Abstract
Background
Effective maintenance therapy options after first-line chemoradiotherapy for limited-stage small cell lung cancer (LS-SCLC) remain limited. Anlotinib, a multi-target tyrosine kinase inhibitor, was evaluated for its efficacy and safety in this setting.
Methods
In this single-center, prospective, randomized controlled trial, 60 LS-SCLC patients who had completed first-line chemoradiotherapy were enrolled and randomly assigned (1:1) to receive either anlotinib maintenance therapy or best supportive care. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included objective response rate (ORR), safety, and quality of life (QoL).
Results
The anlotinib group demonstrated a significantly prolonged median PFS compared to the control group. Furthermore, patients in the anlotinib group experienced earlier and more significant improvement in QoL, and a strong positive correlation was observed between QoL scores and OS. The safety profile of anlotinib was consistent with its known characteristics, with hypertension and proteinuria being the most common adverse events, which were manageable through dose modifications.
Conclusion
Anlotinib as maintenance therapy significantly improved PFS and QoL in patients with LS-SCLC, with a manageable safety profile. This study provides initial evidence supporting the potential role of anlotinib in this treatment paradigm.
Keywords: Small cell lung cancer, Anlotinib, Maintenance therapy, Progression-free survival, Quality of life, Prospective randomized controlled trial
Introduction
Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy, accounting for approximately 15% of all lung cancers, characterized by rapid proliferation, early widespread metastasis, and initial high sensitivity to chemotherapy and radiotherapy [1]. Although the objective response rate (ORR) of limited-stage SCLC (LS-SCLC) patients receiving standard first-line platinum-based chemotherapy combined with thoracic radiotherapy reaches 60–80% [2], the majority of patients experience disease relapse within 6–12 months post-treatment, with a 5-year overall survival rate below 7% [2–4]. The high relapse rate and poor survival are primarily attributed to tumor heterogeneity, rapid acquisition of drug resistance, and the lack of effective maintenance strategies [5]. Currently, traditional maintenance therapies such as topotecan have failed to become standard due to significant toxicity and limited survival benefits [6], highlighting the urgent need to explore novel, effective, and well-tolerated maintenance strategies in SCLC.
In recent years, the successful application of anti-angiogenic therapy in various solid tumors has provided new directions for SCLC treatment. Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) play a critical role in tumor angiogenesis and microenvironment remodeling in SCLC [7]. Anlotinib, a novel oral multi-target tyrosine kinase inhibitor, potently inhibits VEGFR2/3, FGFR1-4, PDGFRα/β, and c-Kit signaling pathways, exerting anti-tumor effects by blocking angiogenesis, suppressing tumor cell proliferation and invasion, and remodeling the immunosuppressive tumor microenvironment [8]. Preclinical studies have demonstrated that anlotinib significantly inhibits SCLC growth and liver metastasis by inhibiting angiogenesis [9]. Furthermore, the phase III ALTER0303 trial has confirmed significant survival benefits of anlotinib in patients with advanced non-small cell lung cancer beyond the second line, with median progression-free survival (PFS) and overall survival (OS) extended to 5.5 months and 9.6 months, respectively [10], providing a strong rationale for its potential application in SCLC.
However, research on anlotinib as maintenance therapy in SCLC remains in its infancy, and its efficacy and safety have not been fully validated. This prospective randomized controlled trial (RCT) aims to systematically evaluate the clinical efficacy and safety of anlotinib as maintenance therapy following first-line chemoradiotherapy in limited-stage SCLC and to explore potential biomarkers, thereby providing new evidence-based insights for personalized SCLC treatment.
Methods
Study design and patient enrollment
This prospective RCT evaluated the clinical efficacy and safety of anlotinib maintenance therapy in patients withLS-SCLC. Conducted at Jiamusi City Cancer Hospital from January 2021 to December 2021, the study enrolled 60 patients who had completed first-line chemoradiotherapy. Participants were randomized at a 1:1 ratio into two groups: the Anlotinib group (anlotinib maintenance therapy, n = 30) and the control group (supportive care, n = 30).
Inclusion and exclusion
CriteriaInclusion criteria comprised ① patients with histologically or cytologically confirmed limited-stage small cell lung cancer (AJCC 8th edition TNM stage I-III) who had completed standard first-line chemoradiotherapy (EP regimen: etoposide plus platinum) combined with thoracic radiotherapy (45 Gy delivered in 15 fractions) and prophylactic cranial irradiation (PCI, 25 Gy in 10 fractions). ② Within 4 weeks post-treatment, patients were required to have a partial response (PR) as assessed by imaging. (RECIST v1.1 criteria). ③ Additionally, patients had to have an ECOG performance status of 0–2 and adequate organ function, including neutrophil count ≥ 1.5 × 10⁹/L, platelet count ≥ 100 × 10⁹/L, hemoglobin ≥ 90 g/L, ALT/AST ≤ 2.5 times the upper limit of normal (ULN), total bilirubin ≤ 1.5 times ULN, and creatinine clearance ≥ 60 mL/min. ④ Patients were also required to have an expected survival of ≥ 3 months. Exclusion criteria included: ① uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg), ② severe cardiovascular disease (e.g., NYHA class III-IV heart failure or myocardial infarction within the past 6 months), ③ active bleeding or thrombotic disorders, ④ allergy to Anlotinib components, ⑤ prior treatment with immunotherapy, targeted therapy, or other investigational drugs within 4 weeks before enrollment, ⑥ and poor compliance or refusal to sign informed consent.
Baseline data collection
Baseline data included gender, age, Eastern Cooperative Oncology Group (ECOG) performance status, response to first-line treatment [complete response (CR) or PR], smoking history, and laboratory parameters (lactate dehydrogenase [LDH] and neuron-specific enolase [NSE]). Data were collected from medical records and standardized questionnaires, with verification by the research team. ECOG performance status was assessed by the attending physician. Treatment response to first-line therapy was evaluated by two independent radiologists blinded to group allocation, using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Interventions
Patients in the experimental arm received oral anlotinib hydrochloride at a fixed dose of 12 mg once daily, administered within 30 min after breakfast for 14 consecutive days, followed by a 7-day treatment-free interval (21-day cycle). Treatment cycles were repeated until radiographically or clinically confirmed disease progression (per RECIST v1.1 criteria), intolerable ≥ Grade 3 treatment-emergent adverse events (TEAEs, CTCAE v5.0), or patient-initiated withdrawal. A predefined dose modification protocol was implemented: For Grade 1 TEAEs (e.g., asymptomatic hypertension with systolic blood pressure ≤ 150 mmHg and diastolic ≤ 90 mmHg), the original dose was maintained with intensified ambulatory blood pressure monitoring and symptom-directed interventions. In the event of Grade 2 TEAEs (e.g., proteinuria ≥ 2 + or symptomatic hand-foot syndrome), treatment was withheld until toxicity resolved to ≤ Grade 1, followed by dose reduction to 10 mg daily. For ≥ Grade 3 TEAEs (e.g., hypertensive urgency or symptomatic thromboembolic events), Anlotinib was permanently discontinued, and protocol-specified emergency management was initiated. Patients in the control arm received protocol-defined best supportive care (BSC), including standardized pain management (aligned with WHO analgesic ladder), enteral/parenteral nutritional supplementation, 5-HT3 antagonist-based prophylaxis for chemotherapy-induced nausea and vomiting (CINV), and recombinant human erythropoietin for anemia correction, with strict prohibition of systemic antitumor therapies (cytotoxic chemotherapy, molecular-targeted agents, or immune checkpoint inhibitors).
Efficacy and safety assessments
Efficacy was assessed by chest computed tomography (CT) every six weeks, with systemic lesions evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Intracranial lesions were assessed using brain magnetic resonance imaging (MRI) every 12 weeks. Furthermore, safety monitoring was performed every three weeks, with adverse events recorded following Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Key safety metrics included blood pressure changes, urine protein levels, fatigue, dyspnea, diarrhea, and decreased appetite. In this study, the primary endpoints were PFS and OS. Secondary endpoints includedORR and safety assessment.
Quality of life assessment and patient-reported outcomes analysis [11]
Quality of life (QoL) was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), a internationally validated and widely used instrument for assessing cancer-specific QoL. The questionnaire comprises the Global Health Status/QoL (GHS/QoL) scale, five functional scales (physical, role, cognitive, emotional, and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Raw scores for all scales and items were linearly transformed to standardized scores ranging from 0 to 100.
For functional scales and global health status, higher scores indicate better functioning, while for symptom scales and financial difficulties, higher scores represent more severe symptoms or greater financial impact. A change of ≥ 10 points from baseline was considered clinically significant for symptom “deterioration” or “improvement”, while changes within 10 points were defined as “stable”. Time to deterioration was defined as the time from randomization to the first occurrence of either a ≥ 10-point decrease in functional scale scores or a ≥ 10-point increase in symptom scale scores, with death considered as a competing risk event.
The schedule for QoL assessments spanned 12 months. Following the baseline assessment prior to initial drug administration, subsequent evaluations occurred at 12 weeks and then every 12 weeks until either intracranial or systemic disease progression or death. The internal consistency of the scale, as measured by Cronbach’s alpha coefficient, ranged from 0.7 to 0.9. A Global Health Status score below 50 was defined as poor QoL.
The analysis of patient-reported outcomes (PROs) included all participants who submitted at least one follow-up questionnaire via the online platform. Questionnaire compliance was calculated as the proportion of patients who completed the online assessment at each predefined time point. Mean changes in scores from baseline across the five time points were compared between groups using the least squares method. In this analysis, a positive change score denoted an improvement for functional scales but a worsening for symptom scales. Analyses of mean change incorporated only patients with data at both baseline and the specific time point, whereas the time-to-deterioration analysis utilized all submitted questionnaires.
Long-term follow-up and survival analysis
All patients underwent long-term follow-up until December 2024, with a median follow-up duration of 36 months. Follow-up data included disease progression, survival status, occurrence of adverse events and changes in QoL. It is worth noting that this study was designed to evaluate the efficacy of anlotinib as maintenance therapy, with statistical power based on PFS and OS endpoints. As the study design focused on prospective data collection during the maintenance phase, information on subsequent therapies after disease progression was not systematically collected or audited per protocol. Therefore, formal comparisons of time to next treatment (TTNT) or second PFS (PFS2) were not incorporated into the analysis. The interpretation of OS is based primarily on the intent-to-treat analysis from the time of randomization.
Statistical analysis
All statistical analyses were performed using SPSS software (version 22.0; IBM Corp., Armonk, NY, USA). Measurement data were assessed for normality using the Shapiro-Wilk test. Normally distributed variables are expressed as mean ± standard deviation (mean ± SD), and between-group comparisons were conducted using the independent samples t-test. Non-normally distributed variables are expressed as median (interquartile range) [M (IQR)], and between-group comparisons were made using the Mann-Whitney U test. Enumeration data are presented as frequency and percentage (n, %), and between-group comparisons were performed using the χ² test or Fisher’s exact test (when the theoretical frequency was < 5). Survival curves were plotted using the Kaplan-Meier method to calculate median PFS and OS. Between-group differences were compared using the log-rank test, and hazard ratios with their 95% confidence intervals (CI) were calculated. Repeated measures analysis of variance was used to assess between-group and time differences in QoL scores. The Pearson correlation coefficient was employed to analyze the correlation between QoL scores and survival period. All tests were two-sided, and a P-value < 0.05 was considered statistically significant.
Ethics approval and patient consent
The study protocol was approved by the Medical Ethics Committee of Jiamusi Cancer Hospital and conducted in accordance with the Declaration of Helsinki and China’s Ethical Review Measures for Biomedical Research Involving Human Subjects. All participants provided written informed consent prior to enrollment, acknowledging full understanding of the study objectives, potential risks, and benefits, with the right to withdraw at any time without prejudice. Patient data were de-identified and accessed exclusively by the research team under strict confidentiality protocols.
Results
Baseline characteristics and pretreatment clinical parameters in patients with LS-SCLC
This prospective randomized controlled trial evaluated 60 patients with LS-SCLC who had completed first-line chemoradiotherapy, with 30 patients allocated to each group. Following first-line treatment, 8 patients in the control group achieved a CR, compared with 10 in the anlotinib group. Consequently, 22 patients were ultimately included in the control group and 20 in the anlotinib group (Fig. 1). Baseline data indicated no significant differences between the anlotinib and control groups in terms of gender, age, ECOG performance status, response to first-line treatment, smoking history, or laboratory parameters (LDH and NSE) (all P < 0.05) (Table 1). These findings demonstrate well-balanced baseline characteristics and comparability between the two groups.
Fig. 1.
Participant flow diagram. A total of 60 patients were assessed for eligibility, among whom 18 were excluded due to failure to meet the inclusion criteria. Ultimately, 42 patients were randomized to either the Anlotinib group (n = 20) or the control group (n = 22). All randomized patients completed the study protocol and were included in the primary analysis, with no loss to follow-up or discontinuation of intervention
Table 1.
Baseline data of patients
| variable | Control group (n = 30) | Anlotinib group (n = 30) | χ²/t/Z value | P value |
|---|---|---|---|---|
| Sex | 0.373 | 0.542 | ||
| Male | 22 (73.33) | 24 (80.00) | ||
| Female | 8 (26.67) | 6 (20.00) | ||
| Age | 65.56 ± 7.27 | 63.72 ± 10.31 | 0.799 | 0.428 |
| ECOG rating | 0.144 | 0.704 | ||
| 0–1 | 27 (90.00) | 25 (83.33) | ||
| 2 | 3(10.00) | 5 (16.67) | ||
| First-line treatment effect | 0.317 | 0.573 | ||
| CR | 8 (26.67) | 10 (33.33) | ||
| PR | 22 (73.33) | 20 (66.67) | ||
| Smoking history | 0.185 | 0.667 | ||
| Yes | 28 (93.33) | 26 (86.67) | ||
| No | 2 (6.67) | 4 (13.33) | ||
| LDH (U/L) | 248.55 ± 24.73 | 235.27 ± 42.34 | 1.483 | 0.143 |
| NSE (ng/mL) | 18.67 ± 2.12 | 17.83 ± 2.84 | 1.298 | 0.199 |
Anlotinib maintenance therapy can significantly prolong the survival of patients with LS-SCLC and enhance the ORR
Evaluation of the efficacy and safety of anlotinib maintenance therapy in patients with LS-SCLC demonstrated that the anlotinib group had significantly superior PFS compared to the control group (11.60 months vs. 6.60 months, P = 0.019) and significantly longer OS (23.10 months vs. 16.10 months, P = 0.011) (Fig. 2).
Fig. 2.
Impact of Anlotinib Maintenance Therapy on Progression-Free Survival (PFS) and Overall Survival (OS) in Patients with LS-SCLC. (A) The median PFS was 11.60 months in the anlotinib group versus 6.60 months in the control group (Log-rank P = 0.019; HR = 2.468). (B) The median OS was 23.10 months in the anlotinib group compared to 16.10 months in the control group (Log-rank P = 0.011; HR = 2.595)
Furthermore, the antitumor activity during the maintenance phase was assessed by analyzing the objective response rate (ORR) among patients with residual measurable disease (i.e., those in partial response, PR) after chemoradiotherapy. As shown in Table 2, the ORR was 50.00% (10/20) in the anlotinib group, comprising 4 cases of CR and 6 cases of PR. In the control group, the ORR was 22.73% (5/22), with 1 case of CR and 4 cases of PR. It is important to note that the responses observed in the control group are likely attributable to delayed effects from the prior chemoradiotherapy and prophylactic cranial irradiation rather than the supportive care intervention itself. Although the ORR in the anlotinib group was more than twice that of the control group numerically, the difference did not reach statistical significance (χ² = 3.982, P = 0.140).
Table 2.
Comparison of ORR between the two groups [n (%)]
| Evaluation index | Control group (n = 22) | Anlotinib group (n = 20) | χ²value | p-value |
|---|---|---|---|---|
| CR | 1 (4.55) | 4 (20.00) | ||
| PR | 4 (18.18) | 6 (30.00) | ||
| ORR (%) | 5 (22.73) | 10 (50.00) | 3.982 | 0.140 |
In conclusion, these results indicate that anlotinib maintenance therapy can significantly prolong disease control duration and improve tumor response rates beyond the effect of initial chemoradiotherapy.
Anlotinib maintenance therapy was manageable in patients with LS-SCLC
This study systematically evaluated the safety safety profile of anlotinib maintenance therapy was systematically evaluated. As summarized in Table 3, the incidence of adverse events was generally higher in the anlotinib group compared to the control group. The most common treatment-related adverse events were hypertension and proteinuria. The incidence of all-grade hypertension was 85.00% (17/20) in the anlotinib group, with Grade 3–4 events occurring in 20.00% (4/20) of patients. The incidence of all-grade proteinuria was 70.00% (14/20), with Grade 3–4 events in 20.00% (4/20) of patients in the anlotinib group. The incidence of other Grade 1–2 adverse events, such as fatigue, dyspnea, diarrhea, and decreased appetite, was also higher in the anlotinib group. However, none of these differences were statistically significant (all P > 0.05). Overall, the safety profile of anlotinib was consistent with its known effects, and most adverse events were manageable with proactive interventions.
Table 3.
Comparison of treatment-emergent adverse event incidence between the two groups [n (%)]
| Adverse events | Control group (n = 22) | Anlotinib group (n = 20) | χ²value | P-value |
|---|---|---|---|---|
|
Hypertension (All grades) |
14 (63.63) | 17 (85.00) | 2.493 | 0.288 |
| Grade 1–2 | 11 (50.00) | 13 (65.00) | ||
| Grade 3–4 | 3 (13.64) | 4 (20.00) | ||
|
Proteinuria (All grades) |
8 (36.36) | 4.782 | 0.092 | |
| Grade 1–2 | 6 (27.27) | 10 (50.00) | ||
| Grade 3–4 | 2 (9.09) | 4 (20.00) | ||
|
Fatigue (Grade 1–2) |
5 (22.72) | 6 (30.00) | 0.287 | 0.592 |
|
Dyspnea (Grade 1–2) |
2 (9.09) | 4 (20.00) | 0.322 | 0.570 |
|
Diarrhea (Grade 1–2) |
3 (13.64) | 5 (25.00) | 0.295 | 0.587 |
|
Decreased appetite (Grade 1–2) |
2 (9.09) | 4 (20.00) | 0.322 | 0.570 |
Anlotinib maintenance therapy significantly improves QoL and shows strong correlation with survival prolongation in LS-SCLC patients
To evaluate the long-term impact of anlotinib maintenance therapy on QoL and its relationship with survival outcomes, a systematic analysis was conducted. The baseline QoL scores were comparable between the two groups (P = 0.306). After treatment initiation, the anlotinib group demonstrated rapid and sustained QoL improvement, showing a significant increase from baseline by week 12 (P < 0.001), which was also significantly higher than the control group (66.75 ± 8.76 vs. 60.25 ± 9.17, P = 0.024). In contrast, a significant improvement from baseline in the control group was not observed until the 24-week follow-up (P < 0.001). At the 24-week, 36-week, and 48-week follow-ups, the anlotinib group maintained significantly higher QoL scores compared to both their own baseline (all P < 0.001) and the control group at the corresponding time points (73.47 ± 7.82 vs. 66.76 ± 8.99, P = 0.002; 80.48 ± 8.47 vs. 72.65 ± 9.32, P = 0.007; 84.21 ± 7.94 vs. 76.13 ± 6.49, P = 0.001). Repeated-measures ANOVA revealed that the main effects of Group (F = 67.39, P < 0.001) and Time (F = 24.35, P < 0.001), as well as the Group × Time interaction (F = 3.293, P = 0.012), were all statistically significant. Further correlation analysis demonstrated a significant positive association between QoL scores and overall survival (R2 = 0.95, P = 0.008; Fig. 3). In conclusion, these findings indicate that anlotinib not only provides earlier and more significant improvement in patients’ QoL, but also that this improvement is strongly correlated with prolonged survival (Table 4).
Fig. 3.
Correlation between QoL Score and Overall Survival. A significant positive correlation was observed between the QoL score and overall survival time
Table 4.
Assessment of QoL in LS-SCLC patients
| Time Point | Control Group (n = 22) | Anlotinib group (n = 20) | t-value | P-value |
|---|---|---|---|---|
| Baseline | 54.88 ± 8.23 | 52.34 ± 7.59 | 1.036 | 0.306 |
| 12 Week Follow-up | 60.25 ± 9.17ns | 66.75 ± 8.76### | 2.343 | 0.024* |
| 24-Week Follow-up | 66.76 ± 8.99### | 75.47 ± 7.82### | 3.335 | 0.002** |
| 36-Week Follow-up | 72.65 ± 9.32### | 80.48 ± 8.47### | 2.839 | 0.007** |
| 48-Week Follow-up | 76.13 ± 6.49### | 84.21 ± 7.94### | 3.524 | 0.001** |
| (F Group, P Group) | (67.39, <0.001) | |||
| (F Time, P Time) | (24.35, <0.001) | |||
| (F Interaction, P Interaction) | ( 3.293, 0.012) | |||
ns (Not significant) vs. baseline
###P < 0.001 vs. baseline. *P < 0.05, **P < 0.01 vs. control group
Discussion
As the first prospective randomized controlled trial to evaluate the role of anlotinib as maintenance therapy following first-line chemoradiotherapy in LS-SCLC, this study demonstrates significant clinical benefits. Compared to supportive care alone, anlotinib not only significantly prolonged PFS but also provided earlier and sustained improvement in QoL, with a strong positive correlation observed between QoL scores and OS. These comprehensive findings suggest that the value of anlotinib extends beyond mere disease control, potentially improving overall clinical outcomes through multi-dimensional mechanisms.
The marked efficacy observed with anlotinib is likely rooted in its unique multi-target inhibitory profile [8, 12, 13]. By potently inhibiting VEGFR2/3, FGFR1-4, and PDGFRα/β, it not only suppresses tumor angiogenesis but also directly interferes with the VEGF signaling axis, thereby curbing tumor cell proliferation and invasion [8, 12, 13]. Of particular interest is the potential synergistic effect between radiotherapy and anlotinib in modulating the tumor microenvironment. Preclinical evidence suggests that radiotherapy can induce vascular normalization, and anlotinib, by inhibiting the VEGFR pathway, may help sustain this normalized state and reduce vascular leakage, potentially creating a virtuous cycle of “normalized vasculature-improved drug delivery” that enhances antitumor efficacy [14]. Furthermore, the higher 3-year survival rate in the anlotinib group hints that its long-term benefits may involve immunomodulatory mechanisms. Recent studies indicate that anlotinib can reverse the immunosuppressive phenotype of M2 macrophages via FGFR1 blockade and inhibit cancer-associated fibroblast-mediated PD-L1 upregulation, providing a rationale for its potential role in remodeling the immunosuppressive SCLC microenvironment [15].
Placing our findings within the broader context of SCLC research adds further significance. Our results resonate with the survival benefit of anlotinib in later-line treatment of advanced non-small cell lung cancer (NSCLC) as seen in the ALTER0303 trial [10, 16], yet the PFS advantage appears more pronounced in the LS-SCLC maintenance setting [10, 16]. This discrepancy might stem from the distinct biology of SCLC: compared to NSCLC, SCLC often exhibits higher VEGF expression and a more active angiogenic phenotype [17–19], potentially rendering multi-targeted antiangiogenic agents like anlotinib more therapeutically potent. This hypothesis finds indirect support from the failure of the phase III trial evaluating bevacizumab (an anti-VEGF monoclonal antibody) as maintenance therapy in SCLC (CALGB 30504) to significantly improve OS [20], suggesting that single-target inhibition may be insufficient to overcome the molecular heterogeneity and resistance mechanisms in SCLC. Consequently, the multi-pathway synergistic inhibition by anlotinib might lead to more durable disease control by delaying the emergence of resistance.
Complementing the efficacy data, the manageable safety profile of anlotinib observed in this study is crucial for its clinical applicability. Although adverse events such as hypertension and proteinuria were common, and grade ≥ 3 hypertension occurred in 20.00% of patients, these were effectively managed through protocol-defined dose modifications and supportive care. The toxicity profile observed in this study was predominantly characterized by vascular-related events such as hypertension and proteinuria, without the severe myelosuppression commonly associated with traditional cytotoxic chemotherapies, supporting its feasibility for long-term maintenance therapy.
The interpretation of any clinical study must be situated within an evolving treatment landscape. During and after the conduct of our study, results from the phase III ADRIATIC trial established durvalumab consolidation as the new standard of care for patients with LS-SCLC who have not progressed after concurrent chemoradiotherapy [21, 22]. This landmark advancement necessarily reshapes the treatment paradigm for LS-SCLC. In this new context, the positioning of anlotinib requires careful re-evaluation: firstly, it represents an important alternative maintenance option for patients with contraindications to immune checkpoint inhibitors (e.g., active autoimmune diseases); secondly, given the intimate crosstalk between angiogenesis and immunosuppression, strong rationale exists for combining antiangiogenic agents with immunotherapy, making the exploration of anlotinib plus durvalumab a promising future direction; additionally, in regions with limited access to immunotherapy, anlotinib could serve as a more readily implementable maintenance strategy. Thus, while immuno-consolidation is now the standard, anlotinib retains a potential niche within the personalized, multi-modal treatment landscape for LS-SCLC.
Certainly, the findings of this study should be interpreted in light of several limitations, which also provide direction for future research. The primary limitations include the single-center design and relatively small sample size, which may limit the generalizability of our findings and reduce the power to detect rare adverse events. To address these constraints, subsequent confirmatory studies should employ a multicenter, phase III design with a larger cohort to enhance statistical power and external validity. Secondly, the median follow-up duration of 36 months, while substantial, may still be insufficient to fully evaluate certain delayed toxicities (e.g., drug-related cardiac fibrosis). Hence, extending the follow-up period in future studies is necessary to comprehensively assess the long-term safety profile of anlotinib. A third significant limitation is the lack of systematic biomarker analysis (e.g., baseline VEGF levels, dynamic ctDNA monitoring), which precludes the identification of patient subgroups most likely to benefit—a considerable shortcoming in the era of precision medicine. To bridge this gap, future investigations should integrate multi-omics approaches to discover and validate biomarkers predictive of response to anlotinib, thereby enabling personalized treatment selection. Finally, the stringent enrollment criteria, requiring a response (CR/PR) and mandatory PCI, bolster internal validity but potentially limit the applicability of our results to a broader real-world population (e.g., patients with stable disease after chemoradiotherapy or those forgoing PCI). To gauge generalizability, future real-world studies involving more heterogeneous patient cohorts are warranted to validate the efficacy of anlotinib in these subgroups.
Conclusion
This study demonstrates that anlotinib, as maintenance therapy following first-line chemoradiotherapy in patients with responsive limited-stage SCLC, significantly prolongs progression-free survival, improves quality of life, and has a manageable safety profile. Its multi-targeted inhibitory mechanism provides a novel approach to addressing the therapeutic challenges in SCLC. Although immuno-consolidation has become the new standard, anlotinib retains significant potential value for specific populations (e.g., those intolerant to immunotherapy), in combination strategies, and in resource-limited settings. Further validation through large-scale phase III trials and biomarker-driven research is essential to confirm its long-term benefit and identify predictive biomarkers, thereby refining the personalized maintenance therapy paradigm for SCLC.
Acknowledgements
This work was supported by the Heilongjiang Provincial Department of Health Research Project 2020-374. We are grateful to all the patients who participated in this study and their families. We also thank all the medical staff who contributed to patient recruitment and data collection.
National Universal Health Protection Information Platform (Medical Research Registrationand Filing Information System https://www.medicalresearch.org.cn, Number:MR-23-21-005629).
Author contributions
The study was designed and supervised by Xiaohong Zhou. Sha Li, Zhonghua Chen, and Jie Lv contributed equally to this work, participating in patient recruitment, data collection, and preliminary data analysis. All authors were involved in drafting and revising the manuscript. The final version of the manuscript has been approved by all authors.
Funding
Scientific Research Project of Heilongjiang Provincial Health Commission (No. 2020 − 374).
Data availability
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study protocol was approved by the Medical Ethics Committee of Jiamusi Cancer Hospital and conducted in accordance with the Declaration of Helsinki and China’s Ethical Review Measures for Biomedical Research Involving Human Subjects. All participants provided written informed consent prior to enrollment, acknowledging full understanding of the study objectives, potential risks, and benefits, with the right to withdraw at any time without prejudice.
Consent for publication
Patients signed informed consent regarding publishing their data.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Sha Li, Zhonghua Chen and Jie Lv contributed equally to this work and share first authorship.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.