Prolonged fixed dose rate infusion of gemcitabine with autologous haemopoietic support in advanced pancreatic adenocarcinoma

Abstract

This study aimed to define the maximum-tolerated dose (MTD) of fixed dose rate (FDR) of gemcitabine (2 0 -2 0 -difluorodeoxycitidine) infusion with circulating haemopoietic progenitor support and to evaluate the activity of the treatment. Secondary end points were pharmacokinetic of gemcitabine and difluorodeoxyuridina (dFdU) measured at first course and the activity andexpression profile of cytidine deaminase (CdA) on circulating mononuclear cells. Patients with advanced pancreatic carcinoma received escalating dose of gemcitabine 10 mg m À2 min À1 every 2 weeks with circulating haemopoietic progenitor support. First dose level was 3000 mg m À2and the doses were increased by 500 mg m À2 until MTD. In all, 23 patients were enrolled. Toxicities were mild or moderate; the only patient treated at 7000 mg m À2 died because of toxicity; therefore; the MTD was established at 6500 mg m À2 . The overall response rate was 22.2%. The AUC of gemcitabine showed a dose-dependent increase, while the AUC of dFdU reached a plateau at 4500 mg m À2 . A significant relationship was found between the AUC of dFdU and CdA expression and activity (Po0.05). Moreover, progression rate and survival were significantly related to CdA expression and activity levels. The activity of high-dose gemcitabine is not superior to that reported with less intensive FDR schedules. The predictive role of CdA expression and activity on outcome deserves further investigation.

Association of xeroderma pigmentosum group D (Asp312Asn, Lys751Gln) and cytidine deaminase (Lys27Gln, Ala70Thr) polymorphisms with outcome in Chinese non-small cell lung cancer patients treated with cisplatin-gemcitabine

“…Tibaldi et al (2008) suggested that the CDA 27Lys/Lys genotype predicted a better clinical benefit, a higher response rate, and longer TTP and OS compared to the other CDA genotypes. Another clinical study showed a correlation between mRNA expression of CDA in peripheral blood mononuclear cells and clinical outcome in gemcitabine-treated patients (Bengala et al, 2005). Maring et al (2010) investigated the impact of the common non-synonymous SNP in the CDA gene, CDA 27, on gemcitabine pharmacokinetics in NSCLC patients.…”

Noninvasive prediction of tumor responses to gemcitabine using positron emission tomography

“…1 A). Elevated CDA expression has been associated with poor progression rate and survival in advanced pancreatic adenocarcinoma patients treated with dFdC (36). Similar to dFdC, FAC is also susceptible to deamination (D.O.C.…”

Cytidine deaminase single-nucleotide polymorphism is predictive of toxicity from gemcitabine in patients with pancreatic cancer: RTOG 9704

“…15 Only cells transfected with CDA are less sensitive to gemcitabine suggesting the need for very high levels of CDA activity. 16 However, clinical studies show a correlation between mRNA expression of CDA in peripheral blood mononuclear cells and clinical outcome in gemcitabine-treated patients, 17 and CDA gene expression in bone marrow mononuclear cells and hematological toxicity. 18 Similarly, the pharmacogenomics of deamination, including CDA polymorphisms, is conflicting.…”