Skip to main content
NCBI home page
Medicine logoLink to Medicine
. 2020 Jun 19;99(25):e19908. doi: 10.1097/MD.0000000000019908

Meta-analysis on the risk of fatal adverse events by bevacizumab, cetuximab, and panitumumab in 31 randomized trials including 25,000 patients with colorectal carcinoma

Jianxin Chen a, Junhui Wang b, Tao Ni c, Huijuan He b, Qinhong Zheng a,∗
Editor: Giandomenico Roviello
PMCID: PMC7310739  PMID: 32569154

Abstract

Background:

Targeted drugs including bevacizumab, cetuximab, and panitumumab have been widely used during the management of patients diagnosed with colorectal carcinoma, especially as palliative treatment. The present meta-analysis was performed to evaluate the fatal adverse events (FAEs) of targeted drugs including bevacizumab, cetuximab, and panitumumab in patients with colorectal cancer.

Patients and methods:

Studies of prospective, randomized, and controlled feature from EMBASE, Medline, and Cochrane Library, which reported FAEs potentially associated with bevacizumab, cetuximab, and panitumumab were adopted. Clinical characteristics and FAEs were collected from the enrolled literatures, with the quality of which been evaluated. Pooled analysis of FAEs, caused by each agent as first line, second/further line, and adjuvant treatment were performed with relative risks (RRs) and their corresponding 95% confidence intervals (CIs) in software RevMan 5.3.

Results:

Thirty-one studies including 25,939 patients were brought into the final analysis. The RR and its 95% CI of the FAEs among all the agents including bevacizumab, cetuximab, and panitumumab was 1.07 (95% CI, 0.89–1.29; P = .50). The RRs and their 95% CIs of the FAEs as first line, second or further line, and adjuvant treatment related to bevacizumab were 0.91 (95% CI, 0.62–1.32; P = .61), 1.14 (95% CI, 0.57–2.28; P = .71), and 1.10 (95% CI, 0.67–1.79; P = .72). The RRs and their 95% CIs of the FAEs as first line, second or further line, and adjuvant treatment related to cetuximab were 1.02 (95% CI, 0.60–1.76; P = .93), 2.51 (95% CI, 0.49–12.88; P = .27), and 2.40 (95% CI, 1.00–5.77; P = .05). The RRs and their 95% CIs of the FAEs as first line, second or further line treatment related to panitumumab were 1.40 (95% CI, 0.89–2.18; P = .14) and 0.68 (95% CI, 0.43–1.09; P = .11), respectively.

Conclusions:

The present meta-analysis did not show any significantly increased RR of FAEs belonging to bevacizumab, cetuximab, or panitumumab, whether as first line, second/further line, or adjuvant treatment among patients with colorectal carcinoma comparing to placebo or blank treatment.

Keywords: bevacizumab, cetuximab, colorectal cancer, fatal adverse events, panitumumab

1. Introduction

Colorectal cancer is one of the most common malignancies worldwide, accounting for 10.2% (1,846,200) of the new cases and 9.2% (883,200) of the deaths in 2018.[1] Currently, the treatment strategy of colorectal cancer has been established with the alternative including surgery, chemotherapy, radiotherapy, and targeted therapy in recent years. However, approximately 50% to 60% of patients diagnosed with colorectal cancer developed metastatic disease,[2,3] and 80% to 90% of which had unresectable liver metastases.[4–6] In terms of the systematic treatment of the metastatic colorectal cancer, the panel of National Comprehensive Cancer Network (NCCN) recommended five chemotherapeutic regimens, including FOLFOX,[7] FOLFIRI,[8] XELOX,[9,10] 5-FU/LV,[11] and FOLFOXIRI[12,13] based on the relative clinical trials. In particular, targeted agents including bevacizumab, cetuximab, and panitumumab have been deemed as the standard choices, in combination with chemotherapy on the basis of their encouraging results, which prolonged the overall survival of patients with metastatic disease up to 3 years in selected population.[14]

With the wide use of the monoclonal antibodies including bevacizumab, cetuximab, and panitumumab in the systematic therapy in patients with colorectal cancer, the safety of the agents has raised the attention of the clinical physicians. The addition of bevacizumab was associated with significantly increased risk of fatal adverse events (FAEs) among patients with special tumor types including non-small cell lung cancer (NSCLC), pancreatic cancer, prostate cancer, and ovarian cancer (RR was 1.29, 95% confidence intervals (CI): 1.05–1.57, P = .01).[15] Likewise, cetuximab was suggested with an increased risk of severe adverse events in patients with colorectal carcinoma (70.0% versus 51.23%, P < .001).[16] However, few analyses have been conducted to explore the FAEs of the monoclonal antibodies including bevacizumab, cetuximab, and panitumumab, in patients with colorectal carcinoma.

Thus, the present meta-analysis was designed to identify the relative risks (RR) of FAEs in colorectal cancer patients treated with bevacizumab, cetuximab, and panitumumab comparing to placebo/blank, in an attempt to provide some potential evidence for clinicians during the treatment of colorectal carcinoma.

2. Patients and methods

2.1. Literature search

Databases including EMBASE, MEDLINE, and Cochrane Library were reviewed with the main key words “Bevacizumab,” “Cetuximab,” and “Panitumumab” as MeSH terms. Literature review was conducted up to December 31, 2018, without restrictions on start time. The searching procedure was limited to original, published, prospective, randomized, placebo/blank controlled clinical trials, which had been fully published in English. The present meta-analysis was performed in compliance with the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. The pooled analysis was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.[17]

2.2. Inclusion and exclusion criteria

Inclusion criteria:

  • 1.

    Prospective, randomized, placebo/blank controlled clinical trials related to bevacizumab, cetuximab, or panitumumab in patients with colorectal carcinoma;

  • 2.

    Participants were randomly assigned to receive one of the agents (bevacizumab, cetuximab, or panitumumab) as experiment or placebo/blank treatment in the group control in the including studies;

  • 3.

    FAEs, in both of the arms were reported with or without etiology specified.

Exclusion criteria:

  • 1.

    Agents (bevacizumab, cetuximab, or panitumumab) used in the researches were not the comparative ones.

  • 2.

    Case reports, basic experiments, review publication, and correspondences were excluded;

  • 3.

    All the meeting abstracts were excluded because of the potential publication bias.

2.3. Data extraction

Data extraction was conducted by two independent investigators (JXC, JHW). Available data was extracted from all the screened studies with the items as below: first author's name, publication year, sample size of the study, median age, treatment status, European Cooperative Oncology Group Performance Status (ECOG PS), available agents (bevacizumab, cetuximab, or panitumumab), regimens adopted in both of the arms, and the number of FAEs. Administered doses and treatment time of targeted agents were also specified. All the objective FAEs, with or without reasons specified, rather than drug-caused FAEs according to researchers’ judgment, were recorded. Any discrepancies between the two investigators were resolved by consensus with a third participant (TN).

2.4. Quality assessment of included studies

Quality assessment of the included studies was performed by the two reviewers (JXC, JHW) with the criteria of Cochrane Collaboration's tool for assessing risk of bias of RCTs. The items adopted for the evaluation were listed below: random sequence generation, allocation concealment, binding of participants and personnel, binding of outcome assessments, incomplete outcome data, selective reporting and other bias, all of which were presented with figure format.

2.5. Statistical analysis

RRs and their corresponding 95% CIs of FAEs in patients treated with drugs (bevacizumab, cetuximab, or panitumumab) comparing to placebo were considered as the primary objective in the present study. We also explored the RRs of the FAEs related to the agents in the cases of first-line, second or further line, or adjuvant treatment comparing to the control. In addition, etiology-specified FAEs were extracted and classified on the basis of physiology system or symptoms to illuminate the difference between the group experiment and the control. Pooled analysis of RRs was developed with software RevMan 5.3 (Cochrane Collaboration, USA). Between-study heterogeneity was estimated with I2 test. P-value > .1 and I2 < 50% were considered as no substantial heterogeneity. Random effect model or fixed effect model was adopted for the pooled analysis of heterogeneous data or homogeneous one, respectively. A P-value < .05 was supposed to be statistically significant. Potential publication bias was detected by funnel plot with software RevMan 5.3.

3. Results

3.1. Search results

With an integrative review, there were 971 potential literatures totally searched in databases including MEDLINE, EMBASE, and Cochrane Library. About 542 publications were removed because of duplications. Two hundred ninety-three studies were excluded further because of the inconformity of prospective, randomized, placebo/blank controlled feature. With the inclusion criteria, 53 papers were finally considered for further assessment. After reviewed with full texts, 14 researches were conclusively eliminated because of the reasons including negatively reported of FAEs (n = 9), unspecified classification of adverse events (n = 3), nature of research protocol (n = 1), and unmatched comparison of the groups (n = 1). Finally, a total of 31 original researches included in 39 literatures were considered eligible for the eventual analysis. A flow diagram which detailed the selective procedure of included studies was shown in Figure 1.

Figure 1.

Figure 1

Open in a new tab

Study selection procedure with PRISMA flow diagram.

3.2. Quality assessment of the included studies

After quality evaluation was conducted within the criteria of Cochrane Collaboration's tool, which was designed for assessing risk of bias of RCTs, it was revealed that most of the included RCTs accord with the evaluation criterion including allocation concealment, random sequence generation, binding of participants and personnel, and binding of outcome assessments, results of which were shown in Figures 2 and 3.

Figure 2.

Figure 2

Open in a new tab

Risk of bias graph: review authors’ judgments about each risk of bias item presented as percentages among all the included studies.

Figure 3.

Figure 3

Open in a new tab

Risk of bias summary: review authors’ judgments about each risk of bias item for each included study.

3.3. Population characteristics

A total of 25,939 patients enrolled in 31 studies were considered available in the present pooled analysis. The investigative agents in the satisfactory clinical trials include bevacizumab (n = 15), cetuximab (n = 10), and panitumumab (n = 6). All the patients included in the present study possessed a good performance status (PS) as 0, 1, and 2. The baseline characteristics of the included literature were presented in Tables 1  and 2.

Table 1.

Baseline characteristics of the researches included in the present study.

3.3.

Open in a new tab

Table 1 (Continued).

Baseline characteristics of the researches included in the present study.

3.3.

Open in a new tab

Table 2.

Administered doses and treatment time of targeted agents included in the present study.

3.3.

Open in a new tab

3.4. Relative risk of FAEs

A pooled analysis of the RR of the FAEs in patients treated with bevacizumab, cetuximab, and panitumumab comparing to placebo or blank in the control was performed in the 31 prospective, randomized, controlled clinical trials. The RR and its 95% CI of the FAEs among all the agents including bevacizumab, cetuximab, and panitumumab was 1.07 (95% CI, 0.89–1.29; P = .50). The RRs and their 95% CIs of the FAEs related to bevacizumab, cetuximab, and panitumumab were 1.01 (95% CI, 0.76–1.33; P = .96), 1.41 (95% CI, 0.91–2.17; P = .12), and 0.99 (95% CI, 0.72–1.36; P = .95), respectively (Fig. 4).

Figure 4.

Figure 4

Open in a new tab

Forest plot of FAEs in patients treated with bevacizumab, cetuximab, and panitumumab (group experiment) comparing to placebo/blank (group control).

Results of the heterogeneity evaluation among all the including researches did not show statistical heterogeneity (I2 = 0%, P = .37). Likewise, heterogeneity was not detected in patients treated with bevacizumab (I2 = 0%, P = .57), cetuximab (I2 = 0%, P = .51), or panitumumab (I2 = 33%, P = .20)

3.5. Relative risk of FAEs in different treatment status

We evaluated the RRs of FAEs treated with agents (bevacizumab, cetuximab, panitumumab) or placebo/blank as first line, second or further line, and adjuvant treatment separately, to specify the influence of therapeutic status on the incidence of FAEs. As a result, the RRs and their 95% CIs of the FAEs as first line, second or further line, and adjuvant treatment related to bevacizumab were 0.91 (95% CI, 0.62–1.32; P = .61), 1.14 (95% CI, 0.57–2.28; P = .71), and 1.10 (95% CI, 0.67–1.79; P = .72), respectively (Fig. 5). The RRs and their 95% CIs of the FAEs as first line, second or further line, and adjuvant treatment related to cetuximab were 1.02 (95% CI, 0.60–1.76; P = .93), 2.51 (95% CI, 0.49–12.88; P = .27), and 2.40 (95% CI, 1.00–5.77; P = .05), respectively (Fig. 6). The RRs and their 95% CIs of the FAEs as first line, second or further line treatment related to panitumumab were 1.40 (95% CI, 0.89–2.18; P = .14) and 0.68 (95% CI, 0.43–1.09; P = .11), respectively (Fig. 7)

Figure 5.

Figure 5

Open in a new tab

Forest plot of FAEs in patients treated with bevacizumab (group experiment) comparing to placebo/blank (group control) as first line, second or further line, and adjuvant treatment.

Figure 6.

Figure 6

Open in a new tab

Forest plot of FAEs in patients treated with cetuximab (group experiment) comparing to placebo/blank (group control) as first line, second or further line, and adjuvant treatment.

Figure 7.

Figure 7

Open in a new tab

Forest plot of FAEs in patients treated with panitumumab (group experiment) comparing to placebo/blank (group control) as first line, second or further line treatment.

3.6. Specific FAEs

Individual specified causes of FAEs were presented in Figure 8. As it showed, there were 67 cases of FAEs and 62 cases of those specified in the group experiment and the control, respectively. However, there were 71.4% of FAEs in the group experiment and 71.8% of those remaining unspecified etiology. For the FAEs specified in the present study, we classified them according to physiology system or symptoms. FAEs included in cardiovascular system covered heart arrhythmia, myocardial infarction, aortic dissection, venous/artery thrombosis, cardiac failure, cardiac arrest, myocardial ischemia, pulmonary embolism, and circulatory failure, while digestive system covered mucositis, gastrointestinal perforation, hepatic failure, diarrhea, enteritis, gastrointestinal necrosis, and ileus, hematologic system covered agranulocytosis and severe anemia, respiratory system covered respiratory failure, pneumonia, pulmonary fibrosis, interstitial lung disease, and dyspnea, central nervous system covered encephalorrhagia and central nervous system ischemia. As a result, the most common FAEs in the group experiment concentrated upon cardiovascular system (29.9% versus 29.0%), digestive system (17.9% versus 19.4%), and multiple organ failure (16.4% versus 16.1%), respectively.

Figure 8.

Figure 8

Open in a new tab

FAEs specified by types.

3.7. Publication bias

Result of funnel plot did not show significant publication bias (Fig. 9).

Figure 9.

Figure 9

Open in a new tab

Funnel plot for publication bias.

4. Discussion

The present meta-analysis did not show a significantly increased risk of FAEs among patients with colorectal carcinoma enrolled in prospective, randomized, controlled clinical trials who received bevacizumab, cetuximab, or panitumumab therapy compared to placebo or blank treatment. Furthermore, the statistical differences were not detected either, in patients who received the agents as first line, second/further line, or adjuvant treatment.

Targeted agents including cetuximab (KRAS/NRAS wild type and left-side tumors only), panitumumab (KRAS/NRAS wild type and left-side tumors only), and bevacizumab have been emerged as the standard options with or without chemotherapy for the systematic treatment in patients with metastatic colorectal carcinoma. Selected patients with colorectal cancer were benefited from the wide use and the price reduction of the agents, which might make it more extensive in clinical practice. However, anti-tumor therapy with targeted drugs is a double edged sword. The efficacy, rather than safety of the drugs, always played a significant role in the decision-making of the patients, which might lead to the potential incidence of severe and even FAEs during the treatment. Hence, the proper understanding of the adverse events may help to make the decision more objective. According to the results of the present meta-analysis, the administration of monoclonal antibodies including bevacizumab, cetuximab, or panitumumab did not increase the RR of FAEs comparing to placebo/blank in the treatment of colorectal carcinoma.

There have been a few meta-analyses conducted to evaluate the RRs or incidence of the severe/fatal adverse events of bevacizumab, cetuximab, and panitumumab in patients with solid tumors. The anti-VEGFR antibody bevacizumab was showed to be in association with a significant increase in the risk of high-grade adverse events, including hypertension (RR 5.67, 95% CI 3.02–10.65), proteinuria (RR 10.09, 95% CI 4.79–21.27), bleeding (RR 3.45, 95% CI 2.25–5.30), cardiac toxicity (RR 2.15, 95% CI 1.29–3.59), and neutropenic fever (RR 1.51, 95% CI 1.15–2.00) among patients with advanced-stage breast cancer.[49] However, the dose of bevacizumab used in breast cancer in the included studies (10–15 mg/kg) was much more bigger than colorectal cancer in the present analysis (5 mg/kg).[49] The difference of dose between the cancer types might lead to the diversity of the RRs. Another pooled analysis of the adverse events including fatal ones of bevacizumab was conducted in patients with NSCLC.[50] The pooled result of nine clinical trials (bevacizumab 2.5–5 mg/kg) showed that the addition of bevacizumab to therapy in advanced NSCLC increased the RRs of proteinuria (RR = 7.55), hypertension (RR = 5.34), and hemorrhagic events (RR = 2.61), however, rather than arterial/venous thromboembolic events (P = .35, P = .92), gastrointestinal perforation (P = .60), or FAEs (P = .29).[50] The pooled result of FAEs was similar to our own estimates in the current study. This implied that the dose of bevacizumab used in different tumor types might lead to the discrepant risk of FAEs. However, in an earlier published meta-analysis including 34 researches with different tumor types, the pooled results of the RRs induced by bevacizumab showed that the addition of bevacizumab was associated with an increased risk of FAEs among patients with pancreatic cancer (RR = 1.83, 95% CI, 1.07–3.14), prostate cancer (RR = 3.34, 95% CI, 1.35–8.25), and ovarian cancer (RR = 2.35, 95% CI, 1.03–5.33), but not in colorectal carcinoma (RR = 1.29, 95% CI, 0.84–1.99).[15] Owing to that the dose of bevacizumab was similar between the included literatures (2.5–5 mg/kg),[15] tumor types might play another important role in the RRs of FAEs.

The RRs of FAEs with cetuximab has been former assessed by another meta-analysis,[16] the result of which showed that cetuximab was not associated with increased risk of FAEs (odd ratio, 1.41; 95% CI, 0.99–2.03; incidence, 1.8% versus 1.3%). The present updating analysis with the addition of another four researches still supported the conclusion that there was no evidence of an increased risk of FAEs with cetuximab in patients with colorectal carcinoma. However, another pooled analysis revealed that the incidence of grade 3/4 adverse events, including skin toxicity (RR = 20.76, 95% CI, 3.87–111.33, P = .000), diarrhea (RR = 1.48, 95% CI, 1.33–1.64, P = .000), hypertension (RR = 1.69, 95% CI, 1.17–2.46, P = .006), anorexia (RR = 1.57, 95% CI, 1.18–2.10, P = .002), and mucositis/stomatitis (RR = 2.69, 95% CI, 1.90–3.80, P = .000), was statistically higher in the combined therapy group (chemotherapy plus cetuximab) than in the chemotherapy-only group, while without the RRs or incidence of FAEs reported.[51] Interestingly, the result of a recent phase II clinical trial suggested that severe early skin reactions caused by cetuximab predicted favorable overall survival for patients treated with cetuximab plus chemotherapy without impairing quality of life (hazard ratio, 0.48; 95% CI, 0.21–0.97; P = .04).[52] However, the conclusion of the above study might be limited by its relatively small sample size (n = 140) and the deficiency of control group, which hampered part of the statistical analyses. Thus, future studies are required to build on the findings of the study. Besides, with the clinical experience, we do suggest that the severe skin reactions really harm the quality of life in selected patients. There was a recently published meta-analysis conducted to evaluate the different toxicities between cetuximab and panitumumab, the results of which revealed that cetuximab was associated with fewer high grade (grade 3–4) skin toxicities (RR, 0.62, 95% CI 0.53–0.62), frequent high grade acne-like rash (RR, 1.24, 95% CI 1.04–1.48), and paronychia (RR, 1.36, 95% CI 1.1–1.7) than panitumumab.[53] However, in the present study, the results of pooled analysis did not reveal any increased risk of FAEs of panitumumab or cetuximab comparing to placebo or blank, which had not been reported before. In addition, we further investigated the influence of treatment status including first line, second/further line, and adjuvant therapy on the risk of FAEs, the results of which did not show any evidence of increased risk of FAEs by bevacizumab, cetuximab, or panitumumab as first line, second/further line, or adjuvant treatment in patients with colorectal cancer. Although the FAEs not specified in the majority of the included literatures, we still identified the specified ones by physiology system or symptoms. The limited outcome did not reveal any differences between the targeted agents and placebo either.

There were several limitations existing in the present meta-analysis. First, and most obviously, was heterogeneity, which was caused by the diversity of dose of drugs (bevacizumab, cetuximab, and panitumumab), as well as the different chemotherapy regimens combined in the present study. We tried to conduct a meta-regression to reduce that. However, the relevant coefficient seemed to be untoward to specify, especially among studies with various chemotherapeutic regimens used in the enrolled literatures. It seems difficult to figure out whether there existed potential synergistic side-effects between targeted agents and different chemotherapy regimens. In addition, the diversity of duration of drugs exposure came with another potential heterogeneity, which may lead to another bias in the pooled assessment of relative risks. Finally, most of the FAEs (71.6%) were not etiology specified in the present study. Lacking of the essential information may bring with some potential bewilderment to readers. However, we could not establish more convinced results with the limitations.

In conclusion, the present meta-analysis did not show a significantly increased relative risk of FAEs belonging to bevacizumab, cetuximab, or panitumumab, whether as first line, second/further line, or adjuvant treatment among patients with colorectal carcinoma comparing to placebo or blank treatment.

Author contributions

JXC designed the study and wrote this manuscript. JHW retrieved database and reviewed the studies. TN reviewed the included studies. QHZ and HJH reviewed the manuscript and supervised the conduction of the present study. JXC and JHW extracted data and performed the analysis. All of the authors have read and approved the final manuscript.

Footnotes

Abbreviations: AE = adverse events, B = bevacizumab, BSC = best supportive care, C = cetuximab, CI = confidence interval, CT = chemotherapy, ECOG PS = Eastern Cooperative Oncology Group, performance status, FAE = fatal adverse event, FOLFIRI = irinotecan + fluorouracil + leucovorin, FOLFOX = oxaliplatin + fluorouracil + leucovorin, IFL = irinotecan + fluorouracil + leucovorin, MOF = multiple organ failure, N/R = not reported, NCCN = National Comprehensive Cancer Network, NSCLC = non-small cell lung cancer, P = panitumumab, PHD = physical health deterioration, PL = placebo, PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses, RR = relative risk, XELIRI = irinotecan + capecitabine, XELOX = oxaliplatin + capecitabine.

How to cite this article: Chen J, Wang J, Ni T, He H, Zheng Q. Meta-analysis on the risk of fatal adverse events by bevacizumab, cetuximab, and panitumumab in 31 randomized trials including 25,000 patients with colorectal carcinoma. Medicine. 2020;99:25(e19908).

QZ and HH contributed equally to the article and should be considered as co-corresponding authors.

The ethical approval was waived as the present study being a systematic review. This article does not contain any studies with animals performed by any of the authors.

Informed consent was not available in the present study as it was a systematic review.

The authors have no funding and conflicts of interest to disclose.

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

References

  • [1].Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394–424. [DOI] [PubMed] [Google Scholar]
  • [2].Lee WS, Yun SH, Chun HK, et al. Pulmonary resection for metastases from colorectal cancer: prognostic factors and survival. Int J Colorectal Dis 2007;22:699–704. [DOI] [PubMed] [Google Scholar]
  • [3].Van Cutsem E, Nordlinger B, Adam R, et al. Towards a pan-European consensus on the treatment of patients with colorectal liver metastases. Eur J Cancer 2006;42:2212–21. [DOI] [PubMed] [Google Scholar]
  • [4].Muratore A, Zorzi D, Bouzari H, et al. Asymptomatic colorectal cancer with un-resectable liver metastases: immediate colorectal resection or up-front systemic chemotherapy? Ann Surg Oncol 2007;14:766–70. [DOI] [PubMed] [Google Scholar]
  • [5].Kemeny N. Management of liver metastases from colorectal cancer. Oncology (Williston Park) 2006;20:1161–76. 1179; discussion 1179–1180, 1185–1166. [PubMed] [Google Scholar]
  • [6].Dawood O, Mahadevan A, Goodman KA. Stereotactic body radiation therapy for liver metastases. Eur J Cancer 2009;45:2947–59. [DOI] [PubMed] [Google Scholar]
  • [7].Maindrault-Goebel F, Louvet C, Andre T, et al. Oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX6). GERCOR. Eur J Cancer 1999;35:1338–42. [DOI] [PubMed] [Google Scholar]
  • [8].André T, Louvet C, Maindrault-Goebel F, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. GERCOR. Eur J Cancer 1999;35:1343–7. [DOI] [PubMed] [Google Scholar]
  • [9].Cassidy J, Clarke S, Díaz-Rubio E, et al. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 2008;26:2006–12. [DOI] [PubMed] [Google Scholar]
  • [10].Porschen R, Arkenau HT, Kubicka S, et al. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol 2007;25:4217–23. [DOI] [PubMed] [Google Scholar]
  • [11].Jäger E, Heike M, Bernhard H, et al. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1. J Clin Oncol 1996;14:2274–9. [DOI] [PubMed] [Google Scholar]
  • [12].Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 2007;25:1670–6. [DOI] [PubMed] [Google Scholar]
  • [13].Souglakos J, Androulakis N, Syrigos K, et al. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer 2006;94:798–805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [14].Kirstein MM, Lange A, Prenzler A, Manns MP, Kubicka S, Vogel A. Targeted therapies in metastatic colorectal cancer: a systematic review and assessment of currently available data. Oncologist 2014;19:1156–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [15].Huang H, Zheng Y, Zhu J, Zhang J, Chen H, Chen X. An updated meta-analysis of fatal adverse events caused by bevacizumab therapy in cancer patients. PLoS One 2014;9:e89960. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [16].Zhang D, Ye J, Xu T, Xiong B. Treatment related severe and fatal adverse events with cetuximab in colorectal cancer patients: a meta-analysis. J Chemother 2013;25:170–5. [DOI] [PubMed] [Google Scholar]
  • [17].Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009;339:b2700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [18].Shin S, van Hillegersberg R, Schouten SB, et al. Randomized Phase III Study to Assess Efficacy and Safety of Adjuvant CAPOX with or without Bevacizumab in Patients after Resection of Colorectal Liver Metastases: HEPATICA study. Neoplasia 2018;19:93–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].Kerr RS, Love S, Segelov E, et al. Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial. Lancet Oncol 2016;17:1543–57. [DOI] [PubMed] [Google Scholar]
  • [20].Masi G, Salvatore L, Boni L, et al. Continuation or reintroduction of bevacizumab beyond progression to first-line therapy in metastatic colorectal cancer: Final results of the randomized BEBYP trial. Ann Oncol 2015;26:724–30. [DOI] [PubMed] [Google Scholar]
  • [21].Koeberle D, Betticher DC, von Moos R, et al. Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06). Ann Oncol 2015;26:709–14. [DOI] [PubMed] [Google Scholar]
  • [22].Cunningham D, Lang I, Marcuello E, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol 2013;14:1077–85. [DOI] [PubMed] [Google Scholar]
  • [23].Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 2013;14:29–37. [DOI] [PubMed] [Google Scholar]
  • [24].de Gramont A, Van Cutsem E, Schmoll HJ, et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol 2012;13:1225–33. [DOI] [PubMed] [Google Scholar]
  • [25].Guan ZZ, Xu JM, Luo RC, et al. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer 2011;30:682–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Allegra CJ, Yothers G, O’Connell MJ, et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol 2011;29:11–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [27].Tebbutt NC, Wilson K, Gebski VJ, et al. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group Randomized Phase III MAX Study. J Clin Oncol 2010;28:3191–8. [DOI] [PubMed] [Google Scholar]
  • [28].Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008;26:2013–9. [DOI] [PubMed] [Google Scholar]
  • [29].Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007;25:1539–44. [DOI] [PubMed] [Google Scholar]
  • [30].Kabbinavar FF, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005;23:3697–705. [DOI] [PubMed] [Google Scholar]
  • [31].Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New Engl J Med 2004;350:2335–42. [DOI] [PubMed] [Google Scholar]
  • [32].Passardi A, Nanni O, Tassinari D, et al. Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial. Ann Oncol 2015;26:1201–7. [DOI] [PubMed] [Google Scholar]
  • [33].Qin S, Li J, Wang L, et al. Efficacy and Tolerability of First-Line Cetuximab Plus Leucovorin, Fluorouracil, and Oxaliplatin (FOLFOX-4) Versus FOLFOX-4 in Patients With RAS Wild-Type Metastatic Colorectal Cancer: The Open-Label, Randomized, Phase III TAILOR Trial. J Clin Oncol. 2018:JCO2018783183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [34].Ciardiello F, Normanno N, Martinelli E, et al. Cetuximab continuation after first progression in metastatic colorectal cancer (CAPRI-GOIM): a randomized phase II trial of FOLFOX plus cetuximab versus FOLFOX. Ann Oncol 2016;27:1055–61. [DOI] [PubMed] [Google Scholar]
  • [35].Taieb J, Tabernero J, Mini E, et al. Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. Lancet Oncol 2014;15:862–73. [DOI] [PubMed] [Google Scholar]
  • [36].Primrose J, Falk S, Finch-Jones M, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol 2014;15:601–11. [DOI] [PubMed] [Google Scholar]
  • [37].Ye LC, Liu TS, Ren L, et al. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol 2013;31:1931–8. [DOI] [PubMed] [Google Scholar]
  • [38].Alberts SR, Sargent DJ, Nair S, et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA 2012;307:1383–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [39].Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 2011;377:2103–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [40].Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. New Engl J Med 2009;360:1408–17. [DOI] [PubMed] [Google Scholar]
  • [41].Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. New Engl J Med 2009;360:563–72. [DOI] [PubMed] [Google Scholar]
  • [42].Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:2311–9. [DOI] [PubMed] [Google Scholar]
  • [43].Kim TW, Elme A, Park JO, et al. Final analysis of outcomes and RAS/BRAF status in a randomized phase 3 study of panitumumab and best supportive care in chemorefractory wild type KRAS metastatic colorectal cancer. Clin Colorectal Cancer 2018;17:206–14. [DOI] [PubMed] [Google Scholar]
  • [44].Peeters M, Price TJ, Cervantes A, et al. Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol 2014;25:107–16. [DOI] [PubMed] [Google Scholar]
  • [45].Douillard JY, Siena S, Cassidy J, et al. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol 2014;25:1346–55. [DOI] [PubMed] [Google Scholar]
  • [46].Seymour MT, Brown SR, Middleton G, et al. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol 2013;14:749–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [47].Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 2009;27:672–80. [DOI] [PubMed] [Google Scholar]
  • [48].Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007;25:1658–64. [DOI] [PubMed] [Google Scholar]
  • [49].Shin S, Noh Y. Increased risk of adverse drug events secondary to bevacizumab treatment in patients with advanced or metastatic breast cancer: a meta-analysis of randomized controlled trials. Ther Clin Risk Manag 2018;14:833–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [50].Lai XX, Xu RA, Yu-Ping L, Yang H. Risk of adverse events with bevacizumab addition to therapy in advanced non-small-cell lung cancer: a meta-analysis of randomized controlled trials. OncoTargets Ther 2016;9:2421–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [51].Lv ZC, Ning JY, Chen HB. Efficacy and toxicity of adding cetuximab to chemotherapy in the treatment of metastatic colorectal cancer: a meta-analysis from 12 randomized controlled trials. Tumour biol 2014;35:11741–50. [DOI] [PubMed] [Google Scholar]
  • [52].Iwamoto S, Ooki A, Morita S, et al. A prospective Phase II study to examine the relationship between quality of life and adverse events of first-line chemotherapy plus cetuximab in patients with KRAS wild-type unresectable metastatic colorectal cancer: QUACK trial. Cancer Med 2018;7:4217–27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [53].Petrelli F, Ardito R, Ghidini A, et al. Different toxicity of Cetuximab and Panitumumab in metastatic colorectal cancer treatment: a systematic review and meta-analysis. Oncology 2018;94:191–9. [DOI] [PubMed] [Google Scholar]

Articles from Medicine are provided here courtesy of Wolters Kluwer Health

RESOURCES