In the present randomized phase III trial, the primary endpoint, PFS, was comparable between the two treatment groups. Patients assigned to the XELIRI-Bev group had a median PFS of 10.2
months and those assigned to the FOLFIRI-Bev group 10.8
months. In contrast, in the BICC-C randomized trial [2
], patients treated with FOLFIRI presented with a significantly longer PFS compared with those treated with XELIRI. Also, in the EORTC randomized trial [4
], treatment with FOLFIRI resulted in a better PFS and OS than that with XELIRI, but the analysis included only 85 patients, due to the early termination of the trial and therefore no definitive conclusions could be made.
However, data regarding XELIRI combined with Bev are scarce in the literature. Most studies published in full paper form are retrospective in nature [5
], with only Moehler et al. [8
] recently reporting the results of a phase II trial. In the above studies, the major serious toxicities were diarrhea in 15–18% of the patients, nausea/vomiting in 3–7% and neutropenia in 6–7%. Doses were reduced in 31–62% of the patients, while treatment was interrupted due to toxicity in 11–18% of the patients. No treatment related deaths occurred. In the FNCLCC ACCORD 13/0503 randomized non-comparative study [9
], the most frequent grade 3–4 events in patients treated with XELIRI-Bev were neutropenia (18%), asthenia (14%), diarrhea (12%), vomiting (7%) and hand-foot syndrome (6%). However, a lower than usual dose of irinotecan was administered (200
In contrast, in the BICC-C trial [2
], the incidence of the most prominent grade 3–4 adverse events with XELIRI was much higher: diarrhea (47%), neutropenia (32%), dehydration (19%), nausea (18%) and vomiting (16%). Twenty-five percent of the patients discontinued the regimen and the treatment was prematurely terminated. In the CAIRO trial [10
], patients assigned to the XELIRI (combination) arm presented more frequently with diarrhea (27%), nausea-vomiting (9%), neutropenia (7%), febrile neutropenia (7%) and hand-foot syndrome (7%), as grade 3–4 toxicities. Also, in the EORTC 40015 study [4
], patients treated with XELIRI demonstrated high rates of grade 3–4 toxicities: diarrhea (37%), neutropenia (14%), vomiting (7%) and nausea (4%). Fifty-three percent of the patients needed dose reduction and 14% succumbed from toxicity. It seems however, that more recent XELIRI studies present lower rates of serious toxicities. One possible explanation could be that there is now more experience with this regimen and patients are more efficiently instructed and managed. In the present phase III study, serious adverse events were relatively less frequent and only 15% of our patients discontinued treatment due to toxicity.
Among the above-mentioned studies with XELIRI-Bev, only a few [5
] included previously untreated for metastatic disease CRC patients. Response rate was 35–67%, PFS was 12–13
months and OS 24
months. These results were slightly better than ours, but it should be mentioned that they are derived from phase II studies. The toxicity of the systemic treatment for CRC, in combination with the high cost, necessitates the discovery of predictive biomarkers of response.
Angiogenesis is necessary for cancer progression and constitutes a complex process with many different cooperating pathways, where VEGF-A, NO and TGF-β seem to have an important role. Early studies have demonstrated that immunohistochemical expression and high serum levels of VEGF-A and TGF-β1 are associated with adverse prognosis in CRC patients [11
]. In contrast, the significance of NO blood levels in these patients is controversial [18
]. In the present study, the first to evaluate plasma levels of the above molecules in Bev-treated mCRC patients, none of them was found to be associated with prognosis. However, in a recent study, baseline plasma levels of interleukin-8 were correlated with short PFS, while a number of other circulating angiogenic biomarkers, such as basic fibroblast growth factor, placental growth factor, hepatocyte growth factor, stromal-derived factor-1 and macrophage chemoattractant protein-3 were increased before the radiographic development of progressive disease in CRC patients treated with FOLFIRI-Bev [20
Finally, OPN is a glycoprotein, which seems to induce cellular proliferation, survival, metastasis and angiogenesis [21
]. More precisely, it is a soluble, secreted protein that can act as an autocrine and paracrine factor, as well as a modulator of cell adhesion through its interaction with integrins and CD44. It promotes multiple steps of cancer progression, such as cellular adhesion, proliferation, invasion, extracellular matrix degradation and metastasis, cancer immunotolerance and angiogenesis [21
]. In CRC, OPN expression is proportionately increased with tumor stage and seems to be of adverse prognostic significance [22
]. There are limited data in the literature with regard to circulating OPN in the blood of patients with colorectal cancer [27
] and none, to our knowledge, with regard to a possible prognostic or predictive value of circulating OPN in CRC patients. In the present study, baseline plasma OPN concentrations were reduced with antiangiogenic treatment, while patients with low baseline plasma OPN levels had a significantly longer PFS and OS independently of other well-established prognostic factors, such as performance status and the number of organs involved. OPN measurements in plasma could therefore provide valuable prognostic information, which is robust, accurate and easily determined with a relatively low cost compared to other methods, which require adequate tumor tissue.