High-dose intensity oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX 7)

Maindrault-Gœbel, F.; Gramont, Aimery de; Louvet, Christophe; André, Thierry; Carola, Élisabeth; Mabro, May; Artru, Pascal; Gilles, V.; Lotz, Jean‐Pierre; Izrael, V.; Krulik, M

doi:10.1016/s0959-8049(01)00068-5

Cited by 128 publications

(53 citation statements)

References 15 publications

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“…Although the incidence of grade 3 or 4 thrombocytopaenia seems to be higher with SOX compared with the reported result of FOLFOX4 (Diaz-Rubio et al, 1998;Shirao et al, 2004), it was well managed by adequate dose modification of oxaliplatin and S-1 in subsequent cycles (Goldberg et al, 2004). Since the severity of thrombocytopaenia is dependent on the dose of oxaliplatin, FOLFOX7 with oxaliplatin at a dose of 130 mg m À2 caused 9% of grade 3 thrombocytopaenia (Maindrault-Goebel et al, 2001;Tournigand et al, 2006). The median time to first dose reduction was five cycles (range: 2 -7) due to any reason in 16 of the 28 patients at the RD, and 4.5 cycles (range: 3 -5) due to grade 3 or 4 thrombocytopaenia in 6 of the 28 patients.…”

Section: Discussionmentioning

confidence: 87%

Phase I/II study of oxaliplatin with oral S-1 as first-line therapy for patients with metastatic colorectal cancer

Yamada¹,

Tahara

Miya

et al. 2008

Br J Cancer

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Two phase II studies of S-1 monotherapy have shown promising response rates (RR) of 35 -40% with good tolerability in patients with untreated metastatic colorectal cancer. To investigate the usefulness of S-1 plus oxaliplatin (SOX) as an alternative to infusional 5-fluorouracil/leucovorin plus oxaliplatin, the recommended dose (RD) of SOX was determined, and its safety and preliminary efficacy were evaluated in a phase I/II study. Oxaliplatin was administered at a dose of 100 mg m À2 (level 1) or 130 mg m À2 (level 2) on day 1, and S-1 (80 -120) was given twice daily for 2 weeks followed by a 1-week rest. This schedule was repeated every 3 weeks. Level 2 was determined to be the RD. For the 28 patients who received the RD, the median treatment course was 6.5 cycles (2 -14), RR of 50% (1 CR and 13 PR: 95% CI 31 -69%), with a median progression-free survival of 196 days. Survival rate (1 year) was 79%. Peripheral neuropathy was observed in all patients but with no functional disorders. Major grade 3 or 4 adverse reactions at the RD were neutropaenia (14%), thrombocytopaenia (28%), and diarrhoea (3%). SOX regimen is effective and easily manageable without central vein access. Potassium oxonate is an orotate phosphoribosyl transferase inhibitor that is distributed primarily to the gastrointestinal tract. This component of S-1 decreases incorporation of 5-fluorouridine triphosphate into RNA in the gastrointestinal mucosa and reduces the incidence of diarrhoea. F-b-alanine (FBAL) is the main metabolite of 5-FU. F-b-alanine and fluorocitrate are thought to cause the neurotoxic and cardiotoxic effects of 5-FU by inhibiting the tricarboxylic acid cycle (Okeda et al, 1990;Robben et al, 1993;Diasio 1998). The CDHP component of S-1 inhibits DPD, the rate-limiting enzyme in the catabolic pathway of 5-FU. Consequently, the plasma FBAL concentration after oral administration of S-1 is significantly lower than that after continuous infusion of 5-FU (Yamada et al, 2003). Therefore, S-1 may decrease the incidence of neurotoxicity and cardiotoxicity. The response rate of S-1 monotherapy has been found to be 35-40% for patients with metastatic colorectal cancer (Ohtsu et al, 2000;Shirao et al, 2004), with grade 3 or 4 neutropaenia observed in 5-13%, thrombocytopaenia in 0-8%, diarrhoea in 2-3%, and grade 1 hand-foot syndrome (HFS) in 5%.Oxaliplatin is a third-generation platinum compound with less toxicity and improved convenience. The regimen of infusional 5-FU and leucovorin (LV) with oxaliplatin is the standard for firstand second-line chemotherapy in patients with metastatic colorectal cancer (de Gramont et al, 2000;Rothenberg et al, 2003;Goldberg et al, 2004). However, infusional 5-FU with LV has the disadvantages of increased inconvenience, cost, and morbidity related to the use of a portable infusion pump and a central venous catheter. Therefore, oral fluoropyrimidine monotherapy has been commonly used in Japan.The primary objectives of this phase I/II study were to determine the maximum tolerated dose (MTD) of S-1 plus oxal...

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Section: Discussionmentioning

confidence: 87%

Phase I/II study of oxaliplatin with oral S-1 as first-line therapy for patients with metastatic colorectal cancer

Yamada¹,

Tahara

Miya

et al. 2008

Br J Cancer

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“…Interestingly, five patients who developed hypersensitivity reactions to 2-h OHP infusion, when re-exposed to 6-h OHP infusion, did not show any symptoms (Maindrault-Goebel et al, 2001). The mechanism is still unclear, although it is supposed that the maximum concentration reached by the drug is lower in a longer time of infusion.…”

Section: Discussionmentioning

confidence: 98%

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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“…This led to a redesigned schedule, FOLFOX7, which increased the dose of oxaliplatin further to 130 mg m À2 , but reduced the total number of doses administered and focused on 5-FU dose reductions in response to nonneurological toxicity. In a phase II study in relapsed patients, FOLFOX7 produced a response rate of 42% and grade 3/4 neurological toxicity of 15% (Maindrault-Goebel et al, 2001). A subsequent study showed that a modified 5-FU schedule combined with 85 mg m À2 but with reductions of both oxaliplatin and 5-FU for haematologic toxicity once again reducing the oxaliplatin dose, was associated with marked reduction in efficacy in the second line setting -12% in 37 patients but with a remarkable 72% response rate in 25 first-line patients (Cheeseman et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Since 5-FU has previously been shown to contribute more to neutropaenia and since the bolus dose was the most convenient component to modify it was chosen first, followed by the infusional component. This strategy was subsequently also chosen by the French group in designing the Folfox7 regimen (Maindrault-Goebel et al, 2001). Treatment could be recommenced once febrile neutropenia resolved or the ANC improved to X1.5 Â 10 9 l À1 or the platelet count improved to X100 Â 10 9 l À1 .…”

Section: Dose Modificationmentioning

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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High-dose intensity oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX 7)

Cited by 128 publications

References 15 publications

Phase I/II study of oxaliplatin with oral S-1 as first-line therapy for patients with metastatic colorectal cancer

Phase I/II study of oxaliplatin with oral S-1 as first-line therapy for patients with metastatic colorectal cancer

Hypersensitivity reactions related to oxaliplatin (OHP)

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

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