Contributed equally
This meta-analysis aimed to evaluate the currently available evidence on the efficacy and safety of cancer treatment with or without tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-related agents. We conducted a systematic search through Medline, Cochrane Library and EMBASE electronic databases and manually searched the Journal of Clinical Oncology to identify randomized controlled trials (RCTs) conducted between 1995 and 2013 comparing the efficacy and safety results of cancer treatment with and without TRAIL-related agents. The methodological quality of the included RCTs was assessed by the Cochrane Risk of Bias assessment tool. The outcome measurements included objective response rate (ORR), clinical benefit rate (CBR)/disease control rate (DCR) and adverse events (AEs). The relevant data were analyzed using Review Manager 5.2 software. Grading of Recommendations Assessment Development and Evaluation was used to assess the quality of evidence and grade of recommendation. Four RCTs, including a total of 596 patients, were ultimately selected and analyzed. There were no statistically significant differences among the 4 RCTs regarding ORR [relative risk (RR)=0.92, 95% confidence interval (CI): 0.73–1.15, P=0.45], CBR/DCR (RR=0.92, 95% CI: 0.81–1.05, P=0.21), progression-free survival [hazard ratio (HR)=0.89, 95% CI: 0.75–1.05, P=0.16], overall survival (HR=0.90, 95% CI: 0.74–1.09, P=0.27), number of patients with any AEs (RR=0.99, 95% CI: 0.96–1.03, P=0.77), number of patients with any severe AEs (RR=0.95, 95% CI: 0.78–1.55, P=0.58), number of patients with ≥grade 3 AEs (RR=1.13, 95% CI: 0.93–1.38, P=0.22) and number of fatal AEs (RR=1.14, 95% CI: 0.71–1.81, P=0.59). The quality of evidence was considered to be moderate and the recommendation grades were weak. In conclusion, the benefits of TRAIL-related agents in the treatment of cancer patients remain uncertain and further clinical trials are required.
Cancer is a major public health concern worldwide and has been ranked first in the disease spectrum. A total of 1,638,910 new cancer cases and 577,190 cancer deaths were projected to occur in the United States in 2012 (
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), also referred to as Apo2L, was first discovered in 1995. It was observed that full-length TRAIL is expressed on the cell surface and picomolar concentrations of soluble TRAIL rapidly induce apoptosis in a wide variety of transformed cell lines of diverse origin, without affecting normal cells (
Several randomized controlled trials (RCTs) were conducted over the last few years and the majority of the results did not support the addition of TRAIL-related agents to cancer treatment regimens. However, to the best of our knowledge, no systematic review or meta-analysis of the currently available evidence has been conducted thus far. This meta-analysis aimed to investigate the safety and efficacy of TRAIL-related agents.
All the published RCTs comparing TRAIL-related agents with other therapies for cancer treatment were independently searched for by two authors (Sun S and Sun L). Other therapies included drugs that had been applied as first- or second-line cancer treatment. Medline, the Cochrane Library and EMBASE databases were searched. We also performed a manual search of the reference abstracts in the Journal of Clinical Oncology for the American Society of Clinical Oncology, in order to obtain the latest data. RCTs were included if they were conducted between 1995 and May 31, 2013. The publication language was limited to English. The following key words were used to search PubMed: ‘TNF-related apoptosis-inducing ligand’, ‘tumor necrosis factor-related apoptosis-inducing ligand’, ‘TRAIL’, ‘Apo2L’, ‘rhTRAIL’, ‘rhApo2L’, ‘HGS-ETR1’, ‘HGS-ETR2’, ‘Apomab’, ‘TRA-8’, ‘CS-1008’, ‘AMG 655’, ‘LBY135’, ‘PRO95780’, ‘drozitumab’, ‘HGS-TR2J’, ‘KMTR-2’, ‘lexatumumab’, ‘conatumumab’, ‘tigatuzumab’, ‘dulanermin’, ‘mapatumumab’, ‘death receptor 4’, ‘DR4’, ‘death receptor 5’, ‘DR5’, ‘neoplasms’, ‘neoplasm’, ‘tumor’, ‘tumour’, ‘cancer’, ‘clinical trial’ and ‘random controlled trial’.
Only the RCTs comparing TRAIL-related agents with traditional therapies for cancer treatment were included in this study, regardless of whether they were blinded.
Two reviewers (Sun S and Sun L) independently screened the titles of all the retrieved articles. We first reviewed the abstract of the articles that were relevant to the topic. The full text was then obtained through different approaches to retrieve more information on the selected clinical trials. A third reviewer (Xie C) was consulted for the final decision in case of any disagreement on eligibility between the first two reviewers.
The extracted data consisted of two parts: i) general information (study type, time, location, number of cases in each group and gender ratio); and ii) data for the meta-analysis (tumor response, survival and AEs). Two reviewers (Sun S and Li Z) participated in the extraction of data from all the eligible RCTs. The third reviewer (Xie C) was consulted if necessary.
The studies were independently assessed by two reviewers (Sun S and Li Z). A third reviewer (Xie C) was consulted in case of any disagreement. The study assessment included: i) Assessing the risk of bias. The Cochrane Collaboration’s tool for assessing the risk of bias was used (
The outcomes considered in this meta-analysis included the objective response rate (ORR), the clinical benefit rate (CBR)/disease control rate (DCR) and AEs. ORR included complete response (CR) and partial response (PR), whereas CBR/DCR included CR, PR and stable disease (SD).
The meta-analysis was conducted with the Cochrane Collaboration Review Manager 5.2 software (
A total of 2,224 relevant articles were retrieved. The study selection process is summarized in
As shown in
In this meta-analysis, data from 4 RCTs were included. As the subgroup of the 4 RCTs was not consistent, we considered the subgroups as independent clinical trials and analyzed them separately. The data from Soria
The results of the 4 included RCTs are shown in
The 4 included RCTs provided CBR/DCR data and the analysis of the outcome is shown in
As the main endpoint of all 4 RCTs, PFS was reported with PFS events, hazard ratio (HR) and 95% CI. According to the method introduced by Tierney
The results of the OS meta-analysis are shown in
As shown in
A sensitivity analysis was performed by excluding studies one by one. The RRs, HRs, 95% CIs and P-values for ORR, CBR/DCR, PFS, OS and AEs were similar to the results of the all-set analysis. This indicated that no single study had bias on the results of our meta-analysis.
The results of evidence quality and grade of recommendation of the included RCTs are summarized in
Several phase I or II clinical trials assessing the tolerability, pharmacokinetics (
ORR was the main outcome in the majority of stage II/III clinical trials. The number of patients with CR and PR reflected the efficacy of chemotherapy. In our analysis, we failed to demonstrate substantial evidence supporting the addition of TRAIL-related agents to first-line treatments for cancer (RR=0.92, 95% CI: 0.73–1.15, P=0.45). However, our study had certain limitations, which are discussed below. CBR was also used as an index of efficacy. The number of patients with SD did not affect our results. The median heterogeneity may be a result of the different types of cancer and treatment. Although the included RCTs had recruited patients with advanced-stage cancer, different types of cancer exhibit differences in chemo-sensitivity.
Survival data were analyzed using the methods described by Tierney
We also assessed AEs as an endpoint. The common AEs included nausea, alopecia, fatigue, dyspnea, anemia and neutropenia. The majority of the AEs were not associated with the administration of TRAIL-related agents. Although we did not detect a significant difference in this analysis, we consider the data to be reliable. Furthermore, patients with advanced cancer tolerated TRAIL-related agents well, which is consistent with the results of the majority of the phase I clinical trials (
There were several limitations to this study. First, the meta-analysis was limited to articles published in English, leading to a selection bias in language. Second, the control groups from 2 studies were used twice, which may enhance the effect of the control group. Third, the total number of patients was limited and all patients were diagnosed with advanced-stage cancer; therefore, the prognosis was worse compared to that of patients with early-stage cancer, which may have masked the effects of TRAIL-related agents. Moreover, the 4 included RCTs experimented on different types of cancer and treatment strategies and we had to overlook the differences among them in order to gain preliminary results on this topic. Finally, the treatment cost was not taken into consideration; this, however, is a factor that may affect the patients’ perspective regarding this type of treatment.
In conclusion, this meta-analysis compared the outcome of patients with advanced cancer who were treated with or without TRAIL-related agents. There were no significant differences in all 8 outcome measures, including ORR, CBR/DCR, PFS, OS, number of patients with any AEs, number of patients with any severe AEs, number of patients with ≥grade 3 AEs and fatal AEs. Therefore, the benefits of the addition of TRAIL-related agents to standard chemotherapy regimens for the treatment of cancer patients remain uncertain.
This study was supported by grants from the National Nature Science Foundation of China (grant no. 81071908).
Flow diagram of the selection process for eligible randomized controlled trials (RCTs).
Risk of bias graph.
Summary of the risk of bias of the 4 randomized controlled trials.
Meta-analysis of objective response rate.
Meta-analysis of clinical benefit rate/disease control rate.
Meta-analysis of progression-free survival.
Meta-analysis of overall survival.
Meta-analysis of patients with any adverse events.
Meta-analysis of patients with any severe adverse events.
Meta-analysis of patients with ≥grade 3 adverse events.
Meta-analysis of fatal adverse events.
General characteristics of the included randomized controlled trials.
Studies (refs.) | Sample size (T/C) | Type of tumor | Intervention and comparison | Outcomes |
---|---|---|---|---|
Soria |
128/85 | Advanced NSCLC | Patients with squamous NSCLC and/or CNS metastases received PC every 3 weeks alone (arm 1; n=41) or with dulanermin 8 mg/kg for 5 days (arm 2; n=39). Patients with non-squamous NSCLC received PCB alone (arm 3; n=42) or with dulanermin 8 mg/kg for 5 days ‘(arm 4; n=40) or 20 mg/kg for 2 days (arm 5; n=41) | ORR, PFS, OS, safety, pharmacodynamics biomarker analysis, GaINT 14 expression biomarker analysis |
Demetri |
86/42 | Metastatic or locally advanced unresectable soft tissue sarcomas | This clinical trial consists of three parts: phase I, phase II and rollover. In phase II, patients were randomized (2:1) to receive doxorubicin with either double-blind conatumumab 15 mg/kg (conatumumab-doxorubicin; n=86) or placebo (placebo-doxorubicin; n=42) | PFS as primary efficacy variable; OS, subgroup analysis of PFS according to FCGR3A genotype, patient-reported outcomes, time to response and duration of response as secondary efficacy variables; safety, biomarker analysis, pharmacokinetics |
Kindler |
41/42 | Metastatic pancreatic cancer | Patients with previously untreated metastatic pancreatic adenocarcinoma were randomized 1:1:1 to i.v. gemcitabine 1,000 mg/m2 (days 1, 8 and 15 of each 28-day cycle) combined with open-label ganitumab (12 mg/kg Q2W, n=42), double-blind conatumumab (10 mg/kg Q2W, n=41), or double-blind placebo Q2W (n=42) | Survival and response, safety |
Paz-Ares |
113/59 | Advanced or recurrent NSCLC | Patients (aged >18 years) with previously untreated advanced or recurrent NSCLC were randomized 1:1:1 (stratified by ECOG performance status and disease stage) to receive up to six 3-week cycles of PC combined with conatumumab (arm 1, 3 mg/kg; arm 2, 15 mg/kg) or placebo (arm 3) every 3 weeks Arm 1, n=57; arm 2, n=56; arm 3, n=59 | PFS as primary end-point, ORR, toxicity, pharmacokinetics, subgroup analysis of OS according to FCGR3A 158 polymorphisms |
T/C, trial/control; NSCLC, non-small-cell lung cancer; CNS, central nervous system; ORR, objective response rate; PFS, progression-free survival; OS, overall survival; PC, paclitaxel plus carboplatin; PCB, paclitaxel plus carboplatin and bevacizumab; i.v., intravenous; Q2W, quaque (every) 2 weeks; ECOG, Eastern Cooperative Oncology Group.
Evidence quality and recommendation grade.
Evidence quality assessment | Evidence quality | Importance | Recommendation grade | |||||||
---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||
Outcome | No. of studies | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Publication bias | |||
ORR | 4 | RCT | High |
No | No | No | Undetected | +++, moderate | Critical | Weak |
CBR | 4 | RCT | High |
No | No | No | Undetected | +++, moderate | Critical | Weak |
PFS | 4 | RCT | High |
No | No | No | Undetected | +++, moderate | Critical | Weak |
OS | 4 | RCT | High |
No | No | No | Undetected | +++, moderate | Critical | Weak |
Patients with any AEs | 3 | RCT | High |
No | No | No | Undetected | +++, moderate | Critical | Weak |
Patients with any severe AEs | 3 | RCT | High |
No | No | No | Undetected | +++, moderate | Critical | Weak |
Patients with ≥ grade 3 AEs | 3 | RCT | High |
No | No | No | Undetected | +++, moderate | Critical | Weak |
Fatal AEs | 3 | RCT | High |
No | No | No | Undetected | +++, moderate | Critical | Weak |
An open-label study was included. ORR, objective response rate; RCT, randomized controlled trial; CBR, clinical benefit rate; PFS, progression-free survival; OS, overall survival; AEs, adverse events.
TRAIL-related agents in cancer therapeutics.
Reagents | Target | Description | Company |
---|---|---|---|
rhTRAIL/Apo2L (dulanermin) | DR4/DR5 | rhTRAIL | Amgen |
HGS-ETR1 (mapatumumab) | DR4 | Fully human MAb | Human Genome Sciences |
HGS-ETR2 (lexatumumab) | DR5 | Fully human MAb | Human Genome Sciences |
HGS-TR2J (KMTR-2) | DR5 | Fully human MAb | Human Genome Sciences |
CS-1008 (TRA-8, tigatuzumab) | DR5 | Humanized mouse MAb | Daiichi Sankyo |
AMG 655 (conatumumab) | DR5 | Fully human MAb | Amgen |
PRO95780 (apomab) | DR5 | Fully human IgG1 MAb | Genetech |
LBY135 | DR5 | Humanized MAb | Novartis |
rhTRAIL, recombinant human tumor necrosis factor-related apoptosis-inducing ligand; DR, death receptor; MAb, monoclonal antibody.
Amgen Inc., Thousnad Oaks, CA, USA;
Genetech Inc., South Francisco, CA, USA;
Human Genome Sciences Inc., Rockville, MA, USA;
Daiichi Sankyo Co., Tokyo, Japan;
Novartis, Basel, Switzerland.