Systematic review and meta-analysis of Endostar (rh-endostatin) combined with chemotherapy versus chemotherapy alone for treating advanced non-small cell lung cancer

Lung cancer is one of the most common malignancies in the world. More than one million new cases are reported globally every year, and the five-year survival rate is less than 15%[1]. Non-small cell lung cancer (NSCLC) comprises 80% to 85% of lung cancer cases. Generally, 25% to 30% of NSCLC patients are in locally advanced stage upon diagnosis, and 40% to 50% of patients have distant metastases, losing their opportunities for surgery[2]. The current first-line chemotherapy options for patients with advanced NSCLC, such as the combination of platinum-based agents with paclitaxel, gemcitabine, vinorelbine, or docetaxel, have substantial toxicity and seem to have reached a plateau in terms of efficacy[3, 4]. The use of cytotoxic chemotherapy is associated with a response rate (RR) of 20% to 35% and a median survival time of 10 to 12 months among patients with advanced NSCLC[5]. Novel regimens are needed to improve outcome, and the development of more effective therapies remains challenging.

In recent years, the clinical application of antiangiogenic therapy has brought promise for the treatment of NSCLC and has become an important addition in the treatment of tumor invasion and metastasis. In 1997, Folkman et al. first identified endostatin, the 20 kD internal fragment of the carboxyterminus of collagen XVIII, in the conditioned media of hemangioendothelioma cells as an antiangiogenic molecule[6]. The direct target of endostatin is the new capillary endothelial cells around the tumor. Endostar (YH-16), a novel recombinant human endostatin expressed and purified in Escherichia coli, was approved by China’s State Food and Drug Administration (SFDA) for the treatment of NSCLC in 2005. Compared with rh-endostatin reported in previous literature, an additional nine-amino acid sequence (MGGSHHHHH) was added at the N-terminal of the protein, which resulted in the formation of a six-histidine tag that could be chelated with metal ions such as Ni²⁺ with a relatively high affinity. These changes simplified the purification and improved the stability of the protein[7, 8]. However, the effect of the structural changes on the antiangiogenic efficacy, including the mechanism of action, remains unknown.

To date, several studies discuss the efficacy and safety of Endostar in treating advanced lung cancer. Authentic assessment of Endostar treatment in lung cancer is important and urgent. The current study presents a systematic review to quantify the toxicities and clinical benefits of Endostar combined with platinum-based doublet chemotherapy (PBDC) versus chemotherapy alone for treating advanced NSCLC.

The angiogenesis inhibitors for the treatment of cancer as a new approach are based on Folkman’s theory in 1971[26]. Since then, hundreds of angiogenesis inhibitors were discovered and used in drug development. Endostatin specifically acts on neovascular endothelial cells, inhibits cell migration, and induces cell apoptosis, thus playing a major antiangiogenic role by acting on tumor-associated neovascular endothelial cells[27]. Endostar, a novel recombinant human endostatin expressed and purified in E. coli with an additional nine-amino acid sequence and forming another histidine-tag structure, was approved by the SFDA in 2005 for the treatment of NSCLC[8]. In 2005, SFDA licensed Endostar plus NP to treat advanced NSCLC as a first-line therapy. The decision was mainly based on a phase III study[11], which was a randomized, double-blind, multicenter trial comparing treatment with NP plus endostar and NP alone, first-line, in advanced NSCLC patients.

In recent years, several studies have reported on the efficacy and safety of Endostar in the treatment of advanced lung cancer. This systematic review was performed to quantify better the benefits and toxicities of Endostar combined with PBDC versus PBDC alone for treating advanced NSCLC. In this review, 15 reports of randomized trials were identified by searching from the start of each database up to July 2012. A significant benefit of Endostar plus PBDC in ORR was found (OR = 1.69, 95% CI 1.39 to 2.05), translating into a 14.7% (40.3% to 25.6%) absolute improvement. A meta-analysis of DCR was also conducted (OR = 1.22, 95% CI 1.06 to 1.41). A 13.5% improvement (from 64.7% to 78.2%) of Endostar plus PBDC was found compared with PBDC alone. NP plus Endostar versus NP, GP plus Endostar versus GP, NP plus Endostar plus radiotherapy versus NP plus radiotherapy, and TP/TC plus Endostar versus TP/TC showed improvements of 16.5%, 14.7%, 16.7%, and 19.5% in ORR, respectively, and 10.6%, 16%, 9.5%, and 18.2% in DCR, respectively. From the five reports in the present study, the one-year survival rates in the groups of Endostar plus PBDC and the PBDC alone were 55.4% and 45.3%, respectively, reflecting a 10.1% improvement. Five reports analyzed that the TTP of Endostar combined with PBDC (6.19 ± 0.80 months) for treating NSCLC was significantly longer than that of PBDC alone (3.83 ± 0.73 months). However, only five trials providing relative data were included, which were insufficient to reach a decisive conclusion. Therefore, more research is required to gain a clear understanding of the probability. In the E4599 and AVAIL studies, the antiangiogenesis agent bevacizumab plus chemotherapy not only increased ORR, but also improved PFS[28, 29]. The combination of rh-endostatin with vinorelbine plus cisplatin or paclitaxel plus carboplatin chemotherapy enhanced the antitumor effect in two large multicenter phase III trials in advanced NSCLC patients[30, 31]. The results of present study are consistent with those of reported studies.

The benefit of chemotherapy in incurable cancers needs to be assessed directly through validated health-related QOL instruments, rather than inferred from RRs, survival benefits, and other traditional endpoints[32]. In the present study, 742 eligible patients were enrolled in the assessment of QOL. A significant benefit of Endostar plus PBDC in the overall improvement rate of QOL (OR = 3.93, 95% CI 2.78 to 5.56) was found, translating into a 29.5% (52.3% to 22.8%) absolute improvement. This prospective QOL analysis supports the clinical benefit of the addition of bevacizumab to 5-fluorouracil-based chemotherapy in improving time to disease progression and prolonging overall survival, without compromising the patients’ QOL[32]. In clinical settings, phase I and phase II studies revealed that Endostar was effective as a single agent with good tolerance in pretreated advanced NSCLC patients at a dose of 7.5 mg/m² daily. Special attention should be given to toxic effects typically observed in antiangiogenesis treatment. The AEs found in the present review were mainly hematological reactions, diarrhea, hepatic toxicity, and nausea/vomiting, most of which were grade 1 or 2 and were well tolerated. The results supported that the Endostar combination arms had a similar incidence of AEs compared with PBDC alone. Although no significant differences were found between the two groups, incidences of hematological reactions and nausea/vomiting were slightly higher in the control group (PBDC alone). Whether Endostar combination could relieve the AEs of treatment should be followed up in future studies. Overall, these results indicate that the potential benefit of Endostar may be widely applicable to a patient population closely resembling clinical reality in advanced NSCLC.

Addressing statistical heterogeneity is one of the most important aspects of systematic reviews. The interpretative problems are dependent on heterogeneity because it might affect the conclusions of the meta-analysis. Therefore, heterogeneity among the collection of studies must be quantified. In this review, the included studies were carefully assessed. A good clinical homogeneity was confirmed, and publication bias was not found according to the funnel plot analysis, the Egger’s test, and the Begg’s test. However, some deficiencies in the present meta-analysis were found. First, the quality of subgroup analysis (age, sex, smoking, histology, and treatment status) according to the different agents (Endostar plus PBDC compared with PBDC) was low because the subgroup data were only provided by a few trials. Only two trials fulfilling the subgroup analysis were included, which were insufficient to reach a decisive conclusion. Second, some reports failed to report the method for concealment of allocation, blinding, and ITT. In addition, the partial reports comprise a small sample size, and some of the reports’ experimental control is not very balanced. Most of the included studies were published in Chinese, with heterogeneous data and analysis methods (for example, the different scored scales were used to assess the life quality). In addition, the number of cases available was relatively small. Hence, the validity of the results was compromised. Although such studies were reported to be of low quality, they still contain credible evidence pointing toward such new drugs. Clinical trials are expensive and difficult. Hence, these findings can help choose the most promising agents for study. However, Endostar, as a new strategy, still has many issues to be resolved in further studies. Confirmation of these conclusions in rigorously controlled randomized trials is required before firm conclusions about this therapy can be drawn.

The results showed that Endostar combined with PBDC was associated with higher ORR, DCR, and TTP as well as superior QOL profiles as compared with PBDC alone. Moreover, Endostar combined with PBDC was shown to slightly decrease AEs. Endostar combined with PBDC exhibited superior efficacy and safety in antiangiogenesis treatment compared with PBDC alone. However, Endostar, as a new strategy, still has many issues to be resolved in further studies. The notable efficacy and activity of Endostar in combination with PBDC suggest that this regimen may have a value in the treatment of previously untreated patients, including those who cannot tolerate more aggressive therapies. However, confirmation of these conclusions in rigorously controlled randomized trials is required before firm conclusions about this therapy can be drawn.