Gemcitabine plus metronomic 5-fluorouracil or capecitabine as a second-/third-line chemotherapy in advanced adrenocortical carcinoma: a multicenter phase II study

Abstract

Adrenocortical carcinoma (ACC) is a rare neoplasm characterized by poor prognosis. First-line systemic treatments in advanced disease include mitotane, either alone or in combination with chemotherapy. Studies evaluating second-line therapy options have obtained disappointing results. This trial assessed the activity and toxicity of gemcitabine plus metronomic fluoropyrimidines in heavily pretreated advanced ACC patients. From 1998 to 2008, 28 patients with advanced ACC progressing after mitotane plus one or two systemic chemotherapy lines were enrolled. They received a combination of i.v. gemcitabine (800 mg/m 2 , on days 1 and 8, every 21 days) and i.v. 5-fluorouracil protracted infusion (200 mg/m 2 /daily without interruption until progression) in the first six patients, or oral capecitabine (1500 mg/daily) in the subsequent patients. Mitotane administration was maintained in all cases. The rate of non-progressing patients after 4 months of treatment was 46.3%. A complete response was observed in 1 patient (3.5%); 1 patient (3.5%) obtained a partial regression, 11 patients (39.3%) obtained a disease stabilization and 15 patients (53.7%) progressed. Treatment was well tolerated, with grade III and IV toxicities consisting of leukopenia in six patients (21.4%), thrombocytopenia in one patient (3.5%), and mucositis in one patient (3.5%). Median time to progression and overall survival in the patient population were 5.3 (range: 1-43) and 9.8 months (range: 3-73) respectively. Gemcitabine plus metronomic fluoropyrimidines is a well-tolerated and moderately active regimen in heavily pretreated ACC patients.

Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma

“…It should be noted, however, that mitotane was not withdrawn in the gemcitabine and capecitabine trial as in the present one, and mitotane serum levels within the therapeutic range (14-20 ng/ml) were associated with a prolonged PFS (29). These data suggest that mitotane may potentiate chemotherapy activity even in refractory disease.…”

“…We have recently shown that the combination of gemcitabine and metronomic capecitabine was active in heavily pretreated ACC patients (29). These findings suggest that a metronomic approach deserves interest despite the negative results of the present trial.…”

Cytotoxic activity of gemcitabine, alone or in combination with mitotane, in adrenocortical carcinoma cell lines

“…Primarily, no preclinical data on gemcitabine activity on ACC cell lines have been published, so far, although this drug represents an antitumoral compound used in advanced ACC patients (Sperone et al, 2010). Very few studies in the literature analyzed the effects of different chemotherapeutic agents on the growth and survival of ACC cells in vitro.…”

“…Gemcitabine requires intracellular phosphorylation to its active metabolites, 2'-2'-difluoro-dCDP and 2'-2'-difluoro-dCTP, which, specifically inhibits RRM1 and is incorporated into the DNA leading to chain termination (Gandhi et al, 1995). In ACC, a recent phase 2 study demonstrated that a combination of gemcitabine plus fluoropyrimidine derivatives (5-fluoruracilor capecitabine) and mitotane was active as second or third-line treatment (Sperone et al, 2010). However, no data are currently available on the cytotoxic efficacy of gemcitabine in ACC cells, in vitro.…”

Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts

“…When administered daily, capecitabine efficacy is superior to intravenous 5-FU infusion in the treatment of anthracycline-resistant metastatic breast cancer (19) and is approved for colorectal cancer treatment (20). Recent studies of metronomically dosed capecitabine with gemcitabine show comparable or modestly improved survival times and good tolerability (21,22).…”