After censoring these patients, the median OS was 18.9 months in the pooled XELOX/XELOX-placebo arms and 18.9 months in the pooled FOLFOX4/FOLFOX4-placebo arms, with a corresponding HR of 0.94 (97.5% CI 0.82�C1.08), and 21.6 months in the XELOX-bevacizumab arm and 21.0 months in the Erlotinib solubility FOLFOX4-bevacizumab arm (HR=0.93; 97.5% CI 0.76�C1.13). Safety For the updated safety assessment of XELOX vs FOLFOX4, patients in the pooled XELOX/XELOX-placebo (n=655) and pooled FOLFOX-4/FOLFOX4-placebo (n=648) arms were compared. The updated safety analysis showed that little had changed since the previous analysis (Cassidy et al, 2008a). Predefined adverse events of special interest and key events pooled by body system are presented in Table 3.

Table 3 Adverse events of special interest to chemotherapy and key events pooled by body system (treatment-related and unrelated) In general, XELOX and FOLFOX4 had a similar profile of adverse events. The most common adverse events were gastrointestinal (i.e., diarrhoea, nausea, vomiting and stomatitis) and neurosensory toxicities (i.e., paraesthesia and peripheral neuropathy). However, there were differences between the two regimens in the rates at which key events occurred. FOLFOX4/FOLFOX4-placebo was associated with more grade 3/4 neutropenia/granulocytopenia (44%) and febrile neutropenia (5%) than XELOX/XELOX-placebo (7 and <1%, respectively). Conversely, XELOX/XELOX-placebo was associated with more hand-foot syndrome (all-grade, 31 vs 11% grade 3, 6 vs 1%) and diarrhoea (all-grade, 66 vs 61% grade 3/4, 20 vs 11%) than FOLFOX4/FOLFOX4-placebo, although the rate of grade 4 diarrhoea was 1% with both regimens.

Rates of grade 3/4 neurosensory toxicity were similar with both regimens (17%). Cardiac disorders were reported in 6 (1%) XELOX/XELOX-placebo recipients and 9 (1%) FOLFOX-4/FOLFOX4-placebo recipients. The addition of bevacizumab did not alter the similarities and differences in safety profiles between XELOX and FOLFOX4 (Table 4). Table 4 Adverse events of special interest to chemotherapy and key events pooled by body system (treatment-related and unrelated) Treatment-related mortality up to 28 days after the last treatment dose was documented in 11 (1.7%) FOLFOX4/FOLFOX4-placebo patients and in 15 (2.3%) XELOX/XELOX-placebo patients. The respective 60-day all-cause mortality rates were 2.3% (n=15) and 3.4% (n=22).

Discussion The primary efficacy analysis of study NO16966 showed that XELOX is non-inferior to FOLFOX4 in terms of progression-free survival, OS and overall response rate in the first-line treatment of patients with metastatic colorectal cancer (Cassidy et al, 2008a). This updated analysis of OS again demonstrates that XELOX and FOLFOX4 have similar efficacy and supports the primary efficacy findings. It is also notable that both Drug_discovery XELOX and FOLFOX4 were similar in terms of OS after the addition of bevacizumab.