Research In Prediction System On Metastatic Colorectal Cancer To Antiangiogenic Therapy

Objective: To reviewed clinical characters and features and survival of metastaticcolorectal cancer throught bevacizumab treatment. Adopt the ultrasound contrasttechnology for the patients with hepaticmetastases to get the hemodynamic index(PE,WiAUC,RT、mTTL、WiR、WiPI). To investigate the level of cytokines such asVEGF-A121, sTRAIL、IL-8、HIF-2α、Neuropilin1(NRP1) in the serum of metastaticcolorectal cancer, and discuss the above ultrasound contrast indexes. To explore therelationship of serum levels of cytokines and ultrasound contrast indexes andclinicopathological features. To find some possible predictive bio-markers orimageology markers of metastatic colorectal cancer that could be used to predict theeffect of bevacizumab.Methods:Patients with metastatic colorectal cancer in our department from Dec.2011to Dec.2013were analyzed with their clinical clinicopathological and treatmentfeatures. To detect the level of cytokines in the serum of all patients before first-linetherapy and after6weeks of first-line therapy. To explore the relationship betweenultrasound contrast indexes, the serum level of cytokines and clinicopathologicalfeatures.To compare the differences of ultrasound contrast indexes of different timepoint. To compare the differences of cytokines in serum level before first-line therapyand after6weeks of first-line therapy. Analyse their relationship with survival.Results:1. Up to the follow-up end（Dec.30th,2013）,86patients be chosen, and67(77.9%) patients exhibited progression and9(10.5%) patients died.23(26.7%) hadprogression diease (PD),30(34.8%) had stable disease (SD),.33(38.4%) achievedpartial response (PR), RR is38.4%, DCR is73.3%. Among36patients inbevacizumab-group,22(61.1%) achieved partial response (PR),8(22.2%) had stabledisease (SD),6(16.7%) had progression diease (PD). Among50patients in chemotherapy-group,13（26.0%） patients achieved partial response (PR),21(42.0%)had stable disease (SD),16(32%) had progression diease (PD). Results show that theefficiency of bevacizumab-group is higher than the chemotherapy-group（P=0.005）,.Progression free survival(mPFS) were6.08months while the medianoverall survival(mOS) was not achieved.2. There were36patients in bevacizumab-group, mPFS was10.19months.50patients in chemotherapy-group, mPFS was6.25. Difference of mPFS between thebevacizumab-group and the chemotherapy-group was significant（P=0.005）. Thetreatment of bevacizumab were independent prognostic factor of PFS（P=0.031）.3. Compared findings from DCE-US of36patients in bevacizumab-group betweend0and other time points. RT value increased after treatment than before treatment(p<0.01), while the remaining parameters before and after the treatment was notstatistically significant. Subgroup analysis showed efficacy: RT baseline values, theeffective subgroup was10.78±3.06, invalid subgroup was15.71±1.85, prompt theRT value levels before treatment was related to bevacizumab effects (P <0.01). RTvalue of dynamic observations suggest that effective group RT values rise, whileineffective group show a transient decrease. Survival analysis showed the changetrends and mPFS was associated (P <0.01). RT rising group mPFS (8.16m),wassignificantly better than the decreased group (3.55m).4. The serum level of VEGF-A121、sTRAIL、IL-8、HIF-2α、NRP1in36patientsbefore first-line therapy with bevacizumab was96.45±19.29ng/l、223.27±49.2ng/l、35.94±10.84ng/ml、48.92±12.23ng/l及6.62±1.95ng/l respectively. The serumlevel of cytokines in36patients after6weeks of first-line therapy was87.23±26.50ng/l、244.04±51.04ng/l、45.85±11.32ng/ml、34.73±8.09ng/l及7.22±1.82ng/lrespectively. The level of VEGF-A121，HIF-2α、IL-8showed decreased trend（P＜0.05）, while others had no significant difference between baseline level and after6weeks of first-line therapy (P>0.05).5. According to efficacy evaluation of patients receiving bevacizumab incombination with chemotherapy treatment divided into two subgroups:ineffective group (PD+SD) and effective group (CR+PR). Comparing the two subgroups beforereceiving treatment and after treatment in cytokine concentrations, results suggest that:NRP1pretreatment serum concentration in the effective subgroup was7.33±1.70ng/l,while invalid subgroup was4.93±0.83ng/l, the concentration of serum NRP1may beprompted with bevacizumab therapy efficacy (P=0.003). And Serum level ofVEGF-A121,sTRAIL, IL-8, HIF-2α before treatment between the two subgroups,concentration was not statistically significant.6. Relationships between cytokine concentrations and efficacy of bevacizumabgroup before and after treatment. Effective subgroup concentration of VEGF-A121group did not change before and after treatment, while the ineffective group decreasedVEGF-A121was significant (P <0.01). Effective subgroup sTRAIL concentration aftertreatment was significantly higher than that of before treatment (P=0.029). Effectivesubgroup NPR1concentration did not change between before and after treatment, andthe ineffective group NRP concentrations were significantly increased (P=0.0004).IL-8, HIF-2α concentration decreased after treatment, regardless of the outcome.7. Analyse long-term efficacy with the changes of serume level and trends incytokine concentrations before and after treatment. NPR1group will be divided intohigh and low groups, PFS shows no difference in the two subgroups (P=0.099).According change trends of cytokine concentrations before treatment, the NRP1,sTRAIL, VEGF-A121, respectively rising and falling group group for survival analysis.The results suggest that: NRP1falling group is better than rising group in PFS (8.59mvs4.39m, P=0.021), sTRAIL rise group is better than decreased group (7.45m vs2.64m, P=0.001).8．Carry through multivariate survival analysis with CEUS parameters and cytokinesconcentration, choose the RT change, NRP1, sTRAIL concentration change trends andother factors to conduct COX regression analysis. The results showed that all36patients with mCRC patients receiving bevacizumab therapy, RT level changes,sTRAIL concentration variation trend is an independent prognostic factor for PFS. RTvalues and NRP1concentration is negative correlated in Pearson test (P <0.01).Conclusion:1.mCRC patients received first-line bevacizumab combined with chemotherapy compared to chemotherapy alone could improve the ORR, prolong PFS;2. Application of ultrasound imaging techniques to detect lesions in the liver to obtainthe relevant parameters, the value of pre-treatment levels of RT value was related witheffect of bevacizumab term. The change trends of RT value before and after treatmentwas related with the long-term efficacy of RT;3. Baseline NRP1serum concentrationswere realted with effect of bevacizumab (P=0.003);4. Changes trends of cytokinesbefore and after treatment were associated with long-term effect: NRP1decreasedgroup and sTRAIL rising group shows better long-term effcet;5multivariate analysisshowed: RT level changes, sTRAIL changes trend is an independent prognostic factorfor PFS. RT value level was negatively correlated with the concentration of NRP1.