Endostar acts as a pneumonitis protectant in patients with locally advanced non-small cell lung cancer receiving concurrent chemoradiotherapy

Lung cancer is the most common disease in terms of incidence and the leading cause of cancer death worldwide [1]. Over two-thirds of all cases of lung cancer are non-small cell lung cancer (NSCLC) [2], approximately one-third of which present locally advanced-stage disease at the time of initial diagnosis. Platinum-based chemotherapy plus concurrent radiotherapy is a standard treatment for patients with locally advanced non-small cell lung cancer (LA-NSCLC). A number of studies have shown that radiotherapy with vinorelbine combined with platinum has good efficacy. With these results, concurrent chemoradiotherapy with cisplatin and vinorelbine could be considered one of the new standard regimens for LA-NSCLC, although the employed vinorelbine doses in each phase II study were 12.5 mg/m² and 15 mg/m² [3‐5]. Concurrent chemoradiotherapy (CCRT) followed by immunotherapy consolidation (CIT) can further improve the prognosis for LA-NSCLC patients [6]. However, radiotherapy-associated acute toxicities, especially radiation pneumonitis (RP), restrict the application of CIT after CCRT in patients with stage III unresectable NSCLC [7]. Endostatin is another broad-spectrum angiogenesis inhibitor widely used in antitumor treatment. A phase II trial HELPER study confirmed the synergistic interaction of Endostar and CCRT for patients with unresectable stage III NSCLC, and the incidences of grade 1, grade 2, and grade 3 RP were 10.4%, 7.5%, and 3.0%, respectively [8]. In addition, our previous study found that stage III lung squamous cell cancer (LSCC) patients with serum Lp (a) levels above 218 mg/L who received Endostar combined with concomitant chemoradiotherapy had longer progression-free survival (PFS) and overall survival (OS) [9]. A pooled analysis suggested that endostatin and CCRT combined to treat LA-NSCLC is effective and well-tolerated, and fewer toxicities including any grade and grade≥3 radiation pneumonitis occur [10]. Moreover, recombinant human endostatin (Rh-endostatin, or Endostar) was also identified to enhance radiosensitivity and reduce radiation-related pulmonary events in patients with advanced NSCLC [11]. Endostar was approved to apply in combination with CCRT to treat patients with unresectable stage III NSCLC in 2005 by the Chinese Food and Drug Administration.

The results from murine xenograft lung tumors showed that an anti-angiogenic drug axitinib in combination with radiotherapy could significantly decrease pneumonitis, vascular damage, and fibrosis in lung tissues [12]. Although Endostar in combination with CCRT is effective and well-tolerated, there is a lack of knowledge on whether Endostar can decrease the incidence of RP in patients more than CCRT patients treated without Endostar. Moreover, bilateral lungs receiving 20Gy(V20Gy) were an important dosimetric predictor of pneumonitis for LA-NSCLC patients treated with CCRT followed by CIT [13]. V20Gy in particular was the only factor associated with grade 2 or greater RP in lung cancer patients with NSCLC who were treated with CCRT [14]. Further, on the basis of a preliminary curative effect study [9], this study intended to explore the difference in the occurrence of grade ≥2 RP in LA-NSCLC patients treated with CCRT with or without Endostar, and the difference in LA-NSCLC patients with different V20Gy.

For description, categorical variables are reported as count and percentage. Continuous variables are reported as mean ± standard deviations. The chi-square test and Fisher’s exact test were used for categorical variables. The T test was used for continuous variables. All statistical procedures were performed with SPSS version 23.0 (SPSS Inc., Chicago, IL, USA). P < 0.05 was defined as a statistically significant difference (two-sided).

Radiation-induced lung injury (RILI) is one of the main obstacles to the completion of thoracic radiation therapy, resulting in limited survival benefits in NSCLC patients [21]. The acute injury stage (RP) and the chronic injury stage (radiation pulmonary fibrosis) are the major processes of RILI. Accumulated studies have identified various predictors of RP, such as smoking history, tumor location, age, and dosimetric variables of the lung (V20Gy and MLD) [22‐26]. There was no significant difference in the patients grouped by baseline clinical factors including MLD. Because of V20Gy as an imbalanced risk factor and amifostine as the confounding factor in this study, stratified analysis was performed to determine the change in the incidence of grade ≥ 2 RP in different subgroups. Occurrence of grade ≥ 3 RP is the most common event to estimate radiation-induced intolerable toxicity affecting the prognosis of NSCLC patients [22, 23]. Nowadays, ICIs after CCRT are widely recommended for unresectable LA-NSCLC patients [6]. However, RP accounted for the majority of CCRT toxicities precluding the administration of ICIs and consisting mostly of grade 2 RP consisted [7, 27]. Therefore, the incidence of grade 2 or greater RP was set as the primary endpoint in this study. The dosimetric variable of the lung (V20Gy) was a significant risk factor in predicting the incidence of grade ≥ 2 RP [13, 27, 28]. Thus, we investigated the role of Endostar in LA-NSCLC patients grouped by V20Gy in this study. Our results showed that patients with V20Gy≥25% had a higher incidence of grade ≥ 2 RP.

Amifostine, a classical cytoprotective agent, significantly reduced the incidence of grade ≥2 RP in patients with V20Gy≥25%. Endostar not only reduced the incidence of grade ≥2 RP in patients with V20Gy<25% but also further enhanced amifostine-mediated reduction in the incidence of grade ≥2 RP in patients with V20Gy≥25%. Amifostine is used as a cytoprotective drug to protect normal tissue from radiation exposure, and it is preferentially accumulated in normal tissues through active transport [29]. Activated amifostine is quickly produced by vascular endothelial cell alkaline phosphatase in vivo, which converts inactive amifostine to the active free thiol and inorganic phosphate. Normal tissues preferentially take up the free thiol to eliminate irradiation-induced production of oxygen-free radicals, avoiding the damaging hydroperoxide radical-mediated DNA damage and promoting cell death [30]. Previous clinical investigations showed that amifostine may shield healthy tissues from the unexpected toxicity of radiation therapy and chemoradiotherapy without affecting anti-tumor effectiveness [31, 32]. Lung cancer patients treated with radiotherapy or chemoradiotherapy may benefit from amifostine. According to a meta-analysis [33], amifostine significantly decreased the occurrence of acute pulmonary toxicity by 44% compared to treatment without amifostine. The acute pulmonary toxicity caused by CCRT has been demonstrated to be mitigated by amifostine in many investigations [34‐36]. There were similar results in the present study indicating that amifostine application significantly decreased the incidence of grade ≥2 RP across all subgroup analyses. The extra use of amifostine faces a challenge in economic costs and patient compliance. Amifostine also has side effects such as nausea, vomiting, and hypotension. It is necessary to explore the popular anti-tumor drugs that have an advantage in RP remission.

Endostar, bevacizumab, and anlotinib are the most commonly used anti-angiogenic medications for the anti-tumor treatment of lung cancer patients. Only Endostar has been approved to be applied in combination with radiotherapy or CCRT for LA-NSCLC patients based on its superior safety profile and less harmful side effects. Endostar, a C-terminal fragment naturally derived from type XVIII collagen, performs better simulations of endogenous endostatin in tumor suppression in vivo with fewer side effects than other antiangiogenic drugs. Hypoxia increased macrophage infiltration, transforming growth factor beta (TGF-β) generation, and vascular endothelial growth factor (VEGF) upregulation to form radiation damage [37]. Tanabe et al [38] found that endostatin suppressed peritoneal fibrosis by significantly reducing vascular endothelial growth factor A (VEGF-A), alpha-smooth muscle actin (α-SMA), and the pro-fibrotic factor TGF-β1 in a mouse model. Another investigation revealed that Endostar alleviated radiation-induced pulmonary alveolitis, pulmonary edema, fibrosis, and TGF-β1 release in mice compared to radiation-exposed mice treated without Endostar, suggesting that Endostar can reduce radiation-induced pulmonary lesions [39]. Clinical data also showed that Endostar safely improved the effectiveness of chemoradiotherapy (CRT) in NSCLC [8, 11, 17], and, Endostar might lessen the frequency of acute RILI by suppressing the production of inflammatory markers associated with RILI [39]. In addition, anti-angiogenic medicines can promote the normalization of tumor blood vessels within a specific time window to remodel hypoxia and the immunosuppressive tumor microenvironment [40]. Endostar can regulate metabolism and hypoxia in the tumor microenvironment contributing to synergistically im-proving the anticancer effects of radiotherapy [41]. In this study, patients in the CCRT + Endostar group of the research received treatment every other week, utilizing the effect of antiangiogenic medicines on the "normalization" of tumor blood vessels during the window period of chemoradiotherapy. We found that Endostar effectively reduced the occurrence of grade ≥2 RP in LA-NSCLC patients, which suggested that Endostar may be an effective anti-tumor drug with an advantage in RP remission and can be safely utilized in combination with other anti-tumor treatments.

In addition, Endostar combined with immune checkpoint inhibitors (ICIs) in NSCLC has attracted a great deal of attention in ongoing clinical trials. The completed studies have presented favor results (Table 4) [42‐44]. The research endpoint, including the objective response rate (ORR), disease control rate (DCR), duration of response (DOR), clinical benefit response rate (CBR), PFS, OS, and adverse events (AEs), saw positive results. Above all, Endostar plus CCRT or ICIs is an effective and safe therapeutic strategy for patients with advanced NSCLC.

Moreover, anti-angiogenesis therapy performed synergistic anti-tumor effects in combination with ICIs [45‐47]. Numerous clinical trials have verified that patients with advanced NSCLC can benefit from combining ICIs and anti-angiogenic medicines with an acceptable safety profile [48‐51]. Lv et.al [44] proposed that Endostar combined with nivolumab as a second-line or later treatment demonstrated encouraging effectiveness and good tolerability in patients with advanced NSCLC. However, the IMPOWER 150 study [52] found that patients treated with bevacizumab combined with ICIs suffered severe side effects. These findings suggested that Endostar may be a better option in the combination treatment with ICIs and anti-angiogenesis drugs. Similarly, when anti-angiogenic drugs are combined with ICI and thoracic radiotherapy, Endostar is the best choice because it can reduce the incidence of RP and improve the anticancer effects. These findings need further validation by more multi-center double-blind randomized controlled clinical studies.

This study has some shortcomings, as follows: to begin with, it was a retrospective study with an insufficient sample size, and radiotherapy was performed by 3D-CRT treatment, not intensity-modulated radiation therapy (IMRT). IMRT is a popular radiotherapy technology applied in the clinic to enhance accuracy and reduce toxicity. We have no idea whether the advantages of Endostar will be further developed in combination with IMRT. Moreover, Endostar combined with amifostine showed a further tendency of RP reduction in LA-NSCLC patients with V20Gy≥25%. This result needs prospective randomized clinical trials for confirmation. Addtional research is needed to validate the best dosing, frequency, and duration of Endostar in combination with CCRT for the treatment of inoperable LA-NSCLC.

Endostar and amifostine were shown to decrease the incidence of grade ≥ 2 RP in LA-NSCLC patients treated with CCRT. Endostar can improve the clinical benefits of CCRT while it may reduce the incidence of grade ≥2 RP. When receiving CCRT for LA-NSCLC patients, simultaneous combination of Endostar is recommended to enhance clinical benefit and reduce pulmonary toxicity.