| Objectives:A retrospective analysis of the clinical data of patients with RAS and BRAF wild-type metastatic colorectal cancer（m CRC）receiving anti-epidermal growth factor receptor（EGFR）monoclonal antibody（m Ab）as maintenance therapy in our hospital.To further confirm its efficacy and safety as maintenance therapy,and provide evidence-based medicine for clinical application.Methods:From January 2012 to December 2021,the patients of RAS and BRAF wildtype unresectable m CRC treated with anti-EGFR m Ab alone or combined chemotherapy as maintenance therapy in first-line or second-line treatment were retrospectively analyzed in our hospital,to observe the efficacy and safety.Maintenance therapy refers to the discontinuation of certain toxic chemotherapy drugs and the use of low-intensity,low-toxicity drugs to continue treatment when the standard high-intensity induction therapy achieves the best efficacy and the disease is in a stable state.Efficacy indicators include: progression-free survival（PFS）,PFS1,overall survival（OS）and OS1.PFS refers to the time from the start of first-line or secondline induction chemotherapy to progression disease or death or censored calculation;PFS1 refers to the time from the start of maintenance therapy to the first progression disease or death or censored calculation.OS refers to the time from the start of the first-line or second-line induction chemotherapy to death for any reasons;OS1 refers to the time from the start of maintenance therapy to death for any reasons;PFS1 and OS1 do not include the duration of induction of intensive therapy.Stratified factors: The efficacy data were sub-analyzed according to four indicators,including maintenance therapy strategies（anti-EGFR m Ab,anti-EGFR m Ab + fluoropyrimidines,anti-EGFR m Ab + irinotecan）,stage of maintenance therapy（first-line treatment and second-line treatment）,number of maintenance treatment cycles（<10 cycles and ≥10 cycles）and ECOG performance score（0 and 1-2）.Analysis of factors related to the efficacy of maintenance therapy: Univariate analysis was performed on the gender,age at the beginning of maintenance therapy,ECOG score,location of primary tumor,tissue differentiation of primary tumor,whether primary tumor was removed,stage of maintenance therapy,number of metastases,time of metastasis,maintenance therapy regimen,maintenance therapy single and double drugs,the best evaluation before maintenance therapy and the number of maintenance therapy cycles.On the basis of the factors（the number of maintenance treatment cycles and ECOG score）that were suggested to be related to the outcome events by univariate analysis,five factors including the site of metastases before maintenance therapy,maintenance therapy regimen and premaintenance therapy evaluation were included for multivariate analysis.Adverse side effects: Acne-like rash,myelosuppression,digestive tract reaction,allergic reaction,liver and kidney function impairment,fever,peripheral neurotoxicity,hand-foot syndrome,weight loss,catarrh,according to the Common Terminology Criteria for Adverse Events（CTCAE）version 5.0 of adverse events of general terms during maintenance therapy in patients with statistics and analysis on the occurrence of adverse events.Statistical methods: Kaplan-Meier methods were used to estimate median maintenance treatment duration,median PFS（m PFS）,m OS（m OS）,median PFS1（m PFS1）,median OS1（m OS1）,and 95% confidence intervals.Descriptive Statistics were used for patient demographics and other characteristics Statistical analysis of data was performed using IBM SPSS Statistics 26.0 statistical software.All curves were plotted using Graph Pad Prism 8.0 software.The results of statistical analysis were compared with the data of previously reported clinical studies on maintenance therapy.Results:A total of 45 patients with RAS and BRAF wild-type m CRC were included,and they were maintained on anti-EGFR m Ab ± irinotecan/fluorouracil drugs until progression disease.The median duration of maintenance therapy for all patients was 6.1 months.Forty-two patients received first-line maintenance therapy and 3 patients received second-line maintenance therapy.For all patients,the m PFS was 15.1 months,the m PFS1 was 9.5 months,and the 12-month progression-free survival rate was 71.3%,m OS was 42.7 months and m OS1 was 35.0 months.PR was maintained in 35.6%（16/45）patients and SD was maintained in 48.9%（22/45）patients during maintenance therapy.Subgroup analysis:（1）Different maintenance treatment regimens,the antiEGFR m Ab single maintenance treatment group had a m PFS of 16.0 months,a m PFS1 of 10.6 months,a m OS of 29.7 months,and a m OS1 of 25.3 months.In the anti-EGFR m Ab + irinotecan group,the m PFS was 11.2 months,and the m PFS1 was 6.3 months;the m OS was 21.8 months,and the m OS1 was 21.8 months.The m PFS of the anti-EGFR m Ab + fluorouracil group was 15.6 months,and the m PFS1 was 8.0 months;the m OS was 56.5 months,and the m OS1 was 47.6 months（including the anti-EGFR m Ab + capecitabine maintenance treatment group: the m PFS was 21.5 months,and the m PFS1 was 17.6 months;the m OS was 30.6 months,and the m OS1 was 30.55 months;the anti-EGFR m Ab + 5FU/LV maintenance therapy group : the m PFS was 14.9 month,and the m PFS1 was 7.0 months;the m OS was 56.5 months,and the m OS1 was 47.6 months）.（2）Number of maintenance treatment cycles: the m PFS and m PFS1 of patients with maintenance treatment ≥10 cycles were better than those of patients with maintenance treatment <10 cycles.The m PFS in the two groups was 17.6 months and 11.2 months,respectively（P=0.028）;the m PFS1 in the two groups was 14.16 months and 4.36 months,respectively（P=0.004）.（3）ECOG score: Patients with an ECOG score of 0 had better m OS and m OS1 than patients with an ECOG score of 1-2.The m OS of the two groups was 73.2 months and 30.60 months,respectively（P=0.030）.The m OS1 of the two groups was 64.41 months and 30.55 months,respectively（P=0.021）.（4）Maintenance treatment stage: There was no statistical significance in PFS,PFS1,OS and OS1 in the first-line and second-line maintenance treatment groups.Univariate analysis and multivariate analysis: Univariate analysis showed that the number of maintenance treatments was was correlated with PFS（P=0.028）and PFS1（P=0.04）.ECOG score was correlated with OS（P=0.030）and OS1（P=0.021）.Multivariate analysis showed that maintenance treatment regimen was anti-EGFR mab + fluorouracil（P=0.037）,PR before maintenance（P=0.037）and number of maintenance treatment≥10 cycles（P=0.002）were positively correlated with PFS;PR before maintenance（P=0.034）and number of maintenance treatment ≥ 10 cycles（P=0.001）were positively correlated with PFS1.Maintenance regimens were anti-EGFR mab + fluorouracil（P=0.020）were positively correlated with OS and ECOG performance score of 1-2（P=0.009）was negatively correlated with OS;maintenance regimen of anti-EGFR mab + fluorouracil（P=0.028）was positively correlated with OS1 and ECOG performance score of 1-2（P=0.009）was negatively correlated with OS1.Comparison with data from existing clinical studies of maintenance therapy:（1）Comparison with chemotherapy-single maintenance therapy data: Our results were 15.1 months for m PFS and 42.7 months for m OS.Our results were not only numerically longer than those of OPTIMOX1（m PFS was 8.7 and m OS was 21.2 months）and OPTIMOX2（m PFS was 8.6 and m OS was 23.8 months）studies who received 5FU/LV maintenance therapy,but better than those of the capecitabine maintenance group in the Phase III study of Sun Yat-sen University Cancer Hospital and the Phase II study of Peking University Cancer Hospital.（2）Compared with maintenance therapy with bevacizumab: Our results were numerically longer than those of capecitabine plus bevacizumab in the CAIRO3 study and the Stop and Go Phase III trial（m PFS1 of 8.5 months in CAIRO3;The m PFS in the Stop and Go study was 11.0 months.）The time to failure of strategy（TFS）in the AIO 0207 group receiving 5FU/LV plus Bev maintenance therapy was 6.9 months.The TFS of the Bev monotherapy maintenance group was 6.1 months,and the results of our analysis were numerically longer than these two treatments.（3）Comparison with anti-EGFR m Ab maintenance treatment data: The results showed that the m PFS,m PFS1 and m OS of anti-EGFR m Ab maintenance therapy in our study were numerically longer than those in standard NORDIC-VII,NORDIC-7.5,MACRO2,COIN-B and TIMEPRODIGE 28 clinical maintenance treatment studies.The m PFS and m OS of the anti-EGFR m Ab + 5FU/LV regimen maintenance therapy group were numerically longer than the SAPPHIRE,PANAMA and VALENTINO clinical maintenance treatment data.The m PFS,m PFS1 and m OS of the anti-EGFR m Ab + capecitabine maintenance therapy regimen was numerically longer than those of the TJCC005 phase II study maintenance therapy data.However,the results of the anti-EGFR m Ab + irinotecan maintenance treatment regimen was significantly inferior to the CTR1900026360 single-center clinical study.Toxic side effect: The incidence of adverse events of any grade during maintenance treatment with anti-EGFR m Abs was significantly lower than that during induction chemotherapy,and the incidence of grade 3-4 adverse reactions during maintenance treatment was lower.The incidence of grade 3-4 adverse events during induction therapy and maintenance therapy was 24.4%（11/45）and 13.3%（6/45）,respectively.No patients experienced grade 4 adverse reactions during maintenance therapy,the safety was acceptable,and no patients died.Conclusions:1.For patients with unresectable left-sided RAS and BRAF wild-type m CRC,who achieved good efficacy in receiving standard chemotherapy combined with anti-EGFR m Ab induced remission therapy,and continued with anti-EGFR m Abcontaining maintenance therapy can significantly improve PFS and OS.The efficacy indicators of m PFS,m PFS1 and m OS in this study were numerically longer than standard maintenance therapy data.2.Compared with previous reports,no new toxic and side effects were observed in anti-EGFR m Ab-containing maintenance therapy,and the overall tolerance was well.The toxicity was significantly reduced compared with the induction intensive treatment period,which improved the quality of life of patients and provided a good reserve for subsequent treatment.3.At present,the domestically approved anti-EGFR m Ab is economically feasible due to depreciation and entering the insurance directory.Recent studies have shown that the efficacy of 2-week anti-EGFR m Ab regimen is comparable to that of 1-week regimen.It not only improves the convenience of application,but also has effectiveness and security.Therefore,anti-EGFR m Ab-containing regimen can be used as maintenance therapy after effective induction of intensive therapy for advanced unresected m CRC in Chinese people.4.The results of subgroup analysis showed that RAS BRAF wild-type m CRC patients with good physical status and ECOG score of 0 were more suitable for maintenance therapy containing anti-EGFR m Ab,with significant OS benefits.MCRC patients with ≥ 10 cycles of maintenance therapy were sensitive to maintenance therapy containing anti-EGFR m Ab,showed no obvious resistance,and showed significant benefit of PFS Anti-EGFR m Ab+5FU/LV maintenance therapy may be a better maintenance regimen.5.Our study is a single-center retrospective study and the number of cases included was relatively small,especially the subgroup analysis was not sufficient.In the future,the sample size will be further expanded and multi-center prospective studies will be conducted to confirm this in future.At the same time,subsequent studies will add dynamic ct DNA testing to further screen for biomarkers that can benefit from anti-EGFR m Ab maintenance therapy. |
PDF Full Text Request