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Emerging efficacy endpoints for targeted therapies in advanced renal cell carcinoma.
Gore, ME, Escudier, B
Oncology (Williston Park, N.Y.). 2006;(6 Suppl 5):19-24
Abstract
Several novel targeted agents are being tested for the treatment of advanced renal cell carcinoma (RCC), and results of phase I and II trials have been encouraging. A recently completed phase III, placebo-controlled study showed that median progression-free survival doubled from 12 weeks to 24 weeks in patients treated with the multi-kinase inhibitor sorafenib (Nexavar) (hazard ratio [HR], 0.44; P < .00001), and approximately three-quarters of patients had some degree of tumor regression. Furthermore, interim analysis showed an estimated 39% improvement in overall survival in sorafenib-treated patients (HR, 0.72; P = .018) and an investigator-assessed response rate of 10%, indicating that many more patients had clinical benefit than had tumor regression qualifying as response by traditional criteria. These data and others have added to the evidence of lack of correlation between response rate and clinical benefit in RCC patients (as well as in other tumor types) treated with targeted therapies. Issues surrounding study endpoints and biologic efficacy markers for molecular targeted agents in RCC are discussed in this article, with a focus on results of the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGETs).
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FOLFOX versus FOLFIRI: a comparison of regimens in the treatment of colorectal cancer metastases.
Pasetto, LM, Jirillo, A, Iadicicco, G, Rossi, E, Paris, MK, Monfardini, S
Anticancer research. 2005;(1B):563-76
Abstract
Colorectal adenocarcinoma ranks second as a cause of death due to cancer in the Western world. Already at the time of the primary tumor, 15-25% of the patients present with liver metastases while another 20% will develop metastasis following treatment of the colorectal primary. Without any treatment the median survival after the detection of metastases is approximately 9 months, depending on the extent of the disease at the time of diagnosis. Clinical trials with the "FOLFOX and FOLFIRI families" of drugs, designed for the treatment of metastatic colorectal cancer, their results and the costs of each therapy are examined. For each drug, the cost/mg, the cost/mg/m2 and the cost/therapy (according to its duration) are evaluated according to the prices reported in the Italian Directory of Medicines and Manufacturers, 63rd Edition, November 2003.
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The role of chemotherapy in cholangiocarcinoma.
Thongprasert, S
Annals of oncology : official journal of the European Society for Medical Oncology. 2005;:ii93-6
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Phase II study of leucovorin, 5-fluorouracil and gemcitabine for locally advanced and metastatic pancreatic cancer (FOLFUGEM 2).
André, T, Noirclerc, M, Hammel, P, Meckenstock, R, Landi, B, Cattan, S, Selle, F, Codoul, JF, Guerrier-Parmentier, B, Mokhtar, R, et al
Gastroenterologie clinique et biologique. 2004;(8-9):645-50
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Abstract
AIM: FOLFUGEM 1 (leucovorin 400 mg/m2 combined with 5-flurorouracil (FU) bolus 400 mg/m2 then 5-FU 2-3 g/m2/46 hours and gemcitabine 1000 mg/m2 in 30 min) in patients with locally-advanced and metastatic pancreatic adenocarcinoma appeared to be toxic (neutropenia and alopecia). The aims of this phase II multicentric study were to evaluate the response rate, clinical benefit and tolerance of a new scheme of combined leucovorin, 5-FU and gemcitabine (FOLFUGEM 2). PATIENTS AND METHODS FOLFUGEM 2 associated leucovorin 400 mg/m2 in 2 hours followed by 5-FU 1000 mg/m2 in 22 hours, then gemcitabine 800 mg/m2 (10 mg/m2/min) with cycles every 14 days. Gemcitabine dose could be increased (1000 then 1250 mg/m2) when NCI/CTC toxicity was < or = grade 2. RESULTS Fifty-eight patients were included (locally-advanced tumor: N = 13 and metastatic: N = 45). Among the 39 patients with measurable disease, 11 had partial response (28.2%, 95% confidence interval: 14-42%) and 11 had stable disease (28.2%). On an intent-to-treat analysis, the objective response rate was 19% (95% confidence interval: 9-29%). Clinical benefit rate was 46%. Median progression-free survival and median overall survival were 3.1 and 7.2 months, respectively. There were 13% grade 3-4 neutropenia and 36% complete alopecia. CONCLUSION FOLFUGEM 2 schema has an antitumoral effect in advanced pancreatic cancer and has an acceptable toxicity which appears to be less than that of FOLFUGEM 1.
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Second-line therapy in colorectal cancer.
Berlin, J
Oncology (Williston Park, N.Y.). 2000;(12 Suppl 11):21-6
Abstract
Second-line therapy is a relatively new concept for gastrointestinal oncologists. Although retreatment with fluorouracil (5-FU) is common, offering colorectal cancer patients a different chemotherapeutic agent as second-line therapy is a fairly recent strategy. The focus of this article is on the use and efficacy of oxaliplatin (Eloxatin) as second-line therapy for colorectal cancer. As such, this article will present very limited data on the toxicity of oxaliplatin regimens.
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Downstream molecular determinants of response to 5-fluorouracil and antifolate thymidylate synthase inhibitors.
Van Triest, B, Pinedo, HM, Giaccone, G, Peters, GJ
Annals of oncology : official journal of the European Society for Medical Oncology. 2000;(4):385-91
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Abstract
Thymidylate synthase (TS) is an essential enzyme for the de novo synthesis of thymidylate and subsequently DNA synthesis. TS has been used as a target for cancer chemotherapy in the development of fluoropyrimidines such as 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine and of novel folate-based TS inhibitors such as ZD1694 (Tomudex, Raltitrexed), ZD9331, LY231514 (ALIMTA, Pemetrexed), AG337 (Thymitaq, Nolatrexed) and AG331. Although TS has been considered as a target for chemotherapy, the precise mechanism by which TS inhibition leads to cell death is still not completely resolved. TS inhibition results in depletion of dTTP, an essential precursor for DNA, and an increase in dUTP. This results in the so-called thymine-less death due to misincorporation of dUTP into DNA; its excision, catalysed by uracil-DNA glycosylase, results in DNA damage. Both this imbalance in dTTP/dUTP and DNA damage can result in induction of downstream events, leading to apoptosis. On the other hand a specific interaction exists between oncogenes and TS, by binding of TS protein to the p53 and c-myc RNA, while wt p53 can also inhibit TS promotor activity. TS inhibition by either 5-FU or antifolates can also result in a depression of TS protein mediated inhibition of TS mRNA translation leading to induction of more TS protein synthesis, and p53 protein may further deregulate this process. These complex indirect and direct interactions between oncogenes and TS may have as yet unclear clinical implications, since most data are based on in vitro or in vivo studies and some results are contradictive. In some preliminary clinical studies evidence was postulated for a combined prognostic role for TS and p53. This knowledge should be used to design clinical studies with the aim to deliver effective treatment to potentially sensitive patients both in the adjuvant setting and in advanced stage disease.