Abstract
Background: Temozolomide is efficacious as an oral alternative for patients with metastatic melanoma (MM). Calcitriol has anti-proliferative properties and vitamin D receptor (VDR) polymorphisms are associated with alterations in melanoma susceptibility and progression. Methods: Tem 150 mg/m2 was administered on days 2–8 and 16–22 every 28 days. Calcitriol was given on days 1 and 15 every 28 days. VDR gene analysis was completed using PCR-RFLP based assays. Tolerability was the primary objective with secondary objectives of time to progression (TTP) and overall survival (OS). Results: Twenty pts with MM were registered. Cytopenias and thrombosis were the most common grade 3 or 4 toxicities. Median TTP was 1.8 mo. Pts with high-risk VDR genotype tt+/−ff (n = 6) had an OS of 3.8 mo from time of enrollment, compared to 7.4 mo for those with non-tt/ff genotypes (n = 11), although not statistically significant (HR = 1.20, 95% CI 0.41–3.53, p = 0.74). Conclusions: The extended dosing of Tem with calcitriol is a well-tolerated regimen. The trend toward improved OS in non-tt/ff VDR genotypes is consistent with prior studies associating the tt/ff genotype with biologic aggressiveness.
Highlights
Metastatic melanoma (MM) is relatively resistant to systemic chemotherapy and carries a dismal prognosis in the setting of disseminated disease with a median survival of 8.9 months [1]
Given the favorable effects of calcitriol on chemotherapy toxicity noted in the ASCENT-1 trial [14], and the effect in vitro on vitamin D receptor (VDR) expressing melanoma cell lines, we hypothesized that the combination of calcitriol plus temozolomide might result in enhanced response rates and a more tolerable side effect profile
Chinot et al found 20% grade 3 or 4 thrombocytopenia and lymphopenia, 17% neutropenia, and 18% febrile interstitial pneumonitis associated with profound neutropenia or lymphopenia [7]
Summary
Erin Pettijohn 1,2, Brenda Martone 1, Alfred Rademaker 3 and Timothy Kuzel 1,2,*. Department of Medicine, Northwestern University, 251 E. Received: 19 August 2014; in revised form: 18 September 2014 / Accepted: 23 September 2014 /
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