The Evidence-based Study Of Therapeutic Strategy To Treatment Metastatic Colorectal Cancer

BackgroundColorectal cancer (CRC) is a major public health problem, and is one of the leading causes of cancer deaths worldwide. About 25% of patients are diagnosed in advanced or metastatic stages, and 50%-60% patients will eventually develop into mCRC, and distant metastases still represent the main cause of death. The treatment of metastatic CRC (mCRC) has undergone considerable advances in recent decades with the introduction of new drugs and biological agents. As a consequence, the survival of mCRC has greatly increased. Although various treatment regimens becoming available for advanced CRC, the choice on mCRC treatment strategy remains controversial, such as whether the addition of cetuximab to oxaliplatin-based chemotherapy benefit mCRC compared with oxaliplatin-based chemotherapy or the benefits and harms of non-sustained chemotherapy compared traditional continuous chemotherapy. The aim of the current study was to conduct research on these two issues and systematic evaluate the relevant RCTs to identify the suitable therapeutic strategies by using evidence-based methods.Objective(1) To assess the efficacy and adverse events of cetuximab plus oxaliplatin-based chemotherapy for mCRC.(2) To assess the choice of treatment of mCRC after first-line chemotherapy for those who had responded to treatment or achieved stable disease.MethodsA systematic search of Pubmed, Embase, Science Citation Index Expanded (SCI-EX-PANDED), the Cochrane Central Register of Controlled Trials (CENTRAL), Chinese Biomedical Database (CBM), China National Knowledge Infrastructure/Chinese Academic Journals Full-Text Database (CNKI) were conducted without language restriction or publication status. Conference proceedings (ASCO and ESMO), ongoing trials, and references searching were also performed. Two reviewers independently inspected identified studies and extracted the data. The evaluation of quality of included studies, publication bias and data synthesis were performed by Revman 5.2. Fixed-effect or random effects model was adopted according to heterogeneity.Results(1)7 studies (including 3291) met the inclusion criteria. The pooled hazard ratio (HR) for PFS were 0.89 (95%CI:0.71-1.12,P=0.31) and 0.98 (95%CI:0.86-1.12, P=0.81) in patients with wild type KRAS tumors and total population, respectively. The results of HR for OS were 1.00 (95%CI:0.92-1.09,P=0.97) and 1.02 (95%CI: 0.94-1.11,P=0.64) between the two types of population. The pooled risk ratio for overall response rate were 1.20(95%CI:1.02-1.41,P=0.01),1.25(95%CI:1.03-1.52, P=0.03) between the two types of population. The pooled HR for PFS were 0.69 (HR=0.69,95%CI:0.56～84, P=0.0003) when combined with 5-FU therapy. Overall grade 3 or worse toxicities, especially rash (RR=46.06,95%CI:21.89-96.93, P<0.0001), diarrhea (RR=1.55,95%CI:1.33～1.81,P<0.0001), anaphylactic reaction (RR=1.70,95%CI:1.03～2.79,P=0.04) and fatigue were much more common in the experimental arm.(2) 12 studies met the inclusion criteria. Non-continous chemotherapies were divided into three regimens. After the completion of pre-planned number of first-line chemotherapy cycles, the following regimens including complete cessation of therapy, intermittent chemotherapy or stop and go, and biological agents as maintenance therapy. The pooled HR in PFS and OS for the first complete cessation of therapy versus continuous chemotherapy was 1.30 (p=0.003) and 1.06 (P=0.27). Regarding intermittent chemotherapy versus continuous chemotherapy, the pooled HR for PFS and OS were 1.03(p=0.7),0.92 (p=0.34), respectively. The pooled HR in PFS for trials exploring bevacizumab or cetuximab alone as maintenance therapy was 1.13, (P=0.04), and pooled HR in PFS for the studies investigating bevacizumab plus capecitabine as maintenance therapy compared with continuous chemotherapy was 0.60 (P=0.002). No difference was observed in os between the two groups. Overall grade 3 or worse toxicities, especially neuropathy, hand-foot syndrome were less common in the non-continous chemotherapies group. The available information for QoL also favored non-continous therapy.ConclusionMeta-analysis indicated that:(1) The addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of mCRC clearly increased ORR in the wild type KRAS population and total population, but did not improve PFS and OS, even in the wild type KRAS population, while increasing cumulative toxicity. However, when combined with 5-FU therapy, the PFS showed a statistically difference in favor of experimental group. (2) Complete cessation of chemotherapy and maintenance therapy with targeted agents only was not adequate with a detrimental PFS, whereas intermittent chemotherapy may be an appropriate choice for patients after introduction chemotherapy. Howerer, at present, maintenance therapy with biological agents plus capecitabin may be a better regimen for mCRC.