Antitumor activity of oxaliplatin in combination with 5-fluorouracil and the thymidylate synthase inhibitor AG337 in human colon, breast and ovarian cancers

Raymond, Éric; Buquet-Fagot, Christine; Djelloul, Siham; Mester, JL; Cvitkovic, Esteban; Allain, Philippe; Louvet, C.; Gespach, Christian

doi:10.1097/00001813-199710000-00009

Cited by 219 publications

(95 citation statements)

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“…LOHP as a single agent, shows significant activity in colorectal cancer but, more interestingly, its association with FUFA has been demonstrated to be superior to FUFA in terms of antitumor efficacy in colorectal cancer (De Gramont et al, 2000). These clinical results confirm previous preclinical data indicating synergistic effects when combining these drugs (Raymond et al, 1997;Fischel et al, 1998). In the same way, CPT11 alone is active in colon cancer and, interestingly, in patients refractory to FU (Cunningham et al, 1998;Rougier et al, 1998).…”

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confidence: 76%

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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confidence: 76%

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

et al. 2001

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“…In our experience, a modified schedule of FOLFOX improves convenience without compromising efficacy or toxicity. British Journal of Cancer (2005) Oxaliplatin unlike cisplatin has demonstrated activity against colon carcinoma cell lines in vitro and has also shown synergistic activity in experimental models (Raymond et al, 1997). Several large randomised trials have confirmed the efficacy of the oxaliplatin/5-fluorouracil (5-FU)/leucovorin (LV) combination as first-line therapy in metastatic colorectal cancer.…”

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confidence: 99%

Australian experience of a modified schedule of FOLFOX with high activity and tolerability and improved convenience in untreated metastatic colorectal cancer patients

et al. 2005

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This study determined the efficacy and safety of a modified FOLFOX regimen that improved patient convenience without compromising oxaliplatin dose intensity. A total of 62 patients with previously untreated metastatic colorectal cancer were enrolled to receive, entirely as outpatients, 2-weekly cycles of oxaliplatin 100 mg m À2 i.v. over 2 h, together with leucovorin 400 mg m À2 over 2 h, 5-fluorouracil (5-FU) 400 mg m À2 , bolus, followed by a 46-h infusion of 5-FU at 2.4 g m À2 . Treatment was given until progression or unmanageable toxicity. In all, 61 patients received Xone oxaliplatin dose and a median of 11 treatment cycles (range 1 -20 cycles); 22 (36%) reported grade 3/4 neutropenia and 13 patients (21%) experienced grade 3 neurotoxicity; 16 patients (26%) discontinued treatment due to disease progression or death, 15 (25%) due to neurotoxicity and six (10%) due to haematological toxicity. Of the 56 eligible patients, complete or partial responses were observed in 29 or 52% (95% confidence interval 38 -65%). Median progression-free survival was 8.2 months (7.1 -9.9) and median overall survival was 18.7 months (14.0 -23.4). In our experience, a modified schedule of FOLFOX improves convenience without compromising efficacy or toxicity. British Journal of Cancer (2005) Oxaliplatin unlike cisplatin has demonstrated activity against colon carcinoma cell lines in vitro and has also shown synergistic activity in experimental models (Raymond et al, 1997). Several large randomised trials have confirmed the efficacy of the oxaliplatin/5-fluorouracil (5-FU)/leucovorin (LV) combination as first-line therapy in metastatic colorectal cancer. In De Gramont's et al (2000) phase III trial, FOLFOX4 was significantly superior to the infusional regimen, LV5FU2, in response rate and progressionfree survival (PFS) and the combination of chronomodulated 5-FU/LV and oxaliplatin produced a significantly higher response rate and superior PFS to the 5-FU/LV regimen alone (Giacchetti et al, 2000). In a recent three-arm study in 796 untreated patients with metastatic colorectal cancer (Goldberg et al, 2004), FOLFOX4 was significantly superior to the irinotecan and bolus 5-FU/LV combination (IFL) and a third regimen of oxaliplatin plus irinotecan (IROX) in response rate, time to progression and overall survival, and induced fewer Grade 3 or 4 toxicities.The original FOLFOX4 regimen, however, does have drawbacks for patients, as it requires intravenous treatment in hospital for 48-h every 2 weeks. Several variations of this regimen, incorporating oxaliplatin dose intensification or simplification of the LV/5-FU schedule, have been evaluated in clinical trials.A retrospective analysis by Maindrault-Goebel et al (2000) of three phase II studies, in previously treated patients, using three different FOLFOX regimens showed that increased oxaliplatin dose intensity (485 mg m À2 ) improved response rates and PFS without compromising tolerability. One of the more effective regimens, FOLFOX6, utilised an oxaliplatin dose of 100 mg m À2 on da...

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“…Several studies have shown a sequence-specific synergistic cytotoxicity for the combination of raltitrexed with CPT-11 (Aschele et al, 1988), while for the combination of raltitrexed with oxaliplatin both synergistic and additive antineoplastic activities have been observed (Raymond et al, 1997).…”

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confidence: 99%

Phase II randomised trial of raltitrexed–oxaliplatin vs raltitrexed–irinotecan as first-line treatment in advanced colorectal cancer

et al. 2005

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The purpose of this phase II randomised trial was to determine which of two schemes, raltitrexed-irinotecan or raltitrexed-oxaliplatin, offered better activity and less toxicity in patients with advanced colorectal cancer (CRC). A total of 94 patients with previously untreated metastatic CRC were included and randomised to receive raltitrexed 3 mg m À2 followed by oxaliplatin 130 mg m À2 on day 1 (arm A), or CPT-11 350 mg m À2 followed by raltitrexed 3 mg m À2 (arm B). In both arms treatment was repeated every 3 weeks. Intent-to-treat (ITT) analysis showed an overall response rate of 46% (95% CI, 29.5 -57.7%) for arm A, and 34% (95% CI, 19.8 -48.4%) for arm B. Median time to progression was 8.2 months for arm A and 8.8 months for arm B. After a median follow-up of 14 months, 69% of patients included in arm A were still alive, compared to 59% of those included in arm B. Overall, 31 patients (65%) experienced some episode of toxicity in arm A and 32 patients (70%) in arm B, usually grade 1 -2. The most common toxicity was hepatic, with 29 patients (60%) in arm A and 24 patients (62%) in arm B, and was grade 3 -4 in four (8%) and four (9%) patients, respectively. In all, 14 patients (29%) from arm A and 24 patients (52%) from arm B had some grade of diarrhoea (Po0.03). Neurologic toxicity was observed in 31 patients (64%) in arm A, and was grade 3 -4 in five patients (10%), while a cholinergic syndrome was detected in nine patients (19%) in arm B. There were no differences in haematologic toxicity. One toxic death (2%) occurred in arm A and three (6.5%) in arm B. In conclusion, both schemes have high efficacy as first-line treatment in metastatic CRC and their total toxicity levels are similar. Regimens with raltitrexed seem a reasonable alternative to fluoropyrimidines.

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Antitumor activity of oxaliplatin in combination with 5-fluorouracil and the thymidylate synthase inhibitor AG337 in human colon, breast and ovarian cancers

Cited by 219 publications

References 0 publications

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

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

Australian experience of a modified schedule of FOLFOX with high activity and tolerability and improved convenience in untreated metastatic colorectal cancer patients

Phase II randomised trial of raltitrexed–oxaliplatin vs raltitrexed–irinotecan as first-line treatment in advanced colorectal cancer

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