XELOX Plus Bevacizumab vs . FOLFIRI Plus Bevacizumab Treatment for First-line Chemotherapy in Metastatic Colon Cancer : a Retrospective Study of the Anatolian Society of Medical Oncology

Colorectal cancer is one of the most common type of cancer. Although appropriate screening strategies, significant number of patients are still diagnosed at late stages of the disease. Despite all the advances, the treatment of metastatic colorectal cancer (mCRC) remains an important clinical problem in the worldwide. mCRC patients live much longer with new combination of treatment agents. Cytotoxic regimens, include doublet combinations (FOLFOX/XELOX or FOLFIRI), constitute the main treatment in patients with mCRC. Addition of biologic agents, such as bevacizumab, to these regimens has improved clinical outcomes and combination


Introduction
Colorectal cancer is one of the most common type of cancer.Although appropriate screening strategies, significant number of patients are still diagnosed at late stages of the disease.Despite all the advances, the treatment of metastatic colorectal cancer (mCRC) remains an important clinical problem in the worldwide.mCRC patients live much longer with new combination of treatment agents.Cytotoxic regimens, include doublet combinations (FOLFOX/XELOX or FOLFIRI), constitute the main treatment in patients with mCRC.Addition of biologic agents, such as bevacizumab, to these regimens has improved clinical outcomes and combination chemotherapy with biologic agents is recommended for patients with metastatic disease (Temraz et al., 2014;Zhang et al., 2014).Although patients with mCRC have many treatment options, the optimal use and sequence of targeted agents remain to be unclear.
In this study, we aimed to evaluate and compare the efficacy and toxicity of XELOX plus Bevacizumab (XELOX-Bev) vs. FOLFIRI plus Bevacizumab (FOLFIRI-Bev) treatment for first-line chemotherapy in mCRC.

Materials and Methods
Study Population: This study enrolled 409 patients who had received first line chemotherapy combination with bevacizumab between December 2006 and March 2014, from 14 member center of Anatolian Society of Medical Oncology (ASMO) association in Turkey.Data were obtained from chart reviews of mCRC patients.298 patients were administered XELOX-Bev (Group 1) and 111 patients were administered FOLFIRI-Bev (Group 2) as a first-line treatment.Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of patients were two or less and patients had adequate hematological, liver and renal functions.Exclusion criteria were: 1) history of prior chemotherapy for mCRC, 2) history of malignancy other than mCRC, 3) patients with significant cardiovascular, hepatic and renal diseases, hypertension, haemorrhagic diathesis or coagulopathy.

Treatment
XELOX-Bev treatment consisted of 90-min I.V. infusion of bevacizumab (7.5mg/kg) on day 1, followed by oxaliplatin 130mg/m 2 -i.v.infusion over 2h on day 1 in combination with capecitabine orally at a dose of 2,000mg/m 2 /day with first dose on the morning of day 1 and last dose on the evening of day 14 every 3 weeks.FOLFIRI-Bev treatment consisted of a 90-min I.V. infusion of bevacizumab (5mg/kg) on day 1, followed by a 90-min I.V. infusion of irinotecan (180mg/m 2 ) on day 1, leucovorin (200mg/m 2 ) 2h infusion on day 1 and 2, bolus fluorouracil (400mg/m 2 ) on day 1 and 2, 24h infusion of fluorouracil (600mg/m 2 )] on day 1 and 2. Treatment was continued until significant toxicity was observed and progressive disease (PD) was detected.Response evaluation was based on RECIST criteria every 2-3 cycles for XELOX-Bev regimen and 4-6 cycles for FOLFIRI-Bev regimen.We assessed the tumor progression with clinical evalution, imaging methods and tumour markers.Toxicity was evaluated according to the National Cancer Institute (NCI) common toxicity criteria.

Statistical analysis
Statistical analysis was performed using SPSS version 16.0 for Windows, statistical software (SPSS, Chicago, IL).p values of <0.05 were considered statistically significant.Independent two-sided t test, nonparametric Mann-Whitney U test, or chi-square test was applied to compare variables between groups, where appropriate.For correlation of metric and ordinal variables, Spearman rank correlation coefficient was computed.Survival analysis was performed by means of Kaplan-meier survival curves and log-rank test.Univariate and multivariate Cox proportional hazard models were used to identify predictors of progression-free and overall survival.Hazard ratios of >1.0 indicate an increased likelihood of death or recurrence.

Patient characteristics
Patient and tumor characteristics data at baseline were compared across the two treatment groups (Table 1).A similar number of male and female patients were enrolled into each group (110 female in Group 1 and 52 female in Group 2, p=0.068) and the mean age was 61±11 years in Group 1 and 55±10 years in Group 2. All patients had baseline ECOG-PS scores of 0, 1 or 2.

Discussion
Double-agent chemotherapy with either XELOX and FOLFIRI were the most widely used cytotoxic agents in patients with mCRC (Colucci et al., 2005;Hochster et al., 2008;Cetin et al., 2012;Uygun et al., 2013).The combination of doublet chemotherapy regimens with biological agents, such as bevacizumab (a humanized monoclonal antibody that inhibits vascular endothelial growth factor (Ferrara et al., 2003) has been shown to prolong PFS, OS and RR although toxicity was also increased (Kabbinavar et al., 2005;Grothey et al., 2008;Hochster et al., 2008;Saltz et al., 2008;Welch et al., 2010;Macedo et al., 2012).Although all of this findings, the optimal combination of first-line treatment is still unclear (Cunningham et al., 2013).Results of first line some XELOX-Bev and FOLFIRI-Bev chemotherapy studies in mCRC were showed in Table 3.Up to now, each treatment regimens was studied by investigators but the comparison of XELOX-Bev vs FOLFIRI-Bev treatment was made by us for the first time.The primary result of our study was XELOX-Bev is superior to FOLFIRI-Bev in terms of PFS, OS and RR in the first-line treatment of patients with mCRC.Addition of bevacizumab to XELOX resulted in PFS ranging between 9.3-11.4 mo, OS ranging between 20.3-27.4 mo and a RR ranging between 46%-67.5% (Hochster et al., 2008;Tol et al., 2009;Doi et al., 2010;Cassidy et al., 2011;Uchima et al., 2014).Previous studies reported that the median PFS was between 9-12 months and the median OS was between 22-31.3 months and RR was 57.9% with FOLFIRI-Bev (Fuchs et al., 2007;Hecht et al., 2009;Sobrero et al., 2009;Stathopoulos et al., 2010;Ducreux et al., 2013;Becouarn et al., 2014).In our study, the median PFS was 9.6 months in Group 1 and 9 months in Group 2 (p=0.019).The median OS was 25 months in Group 1 and 20 months in Group 2 (p=0.036).Although our study supports the findings of other studies with the median PFS, OS and RR, when the results of XELOX-Bev and FOLFIRI-Bev are compared, XELOX-Bev is better than FOLFIRI-Bev in terms of PFS, OS and RR.
Although the efficiency combination of XELOX-Bev and FOLFIRI-Bev, alone or in different combinations, were executed previously, the first comparison of the two treatment regimens were made in our study.We found that XELOX-Bev is superior to FOLFIRI-Bev in terms of PFS, OS and RR in the first-line treatment of patients with mCRC.We can explain the prolangation of PFS, OS and increasing in RR in Group 1 as follows: 1. Toxic effects (neutropenia and mucositis) were less common in Group 1 than in Group2.Although in previous studies reported that high frequency (Diaz-Rubio et al., 2012) of diarrhea in XELOX-Bev treatment, in our study, the incidence of diarrhea and nausea/vomiting was low and similar in both groups.Incidence of diarrhea and nausea/ vomiting in our study was less than in a study reported from Western patients (Diaz-Rubio et al., 2012) and higher than in a study reported from Japanese patients (Uchima et al., 2014).2. Due to the low toxicity profile and high therapeutic efficacy in Group 1, patients in Group 1 received much more chemotherapy cycle than Group 2 and it is likely to affect the results of the prolangation of PFS. 3. Prolongation of OS may be due to either the prolongation of PFS or chemotherapies that received after first line chemotherapy.
In conclusion, according to our results, the combination of XELOX-Bev induced a significant rate of disease control with safety profile and an acceptable toxicity rate in mCRC when compared with FOLFIRI-Bev.

Figure 1 .
Figure 1.Overall Survival for Colorectal Cancer Patients Treated with XELOX-Bev vs FOLFIRI-Bev in First-line Treatment