A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer

Abstract

The standard de Gramont (dG) regimen of fortnightly leucovorin, bolus fluorouracil and 22-h infusion of fluorouracil, d1+2, and the same regimen plus oxaliplatin, are effective but also cumbersome. We therefore present simplified 'Modified de Gramont' (MdG) regimens. Forty-six advanced gastrointestinal cancer patients entered a dose-exploring study of MdG, including an expanded cohort of colorectal cancer patients at optimum dose. Treatment (fortnightly) comprised: 2-h i.v.i. leucovorin (350 mg d,l-LV or 175 mg l-LV, not adjusted for patient surface area); bolus fluorouracil (400 mg m 72 ), then ambulatory 46-h fluorouracil infusion (2000 -3600 mg m 72 , cohort escalation). Subsequently, 62 colorectal patients (25 unpretreated; 37 fluorouracil-resistant) received MdG plus oxaliplatin (OxMdG) 85 mg m 72 . Fluorouracil pharmacokinetics during MdG were compared with dG. The optimum fluorouracil doses for MdG alone were determined as 400 mg m 72 bolus + 2800 mg m 72 46-h infusion. A lower dose of 400 mg m 72 bolus + 2400 mg m 72 infusion which, like dG produces minimal toxicity, was chosen for the OxMdG combination. Fluorouracil exposure (AUC 0 -48 h ) at this lower dose is equivalent to dG. With OxMdG, grade 3 -4 toxicity was rare (neutropenia 2.8% cycles; vomiting or diarrhoea 51% cycles), but despite this there were two infection-associated deaths. Oxaliplatin was omitted for cumulative neurotoxicity in 17 out of 62 patients. Objective responses in colorectal cancer patients were: 1st-line MdG (22 assessable): PR=36%, NC=32%, PD=32%. 1st-line OxMdG (24 assessable): CR/PR=72%; NC=20%; PD=8%; 2nd line OxMdG (34 assessable): PR=12%; NC=38%; PD=50%. 1988). It was compared with the Mayo Clinic 5-day bolus FU/LV regimen in a 448-patient randomised trial, and showed a better response rate (32.6% vs 14.4%; P=0.0004), and median progression-free survival (27.6 vs 22 weeks; P50.0012) with significantly reduced rates of diarrhoea, mucositis and neutropenia; however, overall survival was not significantly improved (de Gramont et al, 1997). Following this trial dG was adopted as a standard therapy option by many oncologists, especially in France and the UK.Its low toxicity profile makes dG a good basis for combination chemotherapy. Pivotal trials of the design 'dG+new agent' have been performed in first-line therapy of metastatic colorectal cancer using oxaliplatin or irinotecan (Douillard et al, 2000), in each case producing a high response rate and good safety profile. Similar trials are now ongoing in the adjuvant setting.Although dG can be administered on an ambulatory, out-patient basis, many units find it more convenient to admit patients. This, together with the high dose of LV, and a labour-intensive administration schedule, place high demands on healthcare resources (Ross et al, 1998). Furthermore, repeated hospital visits or admissions during dG may detract from the benefits of its low toxicity profile.Along with others (see Discussion), we reasoned that it would be possible to modify the dG regimen, reducing its ...

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

“…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). The discrepancy remains unexplained, but still suggests that the need for enhanced dose intensity of oxaliplatin above 85 mg m À2 requires exploration.…”

Modified de Gramont with oxaliplatin in the first-line treatment of advanced colorectal cancer

“…That trial included 24 assessable patients who received the regimen as first-line therapy for metastatic colorectal cancer, whose case-notes and scans were reviewed by an independent external radiologist and oncologist; 72% had RECIST complete or partial responses, confirmed by a second scan; a further 8% had partial responses that were not confirmed by a second scan (Cheeseman et al, 2002). That high response rate (72% confirmed; 80% confirmed þ unconfirmed) was markedly higher than, although statistically consistent with, other first-line trials of FU/FA with oxaliplatin (De Gramont et al, 2000;Tournigand et al, 2001;Goldberg et al, 2003).…”

“…In our single centre study, this new regimen demonstrated exceptional activity as first-line treatment, and was also well tolerated and convenient (Cheeseman et al, 2002). We now present data from a prospective multicentre phase 2 study of a further 55 patients receiving the same OxMdG schedule as first-line treatment for advanced colorectal cancer.…”

FDA Review of a Panitumumab (Vectibix™) Clinical Trial for First-Line Treatment of Metastatic Colorectal Cancer

“…fluorouracil and bevacizumab. Six oxaliplatin-and two irinotecanbased chemotherapy regimens were allowed (Tables 1 and 2) [3][4][5][6][7][8][9][10]. Patients randomized to the panitumumab treat-ment arm received 6 mg/kg every 2 weeks by i.v.…”