Efficacy and safety of angiogenesis inhibitors in small-cell lung cancer

Objective The purpose of this study was to investigate the efficacy and safety of angiogenesis inhibitors for small-cell lung cancer (SCLC). Methods Totally, 16 controlled trials (1898 cases) involving angiogenesis inhibitors plus chemotherapy (ACT group) versus chemotherapy alone group (CT group) were identified from PubMed, EMBASE, Cochrane Library and Wanfang Data before March 2016. Results Compared with CT group, ACT group obtained a significant benefit on objective response rate (ORR) (RR = 1.34; 95% CI = 1.19-1.51; P < 0.00001) and a trend of prolonging progression-free survival (PFS) (HR = 0.86; 95% CI = 0.73-1.01; P = 0.07) without improving overall survival (OS) (HR = 1.05; 95% CI = 0.94-1.17; P = 0.36). Remarkably, subgroup analysis showed that the antibodies targeting VEGF significantly prolonged PFS (HR = 0.76; 95% CI = 0.64-0.90; P = 0.001). With regard to toxicity, there was no significant difference in severe adverse events (AEs, Grade≥3) between two groups except that gastrointestinal symptom, hypertension, metabolic disorders, neurology and pain were higher in ACT group. Conclusion Compared with chemotherapy alone, antibodies targeting VEGF plus chemotherapy significantly improved ORR and prolonged PFS with an acceptable toxicity profile for patients with SCLC. Therefore, angiogenesis inhibitors, especially antibodies targeting VEGF, combining with chemotherapy may be a potential promising strategy in managing SCLC.


INTRODUCTION
Small-cell lung cancer (SCLC) accounts for approximately 15% of all newly diagnosed cases of lung cancer, which is the leading cause of cancer-related death worldwide [1]. About two-thirds of SCLC patients are initially diagnosed at advanced stage, appearing a poor prognosis [2]. For these patients, being unsuitable for surgery or radiotherapy, chemotherapy (CT) (ie, a platinum agent with etoposide or irinotecan) is the main approach [2][3][4][5]. Despite the initial high response rate of SCLC to chemotherapy, it can only prolong the median survival time to 7-11 months [6]. Moreover, the first-line therapy has remained essentially unchanged for the past two decades. Therefore, it is urgently needed to seek a multimodality therapy to break the bottleneck of SCLC treatment.
Since preclinical studies demonstrated that angiogenesis played a crucial role in tumor growth [7], it is reasonable to make an attempt to combine angiogenesis inhibitors with chemotherapy. Large randomized controlled trials (RCT) on non-small-cell lung cancer showed the superiority of antiangiogenic agents plus chemotherapy over chemotherapy alone in terms of objective response rate (ORR), overall survival (OS) and progression-free survival (PFS) [8][9][10]. As for SCLC, some single-arm trials showed favorable efficacy and safety of angiogenesis inhibitors plus chemotherapy [11-Research Paper www.impactjournals.com/oncotarget 13] while other trials failed to confirm that [14,15]. Thus, the role of angiogenesis inhibitors plus chemotherapy in managing SCLC remains controversial.
Thereby, we performed a meta-analysis to investigate the efficacy and safety of angiogenesis inhibitors plus chemotherapy versus chemotherapy alone.
Data for all characteristics were summarized in Table 2. Gender, ECOG PS (Eastern Cooperative Oncology Group performance status) and stage were available for 14, 6, 12 of the 16 trials, respectively. The number of withdrawn patients was approximately the same in each trial.
The information about the types of agents, dosage, duration and sequence administrated in different trials was summarized in Table 3.

Adverse events
Fourteen included trials [16-23, 25, 26, 28-31] with sufficient data of treatment-related toxicity and severe AEs grading were applied to analyze AEs (Grade≥ 3). Severe hematotoxicity was the most common AEs without a significant difference between ACT and CT group ( Figure  8). On the other hand, the most common non-hematologic AEs were largely mild and tolerable without a significant difference between two arms, with the exception that more patients in ACT group had gastrointestinal symptom (RR = 1.51; 95% CI = 1.15-1.98; P = 0.003), hypertension (RR =  (Figure 9, 10).

DISCUSSION
To our best knowledge, this study is the only metaanalysis to investigate antiangiogenic therapy in SCLC. Antiangiogenic agents consist mainly of antibodies (bevacizumab, ziv-aflibercept) and small molecules agents (rh-endostatin, vandetanib and thalidomide). The antibodies 'deactivate' VEGF via binding to them and blocking their bond to relevant receptors [32], while small molecules agents directly inhibit the kinase activity of VEGFR by competitively binding to receptor tyrosine kinases [33]. This study showed that the addition of angiogenesis inhibitors to chemotherapy possessed a significant benefit in terms of ORR, slightly prolonged the median PFS. Indeed, some small molecules agents analyzed in this study   were mainly multikinase-inhibitors (e.g. vandetanib: EGFR VEGFR RET) or substances (e.g. thalidomide) which affected a lot of cellular processes and antiangiogenesis was only part of anti-cancer mechanisms [34][35][36][37]. Thus the benefits of ORR and PFS could not be clearly attributed to anti-angiogenetic effect. Therefore, we conducted subgroup analysis on angiogenesis inhibitors only targeting VEGF/VEGFR (Bevacizumab, Ziv-aflibercept, rh-Endostatin). The results showed that anti-angiogenetic effect played a critical role in improving ORR and PFS. However, the improvement of ORR and PFS failed to translate into an OS benefit. One possible explanation was that the activation of alternative pro-angiogenic factors swiftly counteracted the effect of angiogenesis inhibitors; another was intrinsic or pre-existing resistance [38]. Considering the fundamental distinction between small molecule angiogenesis inhibitors and antibodies targeting VEGF in many aspects, we further conducted a subgroup analysis of both groups. The results showed that, compared with chemotherapy alone, neither antibodies targeting VEGF nor small molecule angiogenesis inhibitors plus chemotherapy significantly lowered mortality risk. Encouragingly, subgroup analysis exhibited that antibodies targeting VEGF plus chemotherapy significantly prolonged PFS for patients with SCLC. A reasonable explanation was that chemotherapy failed to inhibit angiogenesis in the presence of a reactive resistance, which was mediated by the HIF-1/VEGF pathway in cancer cells, while antibodies   targeting VEGF blocked the reactive resistance, sensitizing cancer cells to chemotherapy [39].
VEGF is also a key mediator of angiogenesis in healthy tissues. VEGF may induce vasodilation by stimulating the release of nitric oxide in endothelial cells [40]. Therefore, inhibition of VEGF may lead to vasoconstriction and result in an increased peripheral vascular resistance [41]. Consequently, the use of angiogenesis inhibitors can lead to vascular disturbances which are the main factor behind the AEs of these drugs [42]. Our study showed that the addition of angiogenesis inhibitors would increase some common adverse events, such as pain, gastrointestinal symptom, hypertension, metabolic disorders and neurology.
Nevertheless, this study confronted following limitations: (i) eligible trials adopted several kinds of antiangiogenic agents; (ii) clinical characteristics such as ECOG performance status as well as stage were not completely equivalent; (iii) trials were mainly conducted in a molecularly unselected population. Thus, it impeded us to conduct a sub-analysis of potential predictive biomarkers to identify the exact benefit population.
Briefly, compared with chemotherapy alone, antibodies targeting VEGF plus chemotherapy significantly improved ORR and prolonged PFS with an acceptable toxicity profile for patients with SCLC. Therefore, angiogenesis inhibitors, especially antibodies  targeting VEGF, combining with chemotherapy may be a potential promising strategy in managing SCLC.

Study Selection
The inclusion criteria were as follows: (i) RCT or clinical controlled trails with voluntarily enrolled patients; (ii) all participants had been histologically or cytologically confirmed; (iii) the trials involving angiogenesis inhibitors plus chemotherapy versus chemotherapy alone; (iv) trials excluded patients with double or multiple primary cancer or presence of unstable systemic disease; (v) trials evaluated at least one of ORR, OS, PFS and severe AEs (Grade≥3); (vi) response rate was determined using the Response Evaluation Criteria in Solid Tumors (RECIST 1.0 or 1.1 standards) [44] or WHO criteria [45]; (vii) adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE 2.0 or 3.0) [46] or WHO criteria [45].

Data extraction and quality assessment
Data were extracted independently by two reviewers (Lin H and Li LN), and any disagreements between the two reviewers were resolved by consensus involving a third reviewer (Xie XH). For each selected publication, we extracted the following items: first author, year of publication, country of original trial, trial phase, line of treatment, number of patients, demographics, clinical parameters, stage at initial diagnosis, interventions and outcomes. To assess study quality and applicability, we used the checklists of The Cochrane Handbook for Systematic Reviews of intervention (Version 5.1.0), based on the following criteria: (i) Random sequence generation; (ii) Allocation concealment; (iii) Blinding of participants and personnel; (iv) Blinding of outcome assessment; (v) Incomplete outcome data; (vi) Selective reporting; (vii) Other bias. Each trial for bias based on the criteria listed above was marked as 'low risk', 'high risk' or 'unclear risk'. Trials quality was defined as following: A rating: meeting all criteria of low risk; B rating: meeting one or more criteria of unclear risk without high risk; C rating: appearing one or more criteria of high risk.

Statistical analysis
Statistical analysis was performed using RevMan 5.3 software (Cochrane Collaboration's Information Management System). Analysis of data comprised pooled risk ratio (RR) for dichotomous endpoints (e.g ORR, severe AEs), using the Mantel-Haenszel method [47]. The events and total number of patients from ACT group and CT group in the trials for ORR and severe AEs were extracted from the trials. OS and PFS were calculated using effect variables and expressed by hazard ratio (HR). HRs with 95% confidence intervals (CI) were directly extracted from trials or from the survival curves using the methods described by Tierney et al. [48] for OS and PFS when HRs were unavailable. The 95% CIs were calculated and presented in forest plots. Two-sided P values less than 0.05 were considered statistically significant. Statistical heterogeneity of different trials was evaluated with the Isquare tests [49]; no heterogeneity existed when I 2 < 50%, a fixed-effect model was applied to pool the study results. Significant heterogeneity was found if I 2 > 50%, and a random-effects statistical model was used [50]. The risk of publication bias was evaluated via visual appraisal of funnel plots.

CONFLICTS OF INTEREST
There is no conflict of interest.