppression with sequential dosing. Continuous dosing may be required to fully inhibit the HH pathway and achieve clinical response.

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Figure.
Effect of Combined Arsenic Trioxide and Itraconazole Treatment

Photographs demonstrate a basal cell carcinoma of the left ear before and after 3 cycles of arsenic trioxide–itraconazole treatment, which shows no clinical improvement. Scales are in centimeters. Computed tomography of lung metastasis before and after treatment also shows no reduction in size.

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