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David Cunningham - One of the best experts on this subject based on the ideXlab platform.
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efficacy and cardiotoxic safety profile of Raltitrexed in fluoropyrimidines pretreated or high risk cardiac patients with gi malignancies large single center experience
Clinical Colorectal Cancer, 2019Co-Authors: Khurum Khan, David Cunningham, Jayant K Rane, David Watkins, Naureen Starling, Eleftheria Kalaitzaki, Martin Forster, Chiara Braconi, Nicola Valeri, Marco GerlingerAbstract:Abstract Background Gastrointestinal (GI) cancer patients may not be considered for therapy with fluoropyrimidines (FPs) because of previous cardiovascular (CV) toxicity or preexisting risk factors; such patients may benefit from Raltitrexed-based therapy. Patients and Methods Patient, tumor, and treatment characteristics, as well as clinical outcomes of all consecutively treated patients with Raltitrexed at the Royal Marsden Hospital between October 1998 and July 2011 were examined. GI cancer patients who developed CV toxicity as a result of FPs and those with significant CV risk factors receiving Raltitrexed were included in this analysis. Results A total of 247 patients (155 and 92 with CV FP-related CV toxicities and significant CV risk factors, respectively) treated with Raltitrexed alone or in combination were examined after a median follow-up of 47.1 months. CV toxicity profiles of patients receiving capecitabine (n = 110) and 5-fluorouracil (n = 45) were largely similar. Of Raltitrexed-treated patients, 13 (5%) experienced CV toxicities and 1 ( Conclusion A Raltitrexed-based regimen is well-tolerated therapy with comparable efficacy to FPs in patients with GI malignancies with significant CV toxicities or risk factors.
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Raltitrexed current clinical status and future directions
Annals of Oncology, 2002Co-Authors: E Van Cutsem, David Cunningham, J Maroun, Andres Cervantes, Bengt GlimeliusAbstract:Raltitrexed ('Tomudex') monotherapy is a conveniently administered alternative to 5-fluorouracil (5-FU) in the first-line treatment of advanced colorectal cancer (CRC), and has single-agent activity in a variety of advanced solid tumours. Although both Raltitrexed and 5-FU are thymidylate synthase inhibitors, Raltitrexed has a specific mode of action and a toxicity profile distinct from 5-FU. The mechanism of action of Raltitrexed is also completely different from that of oxaliplatin, irinotecan and other drugs with which it has been combined. These properties, together with preclinical data, suggested that combinations of Raltitrexed with 5-FU, other chemotherapeutic agents, or radiotherapy could result in improved therapies for a variety of advanced solid tumours, including advanced CRC. This review outlines the appropriate management of patients treated with Raltitrexed, whether as monotherapy or in combination, and discusses the preliminary results of combination studies with Raltitrexed in a range of tumour types including advanced CRC, malignant mesothelioma, gastric, pancreatic, head and neck, and non-small-cell lung cancers. Of particular interest is the combination of Raltitrexed and oxaliplatin, which has shown promising antitumour effects in first-line treatment of advanced CRC and malignant mesothelioma, a disease that is refractory to chemotherapy.
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efficacy tolerability and management of Raltitrexed tomudex monotherapy in patients with advanced colorectal cancer a review of phase ii iii trials
European Journal of Cancer, 2002Co-Authors: David Cunningham, T Maughan, Roger D James, John Zalcberg, Jean A Maroun, Stephen Clarke, M Vincent, Jan Schulz, Gonzalez M Baron, T FacchiniAbstract:Abstract Raltitrexed (Tomudex™), a thymidylate synthase inhibitor, is an alternative to 5-fluorouracil (5-FU)/leucovorin (LV) for the first-line treatment of advanced colorectal cancer. Following the completion of four phase III studies with Raltitrexed at the recommended dose of 3.0 mg/m 2 , it is opportune to review the efficacy and tolerability data of Raltitrexed and suggest guidelines for appropriate patient management. Data are analysed from four phase III and five phase II studies including over 1300 patients with advanced colorectal cancer, some of whom were elderly or received higher doses of Raltitrexed. Median survival with Raltitrexed was comparable to that of bolus or infusional 5-FU/LV in three of the four randomised studies and objective response rates in the four trials were similar for the two agents. Response rates were at least comparable in elderly patients in phase II studies. For the majority of patients, treatment with Raltitrexed was well tolerated even at doses higher than that recommended or in the elderly. As with other cytotoxic agents, serious and potentially life-threatening side-effects can occur; nevertheless, adherence to simple patient guidelines should minimise the incidence of serious side-effects with Raltitrexed; these include the assessment of renal function before each and every treatment, dosage adjustment in the presence of renal impairment and close monitoring with prompt treatment of toxicities, particularly diarrhoea and neutropenia.
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phase i study of irinotecan and Raltitrexed in patients with advanced astrointestinal tract adenocarcinoma
British Journal of Cancer, 2000Co-Authors: Hugo Ford, Timothy J Price, David Cunningham, Paul Ross, Sheela Rao, G W Aherne, T Benepal, A Massey, L Vernillet, G GruiaAbstract:To determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of irinotecan and Raltitrexed given as sequential short infusions every 3 weeks, 33 patients with pretreated gastrointestinal adenocarcinoma (31 colorectal, 2 oesophagogastric) entered this open label dose-escalation study. For the first five dose levels patients received irinotecan 175–350 mg m–2followed by Raltitrexed 2.6 mg m–2. Level VI was irinotecan 350 mg m–2plus Raltitrexed 3.0 mg m–2, level VII was irinotecan 400 mg m–2plus Raltitrexed 2.6 mg m–2; 261 courses were administered. Only one patient at dose levels I–V experienced DLT. At level VI, 5/12 patients experienced DLT: one had grade 3 diarrhoea and lethargy, one had grade 4 diarrhoea and one had lethargy alone. Two others had lethargy caused by disease progression. There was no first-cycle neutropenia. At level VII, 3/6 patients experienced dose-limiting lethargy, one also had grade 3 diarrhoea. Dose intensity fell from over 90% for both drugs at level VI to 83% for irinotecan and 66% for Raltitrexed at level VII. Lethargy was therefore the DLT, and level VII the MTD. Pharmacokinetic data showed no measurable drug interaction; 6/30 patients (20%) had objective responses. This combination is active with manageable toxicity. Recommended doses for further evaluation are irinotecan 350 mg m–2and Raltitrexed 3.0 mg m–2. © 2000 Cancer Research Campaign
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open randomized multicenter trial of Raltitrexed versus fluorouracil plus high dose leucovorin in patients with advanced colorectal cancer tomudex colorectal cancer study group
Journal of Clinical Oncology, 1998Co-Authors: G Cocconi, D J Kerr, E Van Cutsem, David Cunningham, E Francois, Bengt Gustavsson, G Van Hazel, K Possinger, S M HietscholdAbstract:PURPOSETo compare Raltitrexed (Tomudex; Zeneca Pharmaceuticals Ltd, Macclesfield, United Kingdom) a direct, specific thymidylate synthase (TS) inhibitor with fluorouracil (5-FU) plus high-dose leucovorin (LV) as first-line treatment for advanced colorectal cancer (ACC).PATIENTS AND METHODSA total of 495 patients were randomized to Raltitrexed (3 mg/m2) once every 3 weeks or 5-FU (400 mg/m2) plus LV (200 mg/m2) daily for 5 days every 4 weeks.RESULTSThe randomized groups were well balanced demographically. With a minimum 17-month follow-up, median survival was comparable between groups (10.9 months Raltitrexed v 12.3 months 5-FU/LV; hazards ratio, 1.15; 95% confidence interval [CI], 0.93 to 1.42; P=.197), although time to progression was statistically significantly shorter in the Raltitrexed group. Overall objective responses were comparable (19% Raltitrexed v 18% 5-FU/LV), with more than 50% of patients in each group having stable disease. Significantly less World Health Organization (WHO) grade 3 and 4 st...
Xu Zhu - One of the best experts on this subject based on the ideXlab platform.
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hepatic artery infusion with Raltitrexed or 5 fluorouracil for colorectal cancer liver metastasis
World Journal of Gastroenterology, 2017Co-Authors: Jianhai Guo, Hangyu Zhang, Song Gao, Pengjun Zhang, Hui Chen, Xiaodong Wang, Xu ZhuAbstract:Hepatic artery infusion with Raltitrexed or 5-fluorouracil for colorectal cancer liver metastasis
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Hepatic artery infusion with Raltitrexed or 5-fluorouracil for colorectal cancer liver metastasis
WORLD JOURNAL OF GASTROENTEROLOGY, 2017Co-Authors: Guo Jian-hai, Zhang Hang-yu, Gao Song, Zhang Peng-jun, Li Xiao-ting, Chen Hui, Wang Xiao-dong, Xu ZhuAbstract:AIM To evaluate the efficiency and safety of hepatic artery infusion chemotherapy (HAIC) using Raltitrexed or 5-fluorouracil for colorectal cancer (CRC) liver metastasis (CRCLM). METHODS A retrospective analysis of patients with unresectable CRCLM who failed systemic chemotherapy and were subsequently treated with HAIC at our institute from May 2013 to April 2015 was performed. A total of 24 patients were treated with 5-fluorouracil, and 18 patients were treated with Raltitrexed. RESULTS The median survival time (MST) from diagnosis of CRC was 40.8 mo in the oxaliplatin plus Raltitrexed (TOMOX) arm and 33.5 mo in the oxaliplatin plus 5-fluorouracil (FOLFOX) arm (P = 0.802). MST from first HAIC was 20.6 mo in the TOMOX arm and 15.4 mo in the FOLFOX arm (P = 0.734). Median progression-free survival (PFS) from first HAIC was 4.9 mo and 6.6 mo, respectively, in the TOMOX arm and FOLFOX arm (P = 0.215). Leukopenia (P = 0.026) was more common in the FOLFOX arm, and hepatic disorder (P = 0.039) was more common in the TOMOX arm. There were no treatment-related deaths in the TOMOX arm and one treatment-related death in the FOLFOX arm. Analysis of prognostic factors indicated that response to HAIC was a significant factor related to survival. CONCLUSION No significant difference in survival was observed between the TOMOX and FOLFOX arms. HAIC treatment with either TOMOX or FOLFOX was demonstrated as an efficient and safe alternative choice.Capital Medical Development and Scientific Research Fund, China [2014-2-2154]SCI(E)ARTICLE81406-14112
Timothy J Price - One of the best experts on this subject based on the ideXlab platform.
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final results of australasian gastrointestinal trials group arctic study an audit of Raltitrexed for patients with cardiac toxicity induced by fluoropyrimidines
Annals of Oncology, 2014Co-Authors: David Ransom, Kate Wilson, Marion Fournier, R J Simes, Val Gebski, Niall C Tebbutt, Christos S Karapetis, David Ferry, S Gordon, Timothy J PriceAbstract:ABSTRACT Background Cardiac toxicity an uncommon but serious side-effect of some fluoropyrimides. Cardiac toxicity from Raltitrexed is rarely reported. With this background, we initiated this study to investigate the incidence of cardiac events in patients who had switched to Raltitrexed following cardiac toxicity from fluoropyrimidines (5-fluorouracil or capecitabine). Patients and methods Pharmacy records were used to identify patients receiving Raltitrexed from January 2004 till March 2012. Medical records were then reviewed to confirm the use of Raltitrexed after cardiac toxicity from 5-fluorouracil or capecitabine. The primary end point was the rate of further cardiac events after commencing Raltitrexed. Results Forty-two patients were identified and the majority had colorectal cancer. Prior regimens included 5-fluorouracil ± leucovorin, capecitabine alone, FOLFOX, FOLFIRI, epirubicin/cisplatin/5-fluorouracil, and capecitabine/oxaliplatin. Seven patients (17%) had bolus 5-fluorouracil regimens, 26 patients (62%) had infusion 5-fluorouracil regimens, and 9 patients (21%) had capecitabine alone or in combination. Angina was the most common cardiac toxicity from 5-fluorouracil or capecitabine and usually occurred in the first or the second cycle. Four patients after their first cardiac event continued with the same 5-fluorouracil or capecitabine regimen with the addition of nitrates and calcium antagonists but still had further cardiac events. After changing to Raltitrexed, either as a single agent or a continuing combination regimen, no patients experienced further cardiac toxicity. Conclusion Raltitrexed is associated with no significant cardiac toxicity in patients who have experienced prior cardiac toxicity from 5-fluorouracil or capecitabine. Raltitrexed, alone or in combination with oxaliplatin or irinotecan, provides a safe option in terms of cardiac toxicity for such patients.
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final results of australasian gastro intestinal trials group agitg arctic study an international audit of Raltitrexed for patients with cardiac toxicity induced by fluoropyrimidines fp
Annals of Oncology, 2012Co-Authors: Timothy J Price, Kate Wilson, Marion Fournier, R J Simes, Val Gebski, Niall C Tebbutt, Christos S Karapetis, David Ferry, Desmond Yip, David RansomAbstract:ABSTRACT Background Cardiac toxicity (CT) is an uncommon but potentially fatal side effect of FP. The incidence of further CT if the same chemotherapy is continued is reported to be 20%*. Management of these patients remains poorly defined and options include continuing same dose/schedule of FP, adding a nitrate and calcium antagonist, switching administration schedule of FP, or substituting with Raltitrexed, the later based primarily on case reports. Methods AGITG and OCTO (Oncology Clinical Trials Office – Oxford) members identified patients who had CT from FP, and were subsequently switched to Raltitrexed. CT included angina, myocardial infarct (MI) or arrhythmia. A coronary angiogram was not mandatory. Results 42 patients were included in this clinical audit. Cancer diagnoses included colorectal (39pts), oesophageal (2) and ampullary carcinoma (1). Median age - 62 years (range 36-81). 27 patients (64%) were male. Median number of cycles prior to switching to Raltitrexed was 2 (range 1-11). FP regimens included FOLFOX, CAPOX, continuous infusion 5FU, ECF, capecitabine alone. 40 patients had angina, 5 MI, and 2 arrhythmia with some patients experiencing >1 event at that time. 8 patients experienced two separate CT events, and 2 had 3 events prior to switching to Raltitrexed. Following CT, 9 patients received Raltitrexed alone, 32 received Raltitrexed in combination with other agents or radiotherapy and one received Raltitrexed alone followed by combination. Median number of Raltitrexed cycles was 6 (range 1-21). One patient (CT rate 2.4%, 95% CI: 0.1-12.3) experienced a potentially related cardiac event (acute arrhythmia 5 mths into therapy) after switching to Raltitrexed, a CT rate significantly lower than the 20% reported when continuing FP (exact binomial test p = 0.004). Conclusion The rate of recurrent CT after switching from FP to Raltitrexed was low. The strategy of switching to Raltitrexed may represent an acceptable option for patients that are deriving a benefit from FP based chemotherapy but in whom cardiac toxicity is a concern. (* Jensen SA et al. Cancer Chemotherapy & Pharm. 58:487-93, 2006). Disclosure D. Ransom: Unrestricted research grant from Astra Zeneca. All other authors have declared no conflicts of interest.
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phase i study of irinotecan and Raltitrexed in patients with advanced astrointestinal tract adenocarcinoma
British Journal of Cancer, 2000Co-Authors: Hugo Ford, Timothy J Price, David Cunningham, Paul Ross, Sheela Rao, G W Aherne, T Benepal, A Massey, L Vernillet, G GruiaAbstract:To determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of irinotecan and Raltitrexed given as sequential short infusions every 3 weeks, 33 patients with pretreated gastrointestinal adenocarcinoma (31 colorectal, 2 oesophagogastric) entered this open label dose-escalation study. For the first five dose levels patients received irinotecan 175–350 mg m–2followed by Raltitrexed 2.6 mg m–2. Level VI was irinotecan 350 mg m–2plus Raltitrexed 3.0 mg m–2, level VII was irinotecan 400 mg m–2plus Raltitrexed 2.6 mg m–2; 261 courses were administered. Only one patient at dose levels I–V experienced DLT. At level VI, 5/12 patients experienced DLT: one had grade 3 diarrhoea and lethargy, one had grade 4 diarrhoea and one had lethargy alone. Two others had lethargy caused by disease progression. There was no first-cycle neutropenia. At level VII, 3/6 patients experienced dose-limiting lethargy, one also had grade 3 diarrhoea. Dose intensity fell from over 90% for both drugs at level VI to 83% for irinotecan and 66% for Raltitrexed at level VII. Lethargy was therefore the DLT, and level VII the MTD. Pharmacokinetic data showed no measurable drug interaction; 6/30 patients (20%) had objective responses. This combination is active with manageable toxicity. Recommended doses for further evaluation are irinotecan 350 mg m–2and Raltitrexed 3.0 mg m–2. © 2000 Cancer Research Campaign
Aurelie Bertaut - One of the best experts on this subject based on the ideXlab platform.
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hepatic arterial chemotherapy with Raltitrexed and oxaliplatin versus standard chemotherapy in unresectable liver metastases from colorectal cancer after conventional chemotherapy failure hearto a randomized phase ii study
Journal of Cancer Research and Clinical Oncology, 2019Co-Authors: Francois Ghiringhelli, Boris Guiu, Julie Vincent, Leila Bengrine, Christophe Borg, Jean Louis Jouve, Romaric Loffroy, Julie Blanc, Aurelie BertautAbstract:Hepatic arterial infusion (HAI) of chemotherapy could be used in patients with liver-only metastatic colorectal cancer (mCRC) to fight against chemoresistance. We previously reported the efficacy of Raltitrexed plus oxaliplatin (HAI) in a retrospective series. We performed a randomized two-stage phase-II study to evaluate the efficacy of HAI of the combination of Raltitrexed and oxaliplatin in refractory mCRC with only liver metastases in comparison with standard of care. Eligible patients had unresectable mCRC and were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type KRAS). Patients were randomized between HAI Raltitrexed (3 mg/m2 over 1 h) followed by oxaliplatin (130 mg/m2 over 2 h) every 3 weeks and standard of care in a 2:1 ratio. A total of 57 patients (38 in the experimental arm and 19 in the standard of care arm) were to be included. The main objective was to demonstrate 6-month PFS of 45% by intention-to-treat analysis in the experimental arm, compared to theoretical PFS of 20%, with a unilateral alpha risk of 5% and beta risk of 10%. After inclusion of 27 patients, the trial was terminated due to insufficient accrual. In the experimental arm, 11 and 4 patients experienced grade 3 and 4 toxicities, respectively. The most frequent grade 3–4 toxicities were neutropenia, liver toxicity, and abdominal pain. Median progression-free survival was 6.7 months (95% Confidence Interval; 3.9–7.2) in the HAI group and 2.2 months (95% CI 1.2–4.3) with standard of care [HR 0.32 (95% CI 0.14–0.76), p = 0.01]. Median overall survival did not differ between the two groups, at 11.2 months (95% CI 4.8–17.6) for the HAI group and 11.9 months (95% CI 2.8–14.3) for standard of care [HR 0.86 (95% CI 0.36–2.04), p = 0.73]. Although stopped prematurely, this randomized trial provides evidence for the benefit and safety of HAI of a combination of Raltitrexed and oxaliplatin in liver-only mCRC with chemoresistant disease.
Francois Ghiringhelli - One of the best experts on this subject based on the ideXlab platform.
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hepatic arterial chemotherapy with Raltitrexed and oxaliplatin versus standard chemotherapy in unresectable liver metastases from colorectal cancer after conventional chemotherapy failure hearto a randomized phase ii study
Journal of Cancer Research and Clinical Oncology, 2019Co-Authors: Francois Ghiringhelli, Boris Guiu, Julie Vincent, Leila Bengrine, Christophe Borg, Jean Louis Jouve, Romaric Loffroy, Julie Blanc, Aurelie BertautAbstract:Hepatic arterial infusion (HAI) of chemotherapy could be used in patients with liver-only metastatic colorectal cancer (mCRC) to fight against chemoresistance. We previously reported the efficacy of Raltitrexed plus oxaliplatin (HAI) in a retrospective series. We performed a randomized two-stage phase-II study to evaluate the efficacy of HAI of the combination of Raltitrexed and oxaliplatin in refractory mCRC with only liver metastases in comparison with standard of care. Eligible patients had unresectable mCRC and were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type KRAS). Patients were randomized between HAI Raltitrexed (3 mg/m2 over 1 h) followed by oxaliplatin (130 mg/m2 over 2 h) every 3 weeks and standard of care in a 2:1 ratio. A total of 57 patients (38 in the experimental arm and 19 in the standard of care arm) were to be included. The main objective was to demonstrate 6-month PFS of 45% by intention-to-treat analysis in the experimental arm, compared to theoretical PFS of 20%, with a unilateral alpha risk of 5% and beta risk of 10%. After inclusion of 27 patients, the trial was terminated due to insufficient accrual. In the experimental arm, 11 and 4 patients experienced grade 3 and 4 toxicities, respectively. The most frequent grade 3–4 toxicities were neutropenia, liver toxicity, and abdominal pain. Median progression-free survival was 6.7 months (95% Confidence Interval; 3.9–7.2) in the HAI group and 2.2 months (95% CI 1.2–4.3) with standard of care [HR 0.32 (95% CI 0.14–0.76), p = 0.01]. Median overall survival did not differ between the two groups, at 11.2 months (95% CI 4.8–17.6) for the HAI group and 11.9 months (95% CI 2.8–14.3) for standard of care [HR 0.86 (95% CI 0.36–2.04), p = 0.73]. Although stopped prematurely, this randomized trial provides evidence for the benefit and safety of HAI of a combination of Raltitrexed and oxaliplatin in liver-only mCRC with chemoresistant disease.
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Raltitrexed and oxaliplatin hepatic arterial infusion for advanced colorectal cancer: a retrospective study.
Anti-Cancer Drugs, 2010Co-Authors: Cedric Khouri, Boris Guiu, Jean Pierre Cercueil, Bruno Chauffert, Sylvain Ladoire, Francois GhiringhelliAbstract:The aim of this study was to evaluate the efficacy and safety of combined hepatic arterial infusion (HAI), which is a combination of Raltitrexed and oxaliplatin, in refractory colorectal carcinoma with only liver metastases. Seventeen consecutive patients with unresectable metastatic colorectal cancer, after the failure of two lines of systemic chemotherapy, were treated with HAI Raltitrexed (3 mg/m over 1 h) followed by oxaliplatin (130 mg/m over 2 h) every 3 weeks between January 2006 and January 2009. All patients presented with the metastatic disease limited to the liver and had failed at least two lines of chemotherapy, which contained oxaliplatin, irinotecan and a fluoropyrimidine. The median number of cycles was six (range 1-15). We observed three complete responses and eight partial responses among assessable patients (overall response rate in intention to treat, 65%; 95% confidence interval, 44.3-87.7%). The median time to progression was 10.5 months and the median survival time was 27.5 months. Toxicity included grade 3-4 neutropenia (in 17%), grade 3-4 thrombopenia (in 17%), and grade 2 abdominal pain (in 47%). In conclusion, the combination regimen of HAI Raltitrexed and oxaliplatin is feasible and promising in patients who presented isolated hepatic metastases of colorectal cancer after failure of irinotecan and oxaliplatin treatment. Further evaluation of this combination is required.