Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer.

Bertheault-Cvitkovic, F.; Jami, Alain; Ithzaki, M; Brummer, Pekka; Brienza, S.; Adam, René; Kunstlinger, F; Bismuth, H.; Misset, Jean-Louis; Lévi, Françis

doi:10.1200/jco.1996.14.11.2950

Cited by 133 publications

(43 citation statements)

References 16 publications

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“…When OHP is infused in a chronomodulate setting (as a 12-h infusion) or flat infusion for 5 days, these hypersensitivity reactions do not occur. In particular, 151 patients submitted to 1087 constant rate continuous infusion courses of OHP, and 491 patients submitted to 3106 chronomodulate OHP courses did not experience any hypersensitivity reactions (Caussanel et al, 1990;Levi et al, 1992Levi et al, , 1993Levi et al, , 1994bLevi et al, , 1997Levi et al, , 1999Bertheault-Cvitkovic et al, 1996). Therefore, the incapacity of these schedules to produce hypersensitivity might be due to a long time infusion rather than to failure of activation of the immune system (which presents a circadian rhythm) in a chronomodulate setting (Levi et al, 1994a).…”

Section: Discussionmentioning

confidence: 99%

Hypersensitivity reactions related to oxaliplatin (OHP)

et al. 2003

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Patients treated with platinum compounds are subject to hypersensitivity reactions. Our study has highlighted the reactions related to oxaliplatin (OHP) infusion. One hundred and twenty-four patients affected by advanced colorectal cancer were treated with different schedules containing OHP, at the Institute of Haematology and Medical Oncology 'L. and A. Seragnoli' of Bologna and at the Medical Oncology Division of Livorno Hospital. Seventeen patients (13%) showed hypersensitivity reactions after a few minutes from the start of the OHP infusion. Usually, these reactions were seen after 2 -17 exposures to OHP (Mean7s.e.: 9.471.07). No patient experienced allergic reactions at his/her first OHP infusion. Eight patients developed a mild reaction consisting of flushing and swelling of the face and hands, itching, sweating and lachrymation. The remaining nine patients showed a moderatesevere reaction with dyspnoea, wheezing, laryngospasm, psycho-motor agitation, tachycardia, precordial pain, diffuse erythema, itching and sweating. Six patients out of 17 were re-exposed to the drug with premedication of steroids and all except one developed the hypersensitivity reaction again. The cumulative dose, the time of exposure to OHP and the clinical features are variable and unpredictable. The risk of developing hypersensitivity reactions in patients treated with a short infusion of OHP cannot be underestimated.

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Section: Discussionmentioning

confidence: 99%

Hypersensitivity reactions related to oxaliplatin (OHP)

et al. 2003

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“…The platinum compound oxaliplatin is frequently used in the treatment of colorectal cancer patients that are resistant to 5FU, and can also be used in combination with 5FU or CPT-11, improving response rates and progression-free survival (Levi et al, 1993;Bertheault-Cvitkovic et al, 1996;Machover et al, 1996;de Gramont et al, 1997de Gramont et al, , 2000Andre et al, 1999;Maindrault-Goebel et al, 1999;Giacchetti et al, 2000). Oxaliplatin disrupts DNA replication and transcription by forming intrastrand DNA adducts, but the downstream molecular events underlying the cytotoxic effects of this chemotherapeutic agent have not been well characterised.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of action and prediction of response to oxaliplatin in colorectal cancer cells

et al. 2004

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The platinum compound oxaliplatin has been shown to be an effective chemotherapeutic agent for the treatment of colorectal cancer. In this study, we investigate the molecular mechanisms of action of oxaliplatin to identify means of predicting response to this agent. Exposure of colon cancer cells to oxaliplatin resulted in G2/M arrest and apoptosis. Immunofluorescent staining demonstrated that the apoptotic cascade initiated by oxaliplatin is characterised by translocation of Bax to the mitochondria and cytochrome c release into the cytosol. Oxaliplatin treatment resulted in caspase 3 activation and oxaliplatin-induced apoptosis was abrogated by inhibition of caspase activity with z-VAD-fmk, but was independent of Fas/FasL association. Targeted inactivation of Bax or p53 in HCT116 cells resulted in significantly increased resistance to oxaliplatin. However, the mutational status of p53 was unable to predict response to oxaliplatin in a panel of 30 different colorectal cancer cell lines. In contrast, the expression profile of these 30 cell lines, assessed using a 9216-sequence cDNA microarray, successfully predicted the apoptotic response to oxaliplatin. A leave-one-out cross-validation approach was used to demonstrate a significant correlation between experimentally observed and expression profile predicted apoptosis in response to clinically achievable doses of oxaliplatin (R ¼ 0.53; P ¼ 0.002). In addition, these microarray experiments identified several genes involved in control of apoptosis and DNA damage repair that were significantly correlated with response to oxaliplatin.

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“…Several clinical trials have demonstrated that 5- or 14-day schedules of chronomodulated 5-FU-based chemotherapy are less toxic, enable 5-FU dose intensity escalations by approximately 25% and significantly improve antitumor activity [20, 21, 22, 23]. To date, the three-drug chronotherapy regimen with 5-FU, LV and oxaliplatin used by Levi et al [23]is apparently one of the most active regimens in metastatic colorectal cancer with a response rate, validated in multicenter phase III randomized studies, over 50% [23, 30, 31]. In this three-drug regimen, on the basis of preclinical observations, 5-FU and LV were administered as a sinusoidally modulated infusion for 12 h between 10 p.m. and 10 a.m., with peak flow rates at 4 a.m. A similar infusion schedule was used by Bjarnason et al [22], but 5-FU+LV were infused over 14 days and only 62.5% of the total daily dose were administered over 7 h around the infusion peak which occurred at 3–4 a.m.…”

Section: Discussionmentioning

confidence: 99%

Infusions of Fluorouracil and Leucovorin: Effects of the Timing and Semi-Intermittency of Drug Delivery

Falcone¹,

Allegrini²,

Antonuzzo

et al. 1999

Oncology

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Preclinical and clinical studies have demonstrated that the circadian modulation of 5-FU delivery may reduce toxicities and improve antitumor activity. However, the relative importance of the timing of 5-FU delivery has not been clinically addressed. The aims of this study were to determine the toxicities, the maximum tolerable doses and the activity of a regimen with 5-fluorouracil (5-FU) and leucovorin (LV) administered as a 14-day continuous infusion according to a flat or three different chronomodulated rhythms in patients with metastatic gastrointestinal carcinomas. A total of 113 patients entered the study and their characteristics were comparable among the four groups. Toxicities included mainly stomatitis and diarrhea, and a reduced toxicity was observed in all the three chronogroups that allowed the delivery of higher dose intensities. Response rates were not significantly different among the four groups. These results suggest that a reduction in 5-FU+LV toxicity and an increase in 5-FU dose intensity can be obtained by a nonsinusoidally circadian modulated infusion. However, the reduction in toxicity observed seems to be dependent mainly on the quasi-intermittency and not on the timing of 5-FU+LV delivery.

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Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer.

Abstract: This highly effective fully ambulatory outpatient regimen deserves further testing in randomized trials both in chemotherapy-naive patients and before surgery to remove metastases.

Cited by 133 publications

References 16 publications

Hypersensitivity reactions related to oxaliplatin (OHP)

Hypersensitivity reactions related to oxaliplatin (OHP)

Molecular mechanisms of action and prediction of response to oxaliplatin in colorectal cancer cells

Infusions of Fluorouracil and Leucovorin: Effects of the Timing and Semi-Intermittency of Drug Delivery

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