The relative dose intensity of first-line FOLFOXIRI and FOLFOX/FOLFIRI both in combination with bevacizumab affects prognosis of metastatic colorectal cancer patients: A pooled analysis of TRIBE and TRIBE2 studies

Background: The relative dose intensity (RDI) of cytotoxic agents affects cancer patients’ clinical outcome, especially in the curative setting. Poor data are available in metastatic colorectal cancer (mCRC) and with specific regard to the use of the triplet FOLFOXIRI. Methods: We performed a pooled analysis of the phase III TRIBE and TRIBE2 studies comparing FOLFOXIRI/bev to doublets (FOLFOX or FOLFIRI)/bev in order to assess the prognostic impact of the RDI (<80 % versus ≥80 %) during the first 8 cycles of induction treatment of both the triplet and the doublet regimens. Results: Overall, 282/581 (49 %) and 404/580 (70 %) of patients treated with FOLFOXIRI/bev and doublets/bev, respectively, received RDI≥ 80 %. Patients receiving RDI≥ 80 % had more favorable clinical condition and tumor-related prognostic features. RDI≥ 80 % was associated with higher ORR (62 % vs 53 %, OR: 1.44, 95 %CI:1.13 – 1.82; p = 0.0026), and longer PFS (11.5 versus 10.0 months; HR: 0.80, 95 %CI: 0.71 – 0.91; p < 0.001) and OS (27.9 versus 22.2 months; HR: 0.75, 95 %CI: 0.65 – 0.85; p < 0.001). These results were confirmed in multivariable models (p < 0.001). Similar ORR (58 % vs 56 %, OR: 1.09, 95 %CI: 0.81–1.48; p = 0.57), PFS (10.8 versus 10.0 months; HR:0.96, 95 %CI: 0.83–1.12; p = 0.63) and OS (22.9 versus 24.9 months; HR:1.07, 95 %CI: 0.90–1.26; p = 0.46) were observed between patients treated with FOLFOXIRI/bev receiving RDI< 80 % and those treated with doublets/bev receiving RDI≥ 80 %. These results were confirmed after stratification for unbalanced baseline characteristics between these subgroups (stratified pORR=0.55; pPFS=0.70; stratified pOS=0.33). As expected, patients in the RDI< 80 % group experienced a higher incidence of severe chemo-related adverse events (72 % vs 34 %, p < 0.001). Conclusions: Maintaining an adequate RDI in the first-line therapy of mCRC improves patients’ clinical outcomes. Since there is no benefit from chemotherapy intensification in the case of low RDI, the secondary prophylaxis of chemotherapy-related severe adverse events might be preferrable rather than individual agents’ dose reductions.