Gemcitabine-radiotherapy in patients with locally advanced pancreatic cancer

Department of Medical Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
European Journal of Cancer (Impact Factor: 5.42). 07/2002; 38(9):1212-7. DOI: 10.1016/S0959-8049(02)00076-X
Source: PubMed


A feasibility study was performed to assess the toxicity and efficacy of a combination of gemcitabine-radiotherapy in patients with locally advanced pancreatic cancer (LAPC). 24 patients (15 females and 9 males) with measurable LAPC were included; the median age of the patients was 63 years (range 39-74 years). The performance status ranged from 0 to 2. Gemcitabine was administered at a dose of 300 mg/m(2), concurrent with radiotherapy, three fractions of 8 Gy, on days 1, 8 and 15. When compliance allowed, gemcitabine alone was continued thereafter, at 1000 mg/m(2), weekly times 3, every 4 weeks, depending on the response and toxicity. All patients were evaluable for toxicity and response. The objective response rate was 29.2% (1 complete remission+6 partial remissions); 12 patients had stable disease. However, 2 of the radiological partial remissions were shown to be complete remissions by pathology assessment. Median duration of response was 3 months (range 1-35+months). Median time to progression was 7 months (range 2-37+months). Median survival was 10 months (range 3-37+months). Dose reduction or omission of gemcitabine was necessary in 10 patients. Non-haematological toxicity consisted of 87.5% nausea and vomiting grade I-II, diarrhoea 54%, ulceration in stomach and duodenum 37.5% (20.8% ulceration with bleeding); 1 patient developed a fistula between the duodenum and aorta, 5 months after treatment. Anaemia grade III-IV was observed in 8.3% of the patients. Neutropenia grade III-IV was observed in 8.3%, thrombocytopenia grades III-IV in 16.7%. In 1 patient who underwent resection postchemoradiation, no viable tumour cells were found. In addition, in the patient who suddenly died of a fistula between the duodenum and aorta, no viable tumour cells were detectable at autopsy. Although the toxicity of this treatment was occasionally severe, the response and survival are encouraging and warrant further studies of this combination.

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    • "In this series of 24 patients, the authors report a 37.5% incidence of ulceration in the stomach (9 patients) with 5 of these having associated bleeding. Two deaths were reported, including one from a bleeding ulcer and another from the development of an aortoduodenal fistula [35]. "
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    ABSTRACT: Survival in patients with unresectable pancreatic carcinoma is poor. Studies by Mayo Clinic and the Gastrointestinal Tumor Study Group (GITSG) have established combined modality treatment with chemotherapy and radiation as the standard of care. Use of gemcitabine-based chemotherapy alone has also been shown to provide a benefit, but 5‑year overall survival still remains less than 5%. Conventional radiotherapy is traditionally delivered over a six week period and high toxicity is seen with the concomitant use of chemotherapy. In contrast, SBRT can be delivered in 3-5 days and, when used as a component of combined modality therapy with gemcitabine, disruption to the timely delivery of chemotherapy is minimal. Early single-institution reports of SBRT for unresectable pancreatic carcinoma demonstrate excellent local control with acceptable toxicity. Use of SBRT in unresectable pancreatic carcinoma warrants further investigation in order to improve the survival of patients with historically poor outcomes.
    Cancers 09/2010; 2(3):1565-1575. DOI:10.3390/cancers2031565
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    • "The benefit seen in the early combinedmodality trials was modest, however, with a median survival of only 10 months. To improve the efficacy of the treatment, various anticancer agents such as gemcitabine and radiation schedules are being examined in clinical trials (Burris et al, 1997; Blackstock et al, 1999; McGinn et al, 2001; de Lange et al, 2002; McGinn and Zalupski, 2003; Okusaka et al, 2004). As yet, however, no regimen has been shown to be superior to conventional chemoradiotherapy with 5-FU. "
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    ABSTRACT: Gemcitabine (dFdCyd) is a nucleoside analog that produces synergistic killing of tumor cells with ionizing radiation (radiosensitization). Previously, radiosensitization correlated with dATP depletion, mediated by dFdCyd diphosphate inhibition of ribonucleotide reductase, and S-phase accumulation, whereas dFdCyd triphosphate and its incorporation into DNA contributed to cytotoxicity but not radiosensitization. DNA damage caused by dFdCyd can induce p53, and this dissertation examines the roles of wild-type (wt) p53 and a p53-inducible ribonucleotide reductase subunit, p53R2, in the radiosensitizing mechanism. Based on previous findings, it was hypothesized that p53 expression could prevent S-phase accumulation by inducing a G1 block after dFdCyd exposure. Although p53 was induced strongly and rapidly with IC90 dFdCyd, p53 induction occurred as MCF-7 breast cancer cells accumulated in S-phase resulting in radiosensitization. The data demonstrate that p53 induction does not prevent radiosensitization in MCF-7 cells at clinically relevant concentrations of dFdCyd. p53R2 is induced by DNA damage, providing dNTPs for DNA repair. Since dATP depletion is pivotal for radiosensitization, it was important to determine if dFdCyd could induce p53R2 to alter dATP depletion and radiosensitization. p53R2 was induced in response to dFdCyd, even at radiosensitizing but non-cytotoxic concentrations, regardless of cell cycle distribution. Expression of the replication-associated ribonucleotide subunit, R2, increased as cells accumulated in S-phase following dFdCyd addition, and decreased after ionizing radiation as cells accumulated in G1 and G2/M. MCF-7 breast and HCT116 colon carcinoma (wt p53) cells expressed p53R2 after dFdCyd exposure, but dATP depletion and radiosensitization were unaffected compared to p53-deficient counterparts. This suggests that p53R2 induction could not maintain dNTP pools following dFdCyd exposure in these cell lines. The role of p53R2 in radiosensitization was evaluated more directly using siRNA-mediated p53R2 suppression. It was hypothesized that p53R2 silencing would increase dFdCyd-mediated dNTP depletion and radiosensitization. Although p53R2 silencing did not alter cytotoxicity or radiosensitization in the MCF-7 cell line, radiosensitization was increased in the A549 non-small cell lung cancer cells following p53R2 suppression, due to improved dNTP depletion. The data suggest that, in some cell lines, p53R2 is induced to sufficient levels to maintain dNTP pools after dFdCyd exposure, thereby preventing radiosensitization. Ph.D. Pharmacology University of Michigan, Horace H. Rackham School of Graduate Studies
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