Pharmacokinetic evaluation of capecitabine in breast cancer.

INTRODUCTION: Capecitabine , an oral prodrug of 5-fluorouracil (5-FU), is adsorbed in its intact form through the intestine and metabolized to 5-FU in tumour cells. In metastatic breast cancer (MBC), capecitabine is an effective and well-tolerated therapeutic option both in monotherapy and in combination with chemotherapeutic or molecular-targeted agents. AREAS COVERED: We summarized data on pharmacokinetics and pharmacodynamics of capecitabine. We also produced a general review of the most relevant clinical studies of capecitabine in MBC. A literature search was performed using PubMed database including selected articles published in English language up to October 2012. EXPERT OPINION: The unique pharmacodynamic/pharmacokinetic features represent the bases of the reduced toxicity and the activity of capecitabine in several tumours. Although during the past 10 years there has been an increasing use of this drug in MBC both as single agent and in combination, encouraging results of well tolerated and active combinations with novel agents will lead to a more extensive and protracted use of capecitabine. In view of this, some aspects should be further clarified such as the optimal starting dose and the introduction of alternative schedules of treatment.

Anticancer effect of bisphosphonates: new insights from clinical trials and preclinical evidence.

Bisphosphonates (BPs) are cornerstones in the treatment of patients with compromised skeletal integrity (either cancer related or not). However, a major indication for BPs use remains the treatment of patients with advanced cancer metastatic to the bone. Recently, several observations derived from clinical trials, primarily aimed at establishing the impact of BPs on the bone health of cancer patients, suggested a potential role for these agents as direct anti-tumor drugs. Consequently, a series of preclinical works were produced with the aim of clarifying the mechanism underlying this observed effect. However, the impact of such data is still under debate owing to the intrinsic weakness of observations from trials not adequately powered to support them. In conclusion, the entire matter remains one of the most intriguing in oncology, and data from ongoing and planned future studies will surely provide us with more information on the great potential of BPs in the adjuvant setting.

Time spent for activation of non-profit studies in oncology in Italy.

AIM: The aim of this paper is to describe the time spent to activate oncological non-profit clinical trials promoted in Italy by the National Cancer Institute of Naples, following the implementation of recent European laws. METHODOLOGY: Data about the process of activation of 5 non-profit multicentre clinical trials were prospectively collected through a web-based system. The impact of European guidelines was assessed by comparing the efficiency of the process between applications started before and after the decree introducing in Italy the Clinical Trial Application form (MD-CTA). Outcomes of the descriptive analyses were the time to EC opinion, the time to administrative agreement signature after a positive EC opinion, and the cumulative percentage of submissions that came to closure (either positive or negative) within four subsequent time cohorts. PRINCIPAL FINDINGS: From March 2007 to October 2009, 202 applications were submitted to 107 centres. Forty-four (59%) applications of those submitted before were successful, compared to 71 (55%) of those submitted after MD-CTA. Most of the failures were due to missing EC response (27% and 22%) or administrative reasons (10% and 16%, before and after, respectively); very few (4% and 7%) were due to EC refusal. The impact of the MD-CTA on time to EC opinion looked positive (median 4.1 vs 2.4 months, before and after, respectively) but a subgroup analysis revealed that the impact was limited to a comparison biased by the selection of EC. After a positive EC opinion, there was no difference before and after MD-CTA in the time to administrative agreement signature (median 3.6 and 3.8 months, respectively). A trend to shortening time to closure of the whole submission process over the time was evident, with 58% of the applications coming to closure within 6 months from submission in the most recent cohort. CONCLUSIONS: In our experience there is reassuring evidence of a trend toward shortening the time spent to activate non-profit clinical trials in Italy, but the whole process still remains inefficient. Efforts should be made to improve the process, also focusing on administrative procedures.

Vinorelbine for non-small cell lung cancer.

IMPORTANCE OF THE FIELD: Vinorelbine is a 'third-generation' vinca alkaloid approved for the treatment of NSCLC. The introduction of 'third-generation' drugs (vinorelbine, gemcitabine, taxanes) in platinum combination improved survival of patients with advanced NSCLC, with substantially similar results among the different drugs. Treatment toxicities are considerable in this setting. AREAS COVERED IN THIS REVIEW: This narrative review reports a synthesis of evidence available from published clinical trials, systematic reviews and meta-analyses on the activity and safety of vinorelbine, used as single agent or in combination chemotherapy in patients with NSCLC, from 1990 to 2009. WHAT THE READER WILL GAIN: When vinorelbine was administered in a weekly schedule without interruptions, the most common toxicity was neutropenia that often precluded administration of the drug, therefore, reducing the dose intensity. A schedule providing administration of vinorelbine on days 1 and 8 every 3 weeks seemed to improve the tolerability of the drug. Tolerability of the drug did not result lower in the elderly subset. None of the other 'third-generation' drugs were clearly better tolerated than vinorelbine. Moreover, in the adjuvant setting, vinorelbine is the only third-generation drug that demonstrated, in combination with cisplatin, a consistent improvement in survival on a long-term basis. TAKE HOME MESSAGE: Vinorelbine is an active and generally manageable therapeutic option for the treatment of both early and advanced NSCLC.

Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: current status and future directions.

Vandetanib is a novel, orally available inhibitor of different intracellular signaling pathways involved in tumor growth, progression, and angiogenesis: vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and REarranged during Transfection tyrosine kinase activity. Phase I clinical trials have shown that vandetanib is well tolerated as a single agent at daily doses < or =300 mg. In the phase II setting, negative results were observed with vandetanib in small cell lung cancer, metastatic breast cancer, and multiple myeloma. In contrast, three randomized phase II studies showed that vandetanib prolonged the progression-free survival (PFS) time of patients with non-small cell lung cancer (NSCLC) as a single agent when compared with gefitinib or when added to chemotherapy. Rash, diarrhea, hypertension, fatigue, and asymptomatic QTc prolongation were the most common adverse events. Antitumor activity was also observed in medullary thyroid cancer. Four randomized phase III clinical trials in NSCLC are exploring the efficacy of vandetanib in combination with docetaxel, the Zactima in cOmbination with Docetaxel In non-small cell lung Cancer (ZODIAC) trial, or with pemetrexed, the Zactima Efficacy with Alimta in Lung cancer (ZEAL) trial, or as a single agent, the Zactima Efficacy when Studied versus Tarceva (ZEST) and the Zactima Efficacy trial for NSCLC Patients with History of EGFR-TKI chemo-Resistance (ZEPHYR) trials. Based on a press release by the sponsor of these trials, the PFS time was longer with vandetanib in the ZODIAC and ZEAL trials; the ZEST trial was negative for its primary superiority analysis, but was successful according to a preplanned noninferiority analysis of PFS. Ongoing phase II and III clinical trials will better define the appropriate schedule, the optimal setting of evaluation, and the safety of long-term use of vandetanib.