Chronomodulated (Chrono) vs constant (Cst) rate infusional 5-fluorouracil (FU) with or without cisplatin (CDDP) in patients with advanced or metastatic pancreatic cancer. A multicenter randomized trial of the Chronotherapy Group of the European Organisation for Research and Treatment of Cancer (EORTC 05962)

Abstract

4117 Background: Tolerability and activity of 5-day (d) infusional FU-oxaliplatin were improved with Chrono as compared with Cst in colorectal cancer pts(Lévi et al, Lancet 1997). CDDP addition to FU tended to prolong Progression-Free Survival (PFS) in pancreatic cancer pts(Ducreux et al, Ann Oncol 2002). Methods: A factorial design tested the relative effects of CDDP addition (100 mg/m2/course, c) to FU (c1/c2/c3 : 5/6/6.5 g/m2) and Cst vs Chrono (FU : 10 pm-10 am, peak at 4 am; CDDP : 10 am-10 pm, peak at 4 pm) 5 d q21d. Pts with advanced (25) or M (82) histologically-proven pancreatic cancer were registered in 15 centers. CTC toxicity was assessed q10 d and response q 3c. Survival was the main endpoint. Results: Characteristics : CDDP no/yes, 55/52 pts; Chrono no/yes, 54/53 pts; median age, 63 y; WHO PS 0/1/2, 35/52/20 pts; M sites 0/1/2+, 16/51/36 pts. CDDP increased median PFS from 2.1 months (mo.) [95% CL, 1.9–2.3] to 3.2 mo. [2.5–5.0] and median survival from 5.4 mo. [3.9–8.4] to 8.3 mo. [5.7–11.9]. Median survival (mo.) was 6.1 on Cstand 6.7 on Chrono(NS). CDDP addition reduced the risk of P by 44% (Log rank, p = 0.005) and that of death by 20% (p = 0.26). CDDP significantly increased grade 3–4 toxicity per patient : neutropenia (58 vs 6%), thrombopenia (38 vs 2%), anemia (25 vs 12%). The dose intensities of FU and CDDP were higher with Chrono (p = 0.03). Despite this, Chrono decreased the incidence of grade 3–4 mucositis (8 vs 27%, p = 0.01), anorexia (10 vs 23%) and diarrhea (2 vs 10%). Conclusions: CDDP addition to FU near maximum tolerated doses prolonged PFS in pancreatic cancer pts, with a trend toward improved survival. Chronoameliorated non haematological tolerability and allowed to administer higher DIs. Chrono FU should be combined with a less toxic Pt complex to concurrently improve antitumor efficacy and tolerability in M pancreatic cancer. Support: NCI, ARC (grant 9033), ARTBC, hôp. P Brousse, Villejuif (F). No significant financial relationships to disclose.