A randomized trial of first-line irinotecan/fluoropymidine combinations with or without celecoxib in metastatic colorectal cancer (BICC-C)

Abstract

3506 Background: This multicenter, randomized study assessed efficacy & safety for 3 irinotecan/fluoropyrimidines combinations in previously untreated mCRC. In a 3 × 2 factorial design, we also assessed whether celecoxib added to chemotherapy (CT) improved CT efficacy and/or reduced toxicity. Methods: Pts were randomized to: FOLFIRI - irinotecan (I) 180 mg/m2, leucovorin (LV) 400 mg/m2, 5-FU bolus 400 mg/m2, & infusional 5-FU 2400 mg/m2 over 46 hours q 2 wks; modified IFL (m-IFL) - I 125 mg/m2, LV 20 mg/m2, & bolus 5-FU 500 mg/m2 wkly × 2, q 3 wks; or CapeIri - I 250 mg/m2 day 1 & capecitabine 1000 mg/m2 po BID × 14 days, q 3 wks. Pts were also randomized to concurrent celecoxib (400 mg po BID) or placebo in a double-blind fashion. Time to progression (TTP) was the primary endpoint. Results: 430 pts were enrolled from 2/03 to 4/04, prior to an amendment that added bevacizumab to CT arms. Baseline characteristics were balanced. TTP for FOLFIRI (median = 8.2 mos) was significantly better than for either m-IFL (6.0 mos; p = 0.01) or CapeIri (5.7 mos; p = 0.01). Overall survival (OS) also favored FOLFIRI (median = 23.1 mos) compared to either m-IFL (17.6 mos; p=0.10) or CapeIri (18.8 mos; p = 0.19). Common grade ≥ 3 toxicities are listed below. CapeIri had the highest rates of nausea, vomiting, diarrhea, dehydration & hand-foot syndrome, whereas FOLFIRI had lower rates. Among all 430 pts, median TTP did not differ for pts randomized to celecoxib compared to placebo (6.9 vs 6.9 mos; p=0.71). Median OS was also similar for celecoxib vs placebo (19.5 vs 18.8 mos; p=0.63). CT toxicities did not differ for celecoxib vs placebo. Rates for MI/stroke were 1.5% for celecoxib and 1.9% for placebo. Conclusions: First-line FOLFIRI offers a superior TTP when compared to m-IFL or CapeIri; OS & toxicity analyses also favored FOLFIRI. Celecoxib neither improved CT efficacy nor reduced CT toxicity. Updated survival data & data on pts enrolled after the addition of bevacuzimab will be presented. [Table: see text] [Table: see text]

Chemotherapy in Elderly Patients with Colorectal Cancer

“…Preliminary findings of a phase II study of CapeIri as a first-line regimen in 60 patients aged 68 -81 years suggested good efficacy and tolerability in older patients, with no treatment-related deaths or grade 3 or 4 toxicities [60]. However, other studies (not elderly-specific) have described less favorable safety [61,62] and a lower efficacy [62] of CapeIri compared with FOLFIRI.…”

Chemotherapy for Colorectal Cancer Liver Metastases

“…Cetuximab added to oxaliplatin or irinotecan regimens increased the RR from 33% to 49% [28], and the addition of bevacizumab to irinotecan increased the RR from 35% to 45% [22]. A median OS time Ͼ20 months is now seen [22,27]. The objectives of chemotherapy in CRC with metastases to the liver have accordingly shifted from palliation to maximization of benefit through prolongation of survival, improving RRs, and downsizing tumors to enable or optimize resection.…”

Bevacizumab, a humanized anti-angiogenic monoclonal antibody for the treatment of colorectal cancer

“…Secondary endpoints, including progression‐free survival (10·6 months vs. 6·2 months, P < 0·001) and overall response rate (44·8% vs. 34·8%, P = 0·004), also significantly improved in the bevacizumab combination therapy arm (Table 1). Trials investigating bevacizumab in combination with infusional 5‐FU/LV plus irinotecan (FOLFIRI) regimens are currently ongoing (58–60). Preliminary median progression‐free survival reported in these trials suggests that FOLFIRI/bevacizumab is at least as efficacious as IFL/bevacizumab.…”