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      Chemotherapy plus Panitumumab Versus Chemotherapy plus Bevacizumab in Metastatic Colorectal Cancer: A Meta-analysis

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          Abstract

          Panitumumab and bevacizumab have been widely used in combination with chemotherapy for patients with wild type RAS metastatic colorectal cancer (mCRC). Whether panitumumab or bevacizumab was the optimal option remained controversial. Thus, we conducted a meta-anaylsis to evaluate chemotherapy plus panitumumab (C + P) versus chemotherapy plus bevacizumab (C + B) in wild type RAS mCRC. Electronic databases including PubMed, Embase, and Web of Science, Cochrane Library, ClinicalTrials.gov, were searched. This meta-analysis estimated the progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and adverse events (AEs). Three randomized controlled trials with a total number of 577 patients were included. In wild type RAS population, PFS [hazard ratio (HR) = 0.96; 95% confidence interval (CI), 0.76 to 1.15] and OS (HR = 0.90; 95% CI, 0.54 to 1.27) and ORR [relative ratio (RR) = 2.06; 95% CI, 0.86 to 4.90] appeared similar between the two treatments, the incidence of AEs slightly increased (RR = 1.16; 95% CI 1.08 to 1.26). In conclusion, there was insufficient evidence to precisely conclude that combination treatment of C + P had an improved efficacy compared with C + B. Further large-scale and better-designed clinical trials are still needed to evaluate the combination treatment of C + P in patients with wild type RAS mCRC.

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          Global cancer statistics.

          Ahmedin Jemal, Freddie Bray, Melissa M Center … (2011)
          The global burden of cancer continues to increase largely because of the aging and growth of the world population alongside an increasing adoption of cancer-causing behaviors, particularly smoking, in economically developing countries. Based on the GLOBOCAN 2008 estimates, about 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these, 56% of the cases and 64% of the deaths occurred in the economically developing world. Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths. Lung cancer is the leading cancer site in males, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. Breast cancer is now also the leading cause of cancer death among females in economically developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Further, the mortality burden for lung cancer among females in developing countries is as high as the burden for cervical cancer, with each accounting for 11% of the total female cancer deaths. Although overall cancer incidence rates in the developing world are half those seen in the developed world in both sexes, the overall cancer mortality rates are generally similar. Cancer survival tends to be poorer in developing countries, most likely because of a combination of a late stage at diagnosis and limited access to timely and standard treatment. A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination (for liver and cervical cancers), and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake. Clinicians, public health professionals, and policy makers can play an active role in accelerating the application of such interventions globally.
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            Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.

            Rafael Amado, Michael Wolf, Marc Peeters … (2008)
            Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials. KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status. KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P < .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population. Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.
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              Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study.

              Leonard Saltz, Stephen Clarke, Eduardo Díaz-Rubio … (2008)
              To evaluate the efficacy and safety of bevacizumab when added to first-line oxaliplatin-based chemotherapy (either capecitabine plus oxaliplatin [XELOX] or fluorouracil/folinic acid plus oxaliplatin [FOLFOX-4]) in patients with metastatic colorectal cancer (MCRC). Patients with MCRC were randomly assigned, in a 2 x 2 factorial design, to XELOX versus FOLFOX-4, and then to bevacizumab versus placebo. The primary end point was progression-free survival (PFS). A total of 1,401 patients were randomly assigned in this 2 x 2 analysis. Median progression-free survival (PFS) was 9.4 months in the bevacizumab group and 8.0 months in the placebo group (hazard ratio [HR], 0.83; 97.5% CI, 0.72 to 0.95; P = .0023). Median overall survival was 21.3 months in the bevacizumab group and 19.9 months in the placebo group (HR, 0.89; 97.5% CI, 0.76 to 1.03; P = .077). Response rates were similar in both arms. Analysis of treatment withdrawals showed that, despite protocol allowance of treatment continuation until disease progression, only 29% and 47% of bevacizumab and placebo recipients, respectively, were treated until progression. The toxicity profile of bevacizumab was consistent with that documented in previous trials. The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS in this first-line trial in patients with MCRC. Overall survival differences did not reach statistical significance, and response rate was not improved by the addition of bevacizumab. Treatment continuation until disease progression may be necessary in order to optimize the contribution of bevacizumab to therapy.
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                Author and article information

                Contributors
                Xiaoting Wu: wxt1@medmail.com.cn
                Journal
                Journal ID (nlm-ta): Sci Rep
                Journal ID (iso-abbrev): Sci Rep
                Title: Scientific Reports
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2045-2322
                Publication date (Electronic): 11 January 2018
                Publication date PMC-release: 11 January 2018
                Publication date Collection: 2018
                Volume: 8
                Electronic Location Identifier: 510
                Affiliations
                ISNI 0000 0004 1770 1022, GRID grid.412901.f, Department of gastrointestinal surgery, , West China Hospital, Sichuan University, ; Chengdu, Sichuan 610041 China
                Article
                Publisher ID: 19001
                DOI: 10.1038/s41598-017-19001-6
                PMC ID: 5764984
                PubMed ID: 29323221
                SO-VID: 7d21880d-85c3-488b-8f40-26348443c35c
                Copyright © © The Author(s) 2017
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 10 July 2017
                Date accepted : 18 December 2017
                Categories
                Subject: Article
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                issue-copyright-statement © The Author(s) 2018

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