A multicenter evaluation of intensified, ambulatory, chronomodulated chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin as initial treatment of patients with metastatic colorectal carcinoma

L�vi, Francis; Zidani, R.; Brienza, S.; Dogliotti, Luigi; Perpoint, B; Rotarski, M.; Letourneau, Y.; Llory, J; Chollet, Philippe; Rol, A. Le; Focan, C.

doi:10.1002/(sici)1097-0142(19990615)85:12<2532::aid-cncr7>3.0.co;2-1

Cited by 123 publications

(44 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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“…Circadian changes in drug pharmacokinetics, target tissue susceptibility, bone marrow DNA synthesis, 5-FU metabolic and catabolic enzymatic activity (thymidylate phosphorylase and dehydropyrimidine dehydrogenase) and oral/rectal epithelium during night hours vs light hours are some of the explanations of these differences. Concerning drug activity 5-FU dose-intensity seems to be related to drug activity and this could influence survival (Lévi et al, 1999;Garufi et al, 1997).The combination of CPT-11 and L-OHP without 5-FU was also investigated in phase I and II studies, which showed the activity of these drugs in patients heavily pretreated with 5-FU-based regimen (Scheiteuer et al, 1999;Wassermann et al, 1999). Haematologic toxicity has been commonly observed; grade 3 -4 (G3 -4) neutropenia occurred in 20 -33% of patients even though concomitant granulocyte colony-stimulating factor (G-CSF) administration.…”

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confidence: 99%

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confidence: 99%

A phase II study of irinotecan plus chronomodulated oxaliplatin, 5-fluorouracil and folinic acid in advanced colorectal cancer patients

et al. 2003

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The combination of irinotecan (CPT-11), oxaliplatin (L-OHP), 5-fluorouracil (5-FU) and folinic acid (FA) is one of the possibilities to overcome chemoresistance in advanced colorectal cancer (ACRC) patients. The aim of this study was to determine the tolerability and activity of CPT-11 plus chronomodulated infusion of L-OHP, 5-FU and FA in ACRC patients. A total of 35 patients (91% pretreated, 77% with CPT-11, 54% with L-OHP, 42% with both) were treated every 3 weeks with CPT-11, 180 mg m À2 day 1 i.v., plus L-OHP, 20 mg m À2 day À1 , 5-FU, 700 mg m À2 day À1 and FA, 150 mg m À2 day À1 , all three drugs from day 2 to day 5 by chronomodulated infusion. The patients' (pt) data were as follows: male/female 21/14; median age 58 years (range: 38 -70); PS 0: 26 pts (74%), PS 1: 8 pts (23%), PS 2: 1 pt (3%); primary tumour colon/rectum 26/9; involved organs: 1, 14 pts (40%); 2, 17 pts (48%); X3: 4 pts (11%); previous chemotherapy lines 1: 12 pts (34%), 2: 10 pts (28%), X3: 10 pts (28%). A total of 221 courses (c) were performed; no grade 4 toxicity was observed with only one grade 3 (G3) neutropenia and thrombocytopenia (3%) in one out of 221 courses (o1%). Maximal toxicity (G3) was nausea and diarrhoea in 10 pts (28%), occurring in 14 out of 221 c (6%) and 12 out of 221 c (5%) respectively. Seven patients achieved a partial response (20%, confidence interval (c.i.) 6.8 -33.3) and one patient a complete response (2.9%, c.i. 0 -8.4), for a total overall response rate of 22.9% (c.i. 9 -36.8); 15 out of 35 (42.9%, c.i. 26.5 -59.3) had stable disease and 12 out of 35 (34.3%, c.i. 18.6 -50) patients underwent a progression. In conclusion, this four-drug regimen is feasible in advanced pretreated ACRC patients with no significant haematological toxicity and acceptable diarrhoea. The activity of this combination is currently studied in EORTC 05011 study. In the last few years, prospective randomised phase III trials comparing both continuous infusion and bolus 5-FU plus folinic acid (FA) vs the same schedule plus CPT-11 or L-OHP showed significant increase of response rate (RR), time to progression (TTP), overall survival (OS), no quality of life (QoL) detriment with acceptable toxicity profile (De Gramont et al, 2000;Douillard et al, 2000; Saltz et al, 2000;Goldberg et al, 2002).These results suggest that combination of infusional 5-FU plus L-OHP or CPT-11 can now be considered as the standard treatment in this setting of patients.Drug delivery according to circadian rhythm showed an impact on toxicity profile and activity both in preclinical and in clinical setting (Lévi, 2001). It was demonstrated in phase III trials that the combination of L-OHP plus 5-FU and FA delivered by chronomodulated infusion, the FFL regimen, provides more activity and a better toxicity profile when compared to the flat infusion of the same drugs with a five-fold greater mucositis rate due to 5-FU and the double of peripheral neurotoxicity due to L-OHP in the constant infusion regimen (Lévi et al, 1994(Lévi et al, , 1997. Circadian changes in drug...

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“…Incidences of grade 3/4 haematological toxicity, especially neutropenia, during this study were infrequent compared to other studies Levi et al, 1999;Maindrault-Goebel et al, 1999;de Gramont et al, 2000;Giacchetti et al, 2000) considering many patients have been heavily pre-treated. This is presumably due to the nonmyelosuppressive nature of PVI 5-FU.…”

Section: Oxaliplatin and Pvi 5-fu In Advanced Colorectal Cancer 1263mentioning

confidence: 47%

“…No patients were withdrawn from the study due to intolerable toxicities. No functional neurological deficit was noted which was commonly the reason of patient withdrawal or dose reduction in other studies using oxaliplatin Levi et al, 1999;Maindrault-Goebel et al, 1999;Giacchetti et al, 2000). Of the 8 patients that required dose reduction in oxaliplatin during the study, 4 did so because of persistent grade 2 peripheral neuropathy in-between courses.…”

Section: Oxaliplatin and Pvi 5-fu In Advanced Colorectal Cancer 1263mentioning

confidence: 94%

Oxaliplatin and protracted venous infusion of 5-fluorouracil in patients with advanced or relapsed 5-fluorouracil pretreated colorectal cancer

et al. 2001

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SummaryThe purpose of this study was to evaluate the activity and safety of oxaliplatin and protracted venous infusion of 5-fluorouracil (PVI 5-FU) in patients with advanced or relapsed 5-FU pretreated colorectal cancer. 38 patients with advanced or metastatic colorectal carcinoma with documented progression on or within 6 months following 5-FU or thymidylate synthase inhibitor containing chemotherapy were recruited between June 1997 and September 2000. Oxaliplatin (100 mg m -2 ) was given every 2 weeks and PVI 5-FU (300 mg m -2 day -1 ) was administered. Median age of patients was 61 years. 17 patients had >2 sites of disease involvement. 10 had received 5-FU based adjuvant chemotherapy. 16 received oxaliplatin and PVI 5-FU as second-line chemotherapy for advanced disease and 22 as third or subsequent lines. Median follow up was 6.1 months. The best achieved objective tumour response rate was 29% (11 partial responses 95% confidence interval [CI] = 15-46%). 20 patients (52.6%) had stable disease. The median duration of response was 3.9 months. Even for patients who had previously received both 5-FU and irinotecan (n = 22), 27.3% had partial response with oxaliplatin and PVI 5-FU. 37 patients had symptoms on entry into the study. 25 patients had pain, 10 had anorexia and 28 had lethargy. 64%, 70% and 17.9% had symptomatic improvement after treatment respectively. Grade 3-4 toxicities were anaemia 10.6%, neutropenia 2.6%, thrombocytopenia 5.2%, diarrhoea 18.9%, nausea and vomiting 2.7%, infection 5.4% and lethargy 37.8%. The median survival was 9.1 months. Probability of overall survival at 6 months was 58.4% (95% CI = 38.7-73.7%). The median failure-free survival was 4 months. Oxaliplatin and PVI 5FU is an active and well tolerated regimen in patients with heavily pre-treated advanced colorectal cancer.

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A multicenter evaluation of intensified, ambulatory, chronomodulated chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin as initial treatment of patients with metastatic colorectal carcinoma

Cited by 123 publications

References 16 publications

Hypersensitivity reactions related to oxaliplatin (OHP)

Hypersensitivity reactions related to oxaliplatin (OHP)

A phase II study of irinotecan plus chronomodulated oxaliplatin, 5-fluorouracil and folinic acid in advanced colorectal cancer patients

Oxaliplatin and protracted venous infusion of 5-fluorouracil in patients with advanced or relapsed 5-fluorouracil pretreated colorectal cancer

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