Comparison Of Efficacy And Adverse Events Between Bevacizumab And Anti-EGFR Monoclonal Antibody In The Treatment For Metastatic Colorectal Cancer

Objectives: To compare the efficacy and adverse events of Bevacizumab and anti-EGFRmonoclonal antibody in the treatment for metastatic colorectal cancer (mCRC) under thecondition of different lines of treatment, different drug orders, different types of drugs anddifferent KRAS status.Method:135pathologically proved mCRC patients administered between January1st2007andSeptember1st2012who ever received either Bevacizumabor anti-EGFR monoclonal antibodytherapy, with complete records of treatment outcomes, adverse events and survival data, werestudied. Treatment outcomes and adverse events were compared between patients undertakingBevacizumab and anti-EGFR monoclonal antibody based on different lines of treatment,different drug orders, different types of drugs and different KRAS status. Difference of adverseevents between Bevacizumab and anti-EGFR monoclonal antibody was compared. Assessingcriteria of treatment outcomes were based on the Response Evaluation Criteria in Solid Tumors(RECIST)1.0version. Objective Response rate (ORR)%was calculated as the proportion ofpatients with Complete response (CR) and Partial response (PR). Disease control rate(DCR)%was defined as the proportion of patients with Complete response(CR), Partial response (PR)andStable disease (SD). Grading criteria of adverse events was in accordance with the NCI-CTCAE3.0from National Cancer Institute (NCI). Statistical analysis was performed by SPSS18.0.Results: The number of patients who were administered with Bevacizumab or anti-EGFRmonoclonal antibody in first-line therapy was26and34, respectively. ORR for Bevacizumaband anti-EGFR monoclonal antibody groups were76.%and93.9%, respectively (P=0.0649).Median overall survival (mOS) was19.1months in Bevacizumab group and16.2months inanti-EGFR monoclonal antibody group (P=0.9716). Median Progression-free survival (mPFS)was recorded as9.5moths for Bevacizumab group and7.6months for anti-EGFR monoclonalantibody group. No significant difference was observed between two groups over mPFS.35patients were treated with anti-EGFR monoclonal antibodyand21patients were treated withBevacizumabin their second-line therapy. ORR for anti-EGFR monoclonal antibody andBevacizumab groups was9.38%and6.7%, respectively (P=1.0). DCR for both groups was84.38%and73.30%, respectively (P=0.4699). mOS for both groups was10.7months and14.3 months, respectively (P=0.1969). mPFS for both groups was5.8months and3.2months,respectively (P=0.0833), no difference of efficacy and survival was obtained between twogroups. Logistic regression analysis revealed that mPFS in anti-EGFR monoclonal antibodygroup was significantly longer than that in Bevacizumab (P=0.029; HR=2.206). The number ofpatients who received anti-EGFR monoclonal antibody or Bevacizumab in third-line orthird-line above therapy was39and25, respectively. ORR for both groups was12.82%and0.00%(P=0.1492), DCR for both groups were71.79%and69.57%, respectively (P=0.8518).mOS for both groups were3.4months and4.4months (P=0.3507), no significant difference wasobserved over survival between two groups. Patients were grouped based on the administrationorder of the monoclonal antibodies (i.e. anti-EGFR monoclonal antibody+Bevacizumab groupand Bevacizumab+anti-EGFR monoclonal antibody group). Numbers for both groups were13and11, respectively. ORR for first-line treatment of both groups was23.08%and0.00%,respectively (P=0.2292). DCR for both groups was84.62%and90.00%, respectively(P=1.0000). mOS for both groups were19.9months and16.0months, respectively (P=0.7218).mPFS for both groups were6.6months and6.1months, respectively (P=0.0910). No survivaland efficacy difference was obtained between two groups. ORR for second-line treatment ofboth groups was0.00%and9.09%, respectively (P=0.4583). DCR for both groups was53.85%and72.73%, respectively (P=0.4225). mOS for both groups was15.7months and11.5months,respectively (P=0.8253). mPFS for both groups was3.5months and6.0months, respectively(P=0.8158). No significant difference over survival was observed between two groups. Therewere7patients who had been treated with Bevacizumab for the first-line option until theirdisease progressed and was then administrated with Bevacizumab again for other cross-overtherapy.9patients were recorded who had been undertaking anti-EGFR monoclonal antibodyfor their first-line option until disease progressed and was then treated with anti-EGFRmonoclonal antibody again for other cross-over therapy. ORR for both groups was0.00%and11.11%, respectively (P=1.0000). DCR for both groups was71.43%and77.78%, respectively(P=1.0000). No significant difference of efficacy and disease control rate was obtained betweentwo groups. Patients were grouped based on the type of monoclonal antibody they received (i.e.anti-EGFR monoclonal antibody group, Bevacizumab group and anti-EGFR monoclonalantibody+Bevacizumab group). mOS for those three groups were20.7,24.4and41.6months,respectively. OS was significantly longer in anti-EGFR monoclonal antibody+Bevacizumabgroup than that in anti-EGFR monoclonal antibody group (P=0.0241). Result was the samewhen compared OS between anti-EGFR monoclonal antibody+Bevacizumab group andBevacizumab group (P=0.0208). OS for patients treated with monoclonal antibody afterfirst-line therapy and patients who received chemotherapy+monoclonal antibody therapy were 30.8and21.5months, respectively (P=0.0519). Significant difference of survival betweenpatients treated with monoclonal antibody after second-line therapy and patients who underwentchemotherapy+monoclonal antibody therapy for either first-line or second-line option, wasobserved (37months vs.13.7months, P=0.003). Patients ever treated with Irinotecan,Oxaliplatin, Fluorouracil,anti-EGFR monoclonal antibody and Bevacizumab were grouped aschemotherapy+monoclonal antibody used after third-line therapy andchemotherapy+monoclonal antibody used before third-line therapy. mOS were similar betweenthose two groups (50.6months vs.41.5months, P=0.5312). Survival analysis was performedamong patients treated with chemotherapy+monoclonal antibody used after first-line therapy.No significant difference was observed based on PFS of first-line therapy(≤6months or＞6months), KRAS status (Wild type, mutant type and unkown) and PFS status. Number of patientswith confirmed KRAS status, who were treated with Bevacizumab for the first-line therapy andsecond-line therapy, was11and34, respectively. No difference was observed of ORR and DCRbetween KRAS non-mutant group and KRAS mutant group whose patients were treated withBevacizumab for the first-line or second-line therapy. Patients who were treated withBevacizumabwasdivided into two groups based on their KRAS status (i.e. KRAS wild typegroup and KRAS mutant group). Number for those groups was32and13, respectively. mOS forthose two groups were23.7months and17.8months (P=0.5432). Cox regression analysisrevealed that numbers of metastatic sites, treatment lines and surgery history of the primarycancer were associated with patients’ OS (P＜0.05). The more metastatic sites the shorter OS(P=0.0006). The more lines of therapy patients received, the longer OS they had (P=0.0008).Patients whose primary tumor was resected had longer OS than those who did not receive anysurgery (P=0.0067). In terms of adverse events, Bevacizumab was more frequent with1-2gradehypertension, nausea, albuminuria, hemorrhage, anaemia than anti-EGFR monoclonal antibody.The proportion of patients who had3-4grade hypertension was significantly higher than inBevacizumabgroup than that in anti-EGFR monoclonal antibody group (P=0.0311). Anti-EGFRmonoclonal antibody was more frequent with rash, liver dysfunction, allergy, hypokalemia andhypomagnesemia. The frequency of3-4grade rash was significantly higher in anti-EGFRmonoclonal antibody group than that in the Bevacizumab group (P=0.0031). So was thefrequency of fatigue (P＜0.0001).Analysis was performed to investigate on the age factorsassociated with adverse events of Bevacizumab. There were67patients whose age was≤70.8patients was over70.1-2grade hemorrhage was significantly more frequent with patients over70than those whose age was≤70(P=0.0432). No significant difference of other adverseevents was observed between two age groups.Conclusion: The medication order of Bevacizumab and anti-EGFR monoclonal antibody had no significant impact on treatment outcomes and OS among patients whose KRAS was wild.Patients who ever received both Bevacizumab and anti-EGFR monoclonal antibody therapieshad better survival than those who received either Bevacizumabor anti-EGFR monoclonalantibody therapy. Earlier introduction of monoclonal antibody might not associate with bettersurvival. Patients with good tumor biological behavior might benefit from the treatment patternof “chemotherapy comes beforemonoclonal antibody”. Early introduction of monoclonalantibody might work out for those whose tumor was potentially resectable or those with heavytumor burden and rapid tumor progression. Adverse events should not be the key factor affectingphysicians’choice as all of them are manageable for both monoclonal antibodies.