Chemotherapy-induced neutropenia association with survival in metastatic colorectal cancer (MCC): Schedule dependency

• Published in: Journal of clinical oncology Vol. 29; no. 4_suppl; p. 454
• Main Authors: Innominato, P. F., Giacchetti, S., Smaaland, R., Focan, C. N., Garufi, C., Bjarnason, G. A., Iacobelli, S., Tumolo, S., Karaboué, A., Levi, F.
• Format: Journal Article
• Language: English
• Published: 01.02.2011
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2011.29.4_suppl.454

Abstract only 454 Background: Circadian clocks control cellular proliferation and drug metabolism over 24 h. However, circadian chronomodulated chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin (chronoFLO4) offered no survival benefit as compared to the non-time stipulated FOLFOX2 in an international randomized trial involving patients (pts) with previously untreated MCC (EORTC05963). We hypothesized that treatment near maximum tolerated dose could disrupt circadian clocks thus impairing the efficacy of chronoFLO4 but not of FOLFOX2. Methods: Pts with available data (N=556) were categorized into three subgroups according to the worst grade of neutropenia experienced during treatment. Distinct multivariate models were constructed for each treatment schedule. Results: Neutropenia (all grades) occurred in 39% of the pts on chronoFLO4 as compared to 67% of those on FOLFOX2 (p< 0.0001), with G3-4 being encountered in 7% and 25%, respectively (p< 0.0001). In both schedules, neutropenia was more frequent and more severe in women than in men (p<0.04).The occurrence (but not the severity) of neutropenia was significantly associated with improved objective response rate, progression-free and overall survival in pts on FOLFOX2 (p< 0.0001), confirming previous results by others. In pts on chronoFLO4, the occurrence of neutropenia was not associated with any efficacy advantage (p=0.36), and worst survival was observed in pts developing severe neutropenia. Conclusions: Neutropenia was more frequent and severe in women than in men, and on FOLFOX2 than on chronoFLO4. Neutropenia was positively correlated with survival in pts on FOLFOX2 supporting intra-patient dose escalation to achieve toxicity for conventional chemotherapy. No survival prolongation was found in pts with neutropenia on chronoFLO4. Thus, reaching maximum tolerated dose was unnecessary to achieve optimal effectiveness of circadian-timed therapy, and should even be avoided. [Table: see text] No significant financial relationships to disclose.