Efficacy Of Cetuximab Plus Chemotherapy For Wild-KRAS Metastatic Colorectal Cancer

?Backgrounds?Colorectal cancer(CRC) is one of the most common malignant tumors threatening human health. It is the third most frequently diagnosed type of cancer and the fourth cause of cancer-related deaths worldwide. With the rapid economic growth and the change of lifestyles in China, the incidence and mortality of CRC has been reported to increase annually and will continue to rise in the next few years.Approximately 50% of CRC patients develop metastatic colorectal cancer(mCRC)and 5-year survival is less than 10%. The strategy for these patients is palliative treatment to prolong survival. Chemotherapy is limited and the efficacy of two-drug combination is about 40%~50%. Molecular target therapy, especially anti-epidermal growth factor(EGFR)monoclonal antibody such as cetuximab, has widened treatment options for m CRC patients. Several large studies from foreign trials have shown that for m CRC patients with wild-type KRAS, cetuximab combined with chemotherapy has brought notable clinical improvement and prolonged the survival in the first, second, and third line settings. In recent years, early tumor shrinkage(ETS) was proposed. Some researchers have found it may predict progression-free survival(PFS) or overall survival(OS), and proposed that it could be a surrogate biomarker of OS. But large studies are needed to confirm it. In China,cetuximab was approved and applied later, so there is few prospective clinical trials.Meanwhile, the cost associated with cetuximab is very high and usually it is not covered by the serious illness insurance payments in most cities. This restricts the extensive use of cetuximab and lead to insufficient evidence in our country.Based on these realistic backgrounds, we designed to assess the effectiveness and safety of cetuximab plus chemotherapy in different lines treatment of wild-KRAS m CRC,to analyze the factors that may affect the prognosis, to study the relationship between ETS and survival in the present study.?Objectives?To investigate the effectiveness and safety of cetuximab plus traditional chemotherapy for m CRC patients with wild-type KRAS in the first, second and further line settings respectively, to find the best line of cetuximab, to explore the correlation of various clinical factors and survival in this retrospective analysis, to analyze the relationship of ETS and PFS or OS, and to provide reference for clinical practice.?Methods?1. The clinical data of patients with wild-KRAS mCRC admitted in the Xijing Hospital of Digestive Diseases from August 2009 to June 2014 were collected via electronic database. According to the diagnostic criteria, inclusion criteria and exclusion criteria,eligible subjects were screened carefully.2. The efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors1.1(RECIST 1.1). To observe the efficacy of cetuximab plus chemotherapy in the first,second, and third line treatment and to compare their clinical outcomes with data from clinical trials aboard.3. According to the addition of cetuximab, patients were classified into two subgroups:first line cohort and non-first line cohort including the second and third line treatment.To compare the objective response rate(ORR), disease control rate(DCR), ETS, PFS and OS of these two cohorts respectively. And to analyze the potential factors influencing the prognosis by univariate and multivariate analysis.4. Correlation between ETS and PFS or OS was analyzed.5. Safety outcomes based on previously described related adverse events and were classified according to National Cancer Institute-Common Toxicity Criteria Adverse Events version 3.0(NCI-CTCAE v3.0). To compare the incidence of treatment-related adverse events between the two subgroups.?Results?1. A total of 62 patients with wild-KRAS m CRC were admitted to the study cohort,including 45 cases of first line cohort and 17 cases of non-first line cohort(10 patients in second line setting and 7 patients in third line setting). The median follow-up time was 22.6 months(2.5~76.4 months). The median cycles of cetuximab was 12(2~41cycles).2. ORR was 42.2%, DCR was 88.9%, ETS rate was 33.3%, median PFS was 8.5 months,median OS1 was 24.7 months, median OS was 25.2 months in the first line cohort and ORR was 23.5%, DCR was 58.9%, ETS rate was 5.9%, median PFS was 5.5 months,median OS was 24.1 months in the non-first line cohort(ORR was 30.0%, DCR was70.0%, median PFS was 5.8 months, median OS1 was 15.9 months, median OS was24.8 months in the second line treatment. ORR was 14.3%, DCRwas 42.9%, median PFS was 3.7 months, median OS1 was 8.3 months, median OS was 22.7 months in the third line treatment).3. In the first line setting, ORR was lower than the results from randomized controlled trials, median PFS and median OS1 approximated them. In the second line treatment,ORR was higher than the results of EPIC and BOND trials, median PFS and median OS1 improved. The outcomes in the third line setting were consistant to the data from clinical trials.4. ORR and ETS rate were not statistically significant between the two arms(P=0.174 and P=0.06, respectively). DCR was significantly higher(P=0.021). Median PFS was significantly improved in the first line subgroup(P < 0.0001). But there was no statistically significant difference in median OS(P=0.431). The results suggest that non-first line treatment with cetuximab may be a better option with high cost performance.5. Multivariate analysis showed that resection of primary lesion, cycles and lines of cetuximab were independent risk factors of PFS. Meanwhile, resection of primary lesion, pathological differentiation and cycles of cetuximab were independent risk factors of OS.6. Median PFS was 9.7 months of ETS patients and 6.8 months of non-ETS patients(P<0.0001) and median OS was 27.6 months and 23.8 months respectively(P=0.008). The results support that ETS may be an early indicator to predict the prognosis.7. The most common adverse event related to cetuximab was acne-like rash(74.2%). The occurrence of mucositis was 12.9%. Chemotherapy-related side effects included nausea, vomiting, diarrhea, myelosuppression, neurotoxicity, liver dysfunction, and so on. More grade 1~2 adverse events and less grade 3~4 toxic effects. There were no statistically significant differences between the two arms in the occurrence of toxicity events.?Conclusions?In the present study, our results indirectly confirmed the efficacy and safety cetuximab combined with chemotherapy in different lines therapy of wild-KRAS m CRC patients, compared with randomized controlled study. Non-first line treatment with cetuximab may be a better option with high cost performance. Resection of primary lesion,cycles and lines of cetuximab were independent risk factors of PFS. Meanwhile, resection of primary lesion, differentiation and cycles of cetuximab were independent risk factors of OS. ETS may be a indicator of clinical outcomes for m CRC patients, but prospective studies still need to be confirmed.