Phase III Study of Bolus Versus Infusion Fluorouracil With or Without Cisplatin in Advanced Colorectal Cancer

Hansen, Richard M.; Ryan, Louise; Anderson, Tom; Krzywda, Beth; Quebbeman, Edward J.; Benson, Al B.; Haller, Daniel G.; Tormey, Douglass C.

doi:10.1093/jnci/88.10.668

Cited by 116 publications

(41 citation statements)

References 13 publications

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“…Various kinds of cytotoxic agents, according to the theory mentioned above, can be applied to diminish or to regress the tumor mass in experimental models and some patients (25)(26)(27)(28). Similarly we hypothesized that the conventional chemotherapy of TMZ required a treatment-free interval to allow the recovery of tumor cell growth, implying that the presence of microvascular endothelial cells in the tumor bed involves resuming their proliferation and supporting tumor regrowth.…”

Section: Discussionmentioning

confidence: 99%

Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas

Kim

Kim²,

Ko³

et al. 2006

Oncol Rep

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Abstract. Glioblastoma is a highly angiogenic tumor with a dismal prognosis. Temozolomide (TMZ), a methylating agent is one of the most effective chemotherapeutic agents against glioblastoma. To overcome the problem that most of these tumors become resistant to chemotherapeutic regimens within a year, we investigated the antitumor efficacy of metronomic administration of low-dose TMZ in in vitro cell proliferation/ cytotoxicity assay and in vivo rat and nude mouse orthotopic glioma model. By in vitro assay, we elucidated that C6/LacZ rat glioma cells were more resistant to metronomic treatment of TMZ than U-87MG human glioblastoma cells and bEnd.3 mouse brain endothelial cells. Compared with the conventional chemotherapeutic regimen of TMZ, we found that frequent administration of TMZ at a low dose (metronomic treatment) markedly inhibited angiogenesis as well as tumor growth in a TMZ-resistant C6/LacZ rat glioma model. In addition, metronomic treatment of TMZ significantly augmented apoptosis of tumor cells in this model. For the TMZ-sensitive U-87MG cells, even with a very low dose of TMZ, which is not effective to reduce tumor mass, the metronomic treatment of TMZ reduced the microvessel density, i.e. angiogenesis, in a nude mouse orthotopic model. In conclusion, for both models, the metronomic treatment of TMZ decreased angiogenesis. Especially, in TMZ-resistant glioma cells, this regimen increased apoptosis of tumor cells and decreased tumor growth. The metronomic treatment of TMZ in orthotopic glioma models demonstrated a successful antiangiogenic effect which can overcome the chemoresistance in conventional TMZ chemotherapy. IntroductionMalignant gliomas are the most common subtypes of rapidly growing primary brain tumors in adults and the most angiogenic human tumors which are characterized by a remarkable proliferative vascular component (1). They have retained their poor prognosis despite aggressive diverse conventional therapeutic approaches, requiring us to find novel therapeutic strategies (2). Particularly, for management of the growth of tumors including gliomas, which are dependent on angiogenesis, i.e. proliferation of microvascular endothelial cells, vascular targeted therapy has been the focus of recent studies.Temozolomide (TMZ) exhibits broad-spectrum antitumor activity on diverse tumors such as human melanoma, ovarian, colon and brain tumors (3-5). It is a DNA alkylating agent and an imidazotetrazine derivative used in the therapy of malignant gliomas (6,7). Since it has lipophilic property, TMZ is orally available and has shown excellent tissue distribution, including penetration across the blood-brain barrier (3). Although TMZ possesses good antitumor activity, its application in the management of high-grade glioma is limited by various resistant mechanisms (8), which leads many studies to explore the optimization of antitumor efficacy through combination of TMZ with radiation therapy or another agent (6,9-11). It was also reported that the antitumor activity of TMZ is found to be highly ...

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Section: Discussionmentioning

confidence: 99%

Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas

Kim

Kim²,

Ko³

et al. 2006

Oncol Rep

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“…Moreover, incidence of mucositis is higher in patients treated with continuous infusion 5-fluorouracil compared to those receiving intermittent intravenous administration (Hansen et al, 1996). The signs and symptoms of mucositis are oral burning, oral pain, spontaneous bleeding, dysphagia, dysarthria, and odynophagia.…”

Section: Introductionmentioning

confidence: 99%

Expression of salivary biomarkers in patients with oral mucositis: evaluation by SELDI‐TOF/MS

et al. 2016

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OBJECTIVE: This study aims to evaluate changes in proteomic salivary profile of patients with oral mucositis after adjuvant cancer treatments. MATERIALS AND METHODS: Samples were collected from patients after adjuvant cancer therapies, and were analyzed by means of SELDI/TOF. Patients were separated in two groups: patients affected by mucositis (MUCOSITIS) and patient without mucositis (NO MUCOSITIS). All patients were divided in function of the anticancer treatment: patients who had radiotherapy (MUCOSITIS RADIO), had not radiotherapy (MUCOSITIS NO RADIO), had chemotherapy (MUCO-SITIS CHEMO), and those who had not chemotherapy (MUCOSITIS NO CHEMO). Statistical evaluation PCA (Principal Component Analysis) was conducted with the software BIO-RAD Data Manager TM (Version 3.5). RESULTS: We found the increased peaks of 3443, 3487, and 4135 m/z in MUCOSITIS group, while 6237 m/z was reduced. These same peaks would the same modifications in MUCOSITIS RADIO, while in MUCOSITIS CHEMIO are increased 3443 and 6237 m/z but 3487, 4135 m/z are reduced. These data were confirmed by the PCA. CONCLUSION: Anticancer therapy influenced the level expression of many salivary biomarkers in mucositis with a good significance. Therefore, 3443, 3487, 4135, and 6237 m/z are good biomarker candidates of oral mucositis. Oral Diseases (2016) 22, 209-219

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“…Nevertheless, because of its elevated synergism with 5-FU in experimental models, CDDP has been combined with 5-FU in the treatment of patients with advanced colorectal cancer and other tumors [14, 15]. In some studies on colorectal cancer patients, the combination of CDDP and 5-FU resulted in a higher antitumor activity, produced greater toxicity and no significant improvements in survival and, therefore, its use was not recommended [16, 17, 18, 19, 20, 21]. However, the dose and schedules of 5-FU used in these clinical trials were different from those used in combination with oxaliplatin and, perhaps, might have been lesss effective to synergize with CDDP.…”

Section: Introductionmentioning

confidence: 99%

5-Fluorouracil Administered as a 48-Hour Chronomodulated Infusion in Combination with Leucovorin and Cisplatin: A Randomized Phase II Study in Metastatic Colorectal Cancer

Falcone

Allegrini²,

Masi³

et al. 2001

Oncology

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Objective: The primary objective of this trial was to determine the objective response of two regimens with CDDP administered every 2 weeks immediately before or after an ‘optimal’ 48-hour chronomodulated infusion of 5-fluorouracil (5-FU) modulated with leucovorin (LV) in metastatic colorectal cancer patients. Secondary endpoints were toxicity, 5-FU and its metabolites, plasma pharmacokinetics and progression-free and overall survival. Methods: Metastatic colorectal cancer patients with measurable disease who were chemotherapy-naive or pretreated only with a 5-FU-bolus-based chemotherapy were eligible for this study. The study was designed as a randomized phase II clinical trial. Results: Eighty-three patients were entered into the study. Forty-two were randomized to CDDP given before 5-FU and 41 to CDDP given after 5-FU. Patient characteristics were similar among the two groups. Toxicities were also similar among the two arms and the most frequent WHO grade III–IV toxicities were stomatitis (14%) and neutropenia (39–50%). Plasma pharmacokinetic profiles of 5-FU and 5-FUH₂ were not significantly affected by the sequence of CDDP and 5-FU administration. Antitumor activity was similar in the two arms and was very promising both in pretreated patients (response rate 29%; 95% confidence interval 15–46%) and in chemotherapy-naive patients (response rate 56%, complete response 9%, 95% confidence interval 40–71%). Median survival of the patients with and without pretreatment was 12 and 16 months, respectively. Conclusions: These results do not suggest a sequence dependence of the synergism between CDDP and 5-FU. However, they challenge the need of oxaliplatin to improve 5-FU/LV activity in advanced colorectal cancer. In fact, our results with an ‘optimal’ 5-FU dose and scheduling are very similar to those obtained with oxaliplatin plus 5-FU/LV. However, only a randomized phase III study will be able to give an answer to the hypotheses raised by this study.

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Phase III Study of Bolus Versus Infusion Fluorouracil With or Without Cisplatin in Advanced Colorectal Cancer

Cited by 116 publications

References 13 publications

Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas

Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas

Expression of salivary biomarkers in patients with oral mucositis: evaluation by SELDI‐TOF/MS

5-Fluorouracil Administered as a 48-Hour Chronomodulated Infusion in Combination with Leucovorin and Cisplatin: A Randomized Phase II Study in Metastatic Colorectal Cancer

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