Lung cancer is the most frequent cause of tumor death worldwide. Small cell lung cancer (SCLC) is a highly aggressive and deadly malignant tumor, accounting for approximately 10% to 15% of all lung cancers (1–3). SCLC comprises an estimated 250,000 new cases and at least 200,000 deaths worldwide each year (4). Approximately 70% of the patients are diagnosed with extensive-stage SCLC (ES-SCLC) with poor overall survival (OS) (5). It has been reported that the median OS for ES-SCLC patients without systemic therapy is 2 to 4 months (6, 7).

As the gold standard for SCLC therapy, platinum-etoposide chemotherapy has been widely used in the past 40 years. The median progression-free survival (PFS) of platinum-etoposide chemotherapy as the first-line treatment is about 5 months, and the median OS is about 10 months (8). In recent years, the rapid rise of immunotherapy has broken the unshakable position of platinum-etoposide chemotherapy. Atezolizumab, a programmed death-ligand 1 (PD-L1) inhibitor, was studied in IMpower133 clinical trial in combination with platinum-etoposide chemotherapy as the first-line treatment for ES-SCLC. The combined regimen brought survival benefits: the median OS was prolonged for 2 months (12.3 vs. 10.3 months), and the 1-year OS rate was increased by 13.5% (51.7% vs. 38.2%) compared with platinum-etoposide chemotherapy (9). Durvalumab, another PD-L1 inhibitor, was also found to have a similar OS benefit (13.0 vs. 10.3 months) in CASPIAN clinical trial (10). PD-L1 plus platinum-etoposide chemotherapy has become the new first-line therapy for ES-SCLC.

Angiogenesis is a complex process that plays an essential role in tumor growth, invasion and metastasis. Vascular endothelial growth factor (VEGF) is the most critical proangiogenic protein (11). Previous studies found that about 80% of SCLC tissues were positive for VEGF expression, and the VEGF level was an independent prognostic factor in SCLC (12). However, the efficacy of antiangiogenic therapy in SCLC is limited. Bevacizumab, a monoclonal antibody directed against VEGF, showed a promising activity in combination with platinum-etoposide as the first-line treatment of patients with ES-SCLC, and two randomized studies confirmed that bevacizumab improved PFS, but failed to prolong OS (13, 14). Instead, disappointing results have been observed with endostar, sunitinib, sorafenib, vandetanib, and thalidomide in combination with chemotherapy in the first-line setting. Only anlotinib improved PFS and OS as third-line therapy in Chinese patients with SCLC (15). As an oral antiangiogenic tyrosine kinase inhibitor (TKI), anlotinib targets vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptors (PDGFR), fibroblast growth factor receptor (FGFR), and c-kit (16). Based on ALTER 1202 study, anlotinib was approved by the China Food and Drug Administration (CFDA) in 2019 as the third-line and above treatment for SCLC (17). Additionally, some small sample size clinical trials in China have shown the favorable efficacy of anlotinib combined with platinum-etoposide chemotherapy (18–20). The 2021 American society of clinical oncology (ASCO) meeting announced the preliminary result of a phase II clinical study on the efficacy and safety of anlotinib combined with platinum-etoposide chemotherapy in the first-line treatment of ES-SCLC. Twenty patients could evaluate the efficacy, of which the median PFS was 10.0 months, the median OS was 15.0 months, the objective response rate (ORR) was 90%, and the disease control rate (DCR) was 100% (18). It was significantly higher than that of traditional chemotherapy.

In clinical trials, patients are strictly screened. Thus, patients with poor conditions, such as the elderly, combined brain metastases, and the Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2, are often excluded. Therefore, we conducted this multicenter retrospective study to investigate the real-world efficacy and safety of anlotinib combined with platinum-etoposide chemotherapy as the first-line treatment for ES-SCLC.

SCLC has an abnormally high proliferation rate, a strong tendency for early metastasis, and a bleak prognosis (4). As the first-line standard treatment for ES-SCLC in the past 40 years, the PFS of platinum-etoposide chemotherapy is about 5 months, and the median OS is about 10 months (8). Based on the IMpower133 and CASPIAN clinical trials, PD-L1 plus platinum-etoposide chemotherapy has become the new first-line standard therapy in recent years. Although, it only brought the OS benefit for 2 to 3 months (9, 10). Angiogenesis serves a pivotal role in tumor occurrence, invasion, and metastasis (21). However, the efficacy of antiangiogenic therapy in SCLC is limited, such as bevacizumab, sorafenib, sunitinib and so on, except for anlotinib (15, 22–24). In China, anlotinib has been approved by CFDA as the third-line and above treatment for SCLC based on the ALTER 1202 study (17). Several small sample size single arm phase II clinical trials of anlotinib combined with platinum-etoposide chemotherapy as the first-line treatment for ES-SCLC are being carried out in China and the preliminary results have shown the favorable clinical efficacy (18–20).

Antiangiogenic therapy can improve drug delivery efficiency by opening the vascular normalization window, thus exerting a synergistic effect when combined with other regimens (25). In addition, the non-overlapping toxicity spectrum and excellent tolerance of anlotinib allow it to be used in combination with other drugs. In a clinical trial conducted by Kong T et al., 20 ES-SCLC patients received anlotinib plus platinum-etoposide chemotherapy as the first-line therapy, the median PFS was 10.0 months, and the median OS was 15.0 months (18). Similarly, in Deng P’s study, the median PFS and OS were 9.4 and 13.9 months, respectively (20). Supported by these encouraging preliminary results, phase III clinical trials have already begun in China. In this real-world study, the median PFS was 6.0 months, the median OS was 10.5 months, the ORR was 58.6%, and the DCR was 89.6%. Our results are similar to the efficacy of traditional platinum-etoposide chemotherapy. But 20 (34.5%) patients with ECOG PS 2 were included in this study. In contrast, there were no patients with ECOG PS >1 in these clinical trials. The median PFS and OS of patients with ECOG PS 0-1 in this study were 8.5 and 15.0 months, respectively. The 6-month PFS rate was 75.9%, the 6-month OS rate was 100.0%, and the 1-year OS rate was 62.5%. Respectively, the ORR and DCR were 73.7% and 97.4%. Multivariate Cox regression analysis showed that ECOG PS was the independent influencing factor of PFS and OS. This result showed better efficacy compared with traditional chemotherapy and PD-L1 plus chemotherapy, and the OS was similar to the clinical studies of anlotinib plus platinum-etoposide chemotherapy. Since there is no control group in our study, the efficacy of combination therapy still requires further verification by prospective studies with larger sample size.

ES-SCLC patients first receive chemotherapy to control the spread of metastasis. Subsequently, chest radiotherapy is recommended to control local lesions for patients who achieve CR or PR after chemotherapy (26). Some studies found that antiangiogenic therapy can increase the local oxygen partial pressure and oxygen content of tumor tissue, inhibit the angiogenesis induced by radiotherapy, and play the role of radiotherapy sensitization (27). In our study, patients combined with thoracic radiotherapy had more extended PFS (8.3 vs. 4.2 months, P =0.002) and OS (16.8 vs. 7.7 months, P <0.001) benefits in univariate analysis. However, there were no statistical differences in multivariate analysis.

Hypertension and hand-foot syndrome are the most common adverse reactions of anlotinib. Interestingly, more extended PFS benefits were observed in ES-SCLC patients with post-medication hypertension or hand-foot syndrome in Song PF’s study (28). In this research, patients with post-medication hypertension (8.5 vs. 5.4 months, P =0.008) and hand-foot syndrome (8.5 vs. 5.5 months, P =0.040) had longer PFS benefits in univariate analysis. Additionally, we also found that patients with post-medication hypertension (15.9 vs. 8.3 months, P <0.001) had longer OS benefits. Multivariate analysis showed that post-medication hand-foot syndrome (yes vs. no: HR=0.23, 95%CI 0.07-0.72, P =0.012) was the independent predictor of PFS, and post-medication hypertension (yes vs. no: HR=0.18, 95%CI 0.05-0.58, P =0.005) was the independent predictor of OS. Hypertension might be attributed to the mechanism that inhibition of VEGFR in vascular endothelial cells decreased the production of nitricoxide and prostacyclins, thus leading to increased blood pressure (29). Hand-foot syndrome might be induced by decreased reconstruction of skin after restriction of vessels (30). Therefore, hypertension or hand-foot syndrome induced by anlotinib could partly reflect the inherent host biology that caused differences in VEGF/VEGFR blockade (31).

Furthermore, we observed that sex (male vs. female: HR=6.05, 95%CI 1.74-20.98, P =0.005) and T stage (T3-4 vs. T1-2: HR=3.82, 95%CI 1.59-9.18, P =0.003) were the independent influencing factors of PFS. Age (≥65 vs. <65: HR=4.87, 95%CI 1.71-13.82, P =0.003) and hepatic metastases (yes vs. no: HR=3.83, 95%CI 1.41-10.41, P =0.008) were associated with OS in multivariate Cox regression analysis. However, only 11 (19.0%) female patients were included in our study, which might influence the result.

In this research, the toxicity of anlotinib plus platinum-etoposide chemotherapy was generally well tolerated. The grade 3 and above adverse reactions were manageable with dose reduction or drug discontinuation. Similar to previous research, myelosuppression was the most frequent adverse reaction (18–20). As the most common adverse reactions of anlotinib, the incidence of hypertension and hand-foot syndrome were 41.1% and 24.1%, respectively. There were no new anlotinib-related adverse reactions observed in this study, and the toxic profile was similar to other studies of anlotinib in SCLC (17). The incidence of adverse reactions in this research might be lower than actual data in the real world because of the bias of the retrospective study.

This study provided real-world data of anlotinib combined with platinum-etoposide chemotherapy as the first-line treatment for ES-SCLC at the first time. Despite the advantages of this work, there are several inevitable shortcomings in our study. First, as a real-world study, the Chinese undiversified population and small sample size might affect the universality of the results. Thus, well-designed large-scale prospective studies are urgently needed in the future to provide more profound insights into this field. Second, due to the retrospective design of this study, selection bias and information bias could not be avoided. For instance, the majority of patients included in this study are male, which may affect the representation of the study population. Besides, although we identified that post-medication hypertension and foot-hand syndrome may correlated with favorable prognosis after treatment, the sample size of these patients is small and some adverse effects are not well recorded. This further emphasizes the importance of conducting relevant studies in the future. Last but not least, since the dosage was determined by different physicians according to the actual situation of patients, and this may affect the efficacy.

To sum up, our study revealed that anlotinib combined with platinum-etoposide chemotherapy as the first-line treatment for ES-SCLC appears to be effective and well-tolerated in the real-world setting, especially in patients with ECOG PS 0-1. Patients with post-medication hypertension and hand-foot syndrome may confer superior survival benefits. However, well-designed large-scale prospective studies are urgently needed in the future to verify our findings.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

YY contributed to the concept and design of the research; H-RZ established the database; H-RZ, A-MJ, and HG conducted statistical analysis; H-RZ and A-MJ wrote the first draft of the manuscript; HG, NL, X-QZ, XF, Z-PR, TT, XL and YY reviewed and edited the manuscript. All authors participated in the revision of the manuscript, read and approved the submitted version.

This study was funded by International Cooperation Project in Science and Technology of Shaanxi Province (No. 2019KW-074), Nation Natural Science Funding of China (No. 82002437), and Shaanxi Province Technology Innovation Team (No. 2021TD-44).

We would like to thank Xijing Hospital of Air Force Military Medical University, Xianyang Central Hospital, Shaanxi Nuclear Industry 215 Hospital, Hanzhong Central Hospital and Baoji Traditional Chinese Medicine Hospital for providing the clinical data.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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