Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer

Gramont, Aimery de; Vignoud, J.; Tournigand, Christophe; Louvet, Christophe; André, Thierry; Varette, C.; Raymond, Éric; Moreau, S.; Bail, N Le; Krulik, M

doi:10.1016/s0959-8049(96)00370-x

Cited by 352 publications

(146 citation statements)

References 16 publications

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“…Response rates are rarely (and then not reproducibly) above 10% with any of the new agents tested [20]. Oxaliplatin has also a relatively low activity as single agent in second line treatment [21,22], but one small phase II trial reported an unusual high response rate in second line treatment with the combination of oxaliplatinÐ5-FU/LV [23].…”

Section: Discussionmentioning

confidence: 99%

Clinical activity and benefit of irinotecan (CPT-11) in patients with colorectal cancer truly resistant to 5-fluorouracil (5-FU)

Cutsem¹,

Cunningham

Huinink

et al. 1999

European Journal of Cancer

101

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The aim of this prospective study was to assess the eYcacy, clinical bene®t and safety of in patients with stringently-de®ned 5-¯uorouracil-resistant metastatic colorectal cancer (CRC). 107 patients with documented progression of metastatic CRC during 5-FU were treated with CPT-11 350 mg/m 2 once every 3 weeks in a multicentre phase II study. Tumour response and toxicity were assessed using WHO criteria. Changes in performance status (PS), weight and pain were also measured. The WHO response rate was 13/95 (13.7%, 95% CI 7.5% to 22.3%) eligible patients with a median duration of response of 8.5 months (37 weeks, range: 18±53 +). There was also a high rate of disease stabilisation (44.2%) with a median duration of 4.8 months. The probability of being free of progression at 4 months was 50%. Median survival from ®rst administration of CPT-11 was 10.4 months or 45 weeks (range: 3±66 + weeks). There was weight stabilisation or gain in 81% (73/90) of patients, a favourable outcome in PS in 91% (82/90) (improvement of WHO PS 2 or stabilisation of PS 0-1), and pain relief in 54% (26/48). There were no toxic deaths. Neutropenia was short-lasting and non-cumulative. Diarrhoea grade ! 3 occurred in 7% of cycles and 28/107 (26%) of patients. CPT-11 350 mg/m 2 once every 3 weeks has an encouraging degree of activity in progressive metastatic CRC truly resistant to 5-FU with a relatively high rate of tumour growth control translated into clinical bene®t. The toxicity pro®le of CPT-11 is becoming better understood and has been considerably improved. #

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Section: Discussionmentioning

confidence: 99%

Clinical activity and benefit of irinotecan (CPT-11) in patients with colorectal cancer truly resistant to 5-fluorouracil (5-FU)

Cutsem¹,

Cunningham

Huinink

et al. 1999

European Journal of Cancer

101

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“…It is an alkylating agent on DNA and forms DACH-platinum DNA adducts more hydrophobic than those formed by cisplatin (CDDP) and carboplatin (CBDCA). It is effective in advanced colorectal cancer both as a first-line therapy and in 5-fluorouracil (5-FU) refractory patients (BertheaultCvitkovic et al, 1996;De Gramont et al, 1997;Andre' et al, 1999;Maindrault-Goebel et al, 1999).…”

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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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“…Experimental conditions were established so as to adopt a clinically relevant schedule and to take into account previous experimental results . To this end, the LOHP-FUFA schedule was designed so as to reflect the widely used 'de Gramont' protocol in which a 2 h LOHP sequence precedes a 48 h FU exposure (De Gramont, 1997). SN38, the active metabolite of CPT 11, was introduced into this fixed LOHP-FUFA sequence thus giving rise to two different schedules in which SN38 was applied either before (schedule A) or after (schedule B) LOHP.…”

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confidence: 99%

Ternary combination of irinotecan, fluorouracil-folinic acid and oxaliplatin: results on human colon cancer cell lines

et al. 2001

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Summary A marked antitumour efficacy is currently obtained by oxaliplatin (LOHP)-fluorouracil (FU)-folinic acid (FA) combination and by CPT11-FU-FA combination. Logically, the triple association LOHP, CPT11 and FUFA will be soon tested in cancer patients. The aim of the present study was to compare two schedules combining SN38 (the active metabolite of CPT11, irinotecan) with FU-FA and LOHP. The two schedules differed by the SN38 position. The relative contribution of each drug in the resulting global cytotoxicity was evaluated. Two human colon cancer cell lines were used (WIDR and SW620 both p53 mutated). LOHP plus FA were applied for 2 h, just before a 48 h FU exposure. The SN38 sequence was applied for 24 h, starting either 48 h before LOHP-FA (schedule A), or just after LOHP-FA exposure (schedule B). Cytotoxicity was assessed by the 3-(4,5-demethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) test and drug interactions were analysed according to the Chou and Talalay method, based on the computation of a combination index (CI). The SN38 position significantly induces a shift from additivity-antagonism when SN38 was applied after LOHP, towards additivity-synergism when SN38 was applied first (P = 0.03). The relative contribution (RC) of each drug in the overall cytotoxicity of the triple combination was defined as the drug concentration giving 50% cell lethality (IC 50 ) of the double association without that drug divided by the IC 50 of the triple association. Whatever the SN38 position, the larger contribution was made by LOHP (median RC = 2.4) and the smaller by SN38 (median RC = 1.1). In addition, the contribution of FUFA was improved when SN38 was applied first (median RC = 2.2) as compared to the opposite schedule (median RC = 1.2). Results were in agreement between the two explored cell lines. The present data should be taken into account when establishing the rationale of future trials combining CPT11, LOHP and FU-FA.

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Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer

Cited by 352 publications

References 16 publications

Clinical activity and benefit of irinotecan (CPT-11) in patients with colorectal cancer truly resistant to 5-fluorouracil (5-FU)

Clinical activity and benefit of irinotecan (CPT-11) in patients with colorectal cancer truly resistant to 5-fluorouracil (5-FU)

Hypersensitivity reactions related to oxaliplatin (OHP)

Ternary combination of irinotecan, fluorouracil-folinic acid and oxaliplatin: results on human colon cancer cell lines

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