Efficacy and safety of bevacizumab and platinum‑based chemotherapy as neoadjuvant regimen for stage‑IIIA non‑squamous non‑small cell lung cancer: A retrospective study
- Authors:
- Published online on: June 13, 2024 https://doi.org/10.3892/ol.2024.14508
- Article Number: 375
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Copyright: © Jiang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Lung cancer is a prevalent malignant tumor, with annual prevalence and age-standardized mortality rate of 87.65 and 30.2 per 100,000 individuals (1,2). Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, of which ~70% of cases are non-squamous (3,4). Notably, non-squamous NSCLC in clinical tumor-node-metastasis (cTNM) IIIA stage is a highly heterogeneous disease, and ~30–50% of patients are inoperable (5,6). At present, neoadjuvant chemotherapy is considered to increase the likelihood of surgery in inoperable patients or reduce the risk of disease recurrence, which contributes to certain survival benefits to patients with non-squamous NSCLC in cTNM IIIA stage (4,6,7). Unfortunately, current optional neoadjuvant chemotherapy regimens are relatively limited with unsatisfactory efficacy for patients with non-squamous NSCLC in cTNM IIIA stage, especially in those with negative driver genes (8). Therefore, searching for alternative neoadjuvant chemotherapy regimens is crucial to manage patients with non-squamous NSCLC in cTNM IIIA stage with negative driver genes.
Bevacizumab, as an inhibitor of vascular endothelial growth factor (VEGF), restrains growth of tumors by inhibiting angiogenesis, which is considered to contribute to the treatment of NSCLC (9,10). Notably, adjuvant bevacizumab plus platinum-based chemotherapy has provided certain clinical benefits in patients with NSCLC (11,12). For example, one study reported that adjuvant bevacizumab plus platinum-based chemotherapy reduced the recurrences of NSCLC in the brain (11). In addition, another study reported that adjuvant bevacizumab plus platinum-based chemotherapy improved overall survival (OS) to a certain extent in patients with NSCLC (12). However, the relevant research on the application of neoadjuvant bevacizumab plus platinum-based chemotherapy in patients with NSCLC is insufficient. Several studies preliminarily assessed the efficacy of neoadjuvant bevacizumab in patients with NSCLC, which reported that bevacizumab-based regimen as neoadjuvant is feasible and safe in patients with stage III lung cancer (13,14). Furthermore, another study performed with a Chinese cohort reported that bevacizumab combined with platinum-containing neoadjuvant therapy had acceptable efficacy and safety profiles in patients with stage III lung cancer (15). However, more studies are needed to form solid conclusions on supporting the clinical usage of bevacizumab-based neoadjuvant therapy in patients with stage III lung cancer.
Therefore, the present study aimed to compare the efficacy and safety between neoadjuvant bevacizumab plus platinum-based chemotherapy and platinum-based chemotherapy alone in patients with non-squamous NSCLC in cTNM IIIA stage with negative driver genes.
Materials and methods
Subjects
The present retrospective study included 110 patients with non-squamous NSCLC who underwent neoadjuvant therapy (bevacizumab plus platinum-based chemotherapy or platinum-based chemotherapy alone) and sequential surgical resection from January 2019 to October 2022 at Dazhou Central Hospital (Dazhou, China). The inclusion criteria were as follows: i) Non-squamous NSCLC diagnosis as per the guideline from National Comprehensive Cancer Network (16); ii) presence of negative driver genes involving epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1) fusion and v-raf murine sarcoma viral oncogene homolog B1 with amino acid substitution for valine at position 600 (BRAF V600E) mutation; iii) cTNM IIIA stage; iv) bevacizumab plus platinum-based chemotherapy or platinum-based chemotherapy alone as neoadjuvant therapy received; and v) surgical resection after neoadjuvant therapy performed. The exclusion criteria were as follows: i) other malignant diseases, such as other solid tumors or hematological malignancies; ii) no available follow-up data; and iii) current pregnancy or lactation. The Ethics Committee of Dazhou Central Hospital (Dazhou, China) approved the present study (approval no. 2023100). Each subject or their guardian provided written informed consent.
Study flow
Initially, 246 patients with stage IIIA NSCLC who underwent surgical resection were screened. A total of 72 patients who had positive driver genes, 34 patients who did not receive neoadjuvant therapy, 14 patients with incomplete follow-up data, 7 patients (or their family) who could not be contacted, and 9 patients (or their family) who did not agree to participate in the study or did not provide informed consent were excluded. Subsequently, a total of 110 patients were considered eligible for analysis.
Treatment
Patients received bevacizumab plus platinum-based chemotherapy or platinum-based chemotherapy alone as neoadjuvant therapy. In the present study, the administrated regimen of platinum-based chemotherapy included: Paclitaxel-platinum (TP), liposome-encapsulated paclitaxel-platinum (LP) and pemetrexed-platinum (AP). The cycle of neoadjuvant therapy was 2–3 cycles (21-day cycle). The suggested doses were as follows: i) 7.5 mg/kg bevacizumab on the first day per cycle; ii) TP, 135–175 mg/m2 paclitaxel + 75 mg/m2 cisplatin or carboplatin dosed to an area under the curve (AUC) of 5.0–6.0 on the first day of each cycle; iii) LP, 135–175 mg/m2 liposome-encapsulated paclitaxel + 75 mg/m2 cisplatin or carboplatin dosed to an AUC of 5.0–6.0 on the first day of each cycle; iv) AP, 500 mg/m2 pemetrexed + 75 mg/m2 cisplatin or carboplatin dosed to an AUC of 5.0–6.0 on the first day of each cycle. Surgery was performed within 3–4 weeks after neoadjuvant therapy.
Data collection
Demographics, disease-related data and neoadjuvant therapy-linked data were collected. Simultaneously, imaging examination results of patients were collected every 2 months for the first 6 months and every 3 months thereafter. The best overall response was taken to be the best radiological response recorded during the duration of the whole treatment, which was appraised via the Response Evaluation Criteria In Solid Tumors guidelines version 1.1 (17). Subsequently, the overall response rate (ORR) was calculated. Additionally, pathological response was assessed, including major pathologic response (MPR) and pathological complete response (pCR) status. MPR was defined as ≤10% of residual viable tumor present in the resection specimen, and pCR was defined as the lack of any viable tumor cells in the resected lung cancer specimen (including all sampled regional lymph nodes) (18,19). Moreover, follow-up data (including disease status and corresponding time periods) was collected, then disease-free survival (DFS) and OS were assessed in line with it. The definition of DFS was the time from surgery to relapse or death, whilst OS was defined as the period from neoadjuvant therapy initiation to death. Furthermore, adverse events were counted for safety analysis, which was graded by the Common Terminology Criteria for Adverse Events version 5.0 (https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).
Statistical analysis
Unpaired Student's t-test, χ2 test or Mann-Whitney U test were used to perform comparison analysis according to the appropriate conditions. Kaplan-Meier curves were used to assess the DFS or OS, and the log-rank test was used to compared DFS or OS between two groups. In addition, multivariate logistic regression or Cox regression models were used to evaluate independent factors related to pCR or DFS/OS, in which the enter method (where all the factors were forced into the regression model) was used. SPSS v.26.0 (IBM Corp.) was used for data processing and GraphPad Prism v.7.0 (Dotmatics) was used for figure construction. P<0.05 was considered to indicate a statistically significant difference.
Results
Clinical features
The bevacizumab plus chemotherapy group included 14 (28.0%) female and 36 (72.0%) male patients, with a mean age of 55.8±7.9 years. The chemotherapy alone group included 21 (35.0%) female and 39 (65.0%) male patients, with a mean age of 58.9±11.0 years. Notably, there were no significant differences in baseline features between groups, such as age, clinical tumor staging and sex (all P>0.05). Characteristics of the two groups are presented in Table I. The negative driver genes defined in the present study include EGFR, ALK, ROS1 fusion and BRAF V600E mutation. All genetic mutations of the patients are listed in Table SI.
Radiological and pathological responses between groups
Complete response, partial response, stable disease and progressive disease rates in the bevacizumab plus chemotherapy group were demonstrated to be 0.0, 72.0, 28.0 and 0.0%, respectively. Meanwhile, these rates in the chemotherapy alone group were 0.0, 51.7, 45.0 and 3.3%, respectively (Fig. 1A). Notably, ORR significantly increased in the bevacizumab plus chemotherapy group compared with the chemotherapy alone group (72.0 vs. 51.7%; P=0.030; Fig. 1B).
Notably, the MPR rate was significantly increased in the bevacizumab plus chemotherapy group compared with the chemotherapy alone group (64.0 vs. 41.7%; P=0.020; Fig. 2A). However, the pCR rate was not significantly different between the bevacizumab plus chemotherapy group and the chemotherapy alone group (18.0 vs. 8.3%; P=0.130; Fig. 2B).
Factors associated with pCR
The multivariate logistic regression model revealed that bevacizumab plus chemotherapy (vs. chemotherapy alone) was not significantly independently associated with pCR in patients with non-squamous NSCLC [odds ratio (OR)=2.897; P=0.117]. The Eastern Cooperative Oncology Group Performance Status of 1 (vs. 0) was notably independently associated with a lower pCR rate in patients with non-squamous NSCLC, however this was not statistically significant (OR=0.112; P=0.053; Table II).
 | Table II.Multivariate logistic regression model of pathological complete response in patients with non-squamous non-small cell lung cancer. |
Accumulating DFS and OS rates between groups
The accumulating DFS rate was significantly higher in the bevacizumab plus chemotherapy group in comparison with the chemotherapy alone group (P=0.007). The 1-, 2- and 3-year accumulating DFS rates were 100.0, 91.7 and 82.5% in the bevacizumab plus chemotherapy group, respectively, and 91.9, 65.3 and 50.4% in the chemotherapy alone group, respectively (Fig. 3A). Furthermore, the accumulating OS rate was significantly higher in the bevacizumab plus chemotherapy group in comparison with the chemotherapy alone group (P=0.049). The 1-, 2- and 3-year accumulating OS rates were 100.0, 96.0 and 89.1% in the bevacizumab plus chemotherapy group, respectively, and 100.0, 81.4 and 63.4% in the chemotherapy alone group, respectively (Fig. 3B).
Factors linked with DFS and OS
Bevacizumab plus chemotherapy (vs. chemotherapy alone) was significantly independently associated with a longer DFS in patients with non-squamous NSCLC [hazard ratio (HR)=0.251; P=0.042; Table III]. However, bevacizumab plus chemotherapy (vs. chemotherapy alone) was not significantly independently associated with OS in patients with non-squamous NSCLC (HR=0.297; P=0.158; Table IV). Furthermore, all other factors were not demonstrated to be significantly independently associated with DFS or OS in patients with non-squamous NSCLC (all P>0.05; Tables III and IV).
| Table III.Multivariate Cox regression model of disease-free survival in patients with non-squamous non-small cell lung cancer. |
| Table IV.Multivariate Cox regression model of overall survival in patients with non-squamous non-small cell lung cancer. |
Adverse events between groups
No significant differences were demonstrated for the number of adverse events between both groups, such as for fatigue, anemia and hand-foot syndrome (all P>0.05). In the bevacizumab plus chemotherapy group, fatigue (46.0%), alopecia (40.0%), anemia (36.0%), hand-foot syndrome (36.0%), neutropenia (36.0%), nausea and vomiting (36.0%) and hypertension (36.0%) were the most commonly reported adverse events. Moreover, in the chemotherapy alone group, alopecia (33.3%), anemia (33.3%), fatigue (30.0%), hand-foot syndrome (26.7%), neutropenia (25.0%), thrombopenia (25.0%) and nausea and vomiting (23.3%) were the most common. The incidence of hypertension was notably increased in the bevacizumab plus chemotherapy group compared with the chemotherapy alone group (36.0 vs. 20.0%), however the difference was not statistically significant (P=0.061). Furthermore, the adverse events with grade 1–2 were the most commonly reported, compared with those that were grade 3–4. Moreover, the incidence of delayed incision healing was markedly increased in the bevacizumab plus chemotherapy group compared with the chemotherapy alone group, however there was no statistically significant difference (20.0 vs. 8.3%; P=0.076; Table V).
Discussion
VEGF is an important factor for promoting angiogenesis, which participates in the progress of several cancers, such as renal carcinomas, ovarian cancer, breast cancer and NSCLC (20). Notably, bevacizumab blocks the VEGF signaling pathway, which is considered a favorable drug to suppress the growth and metastasis of NSCLC (21). At present, adjuvant bevacizumab plus platinum-based chemotherapy brings certain clinical benefits to patients with non-squamous NSCLC (11,12). For example, one study found that adjuvant bevacizumab plus platinum-based chemotherapy reduced the risk of brain metastases in patients with non-squamous NSCLC (11). Another study showed that adjuvant bevacizumab plus platinum-based chemotherapy increased OS to some extent in patients with non-squamous NSCLC (12). However, the efficacy of neoadjuvant bevacizumab plus platinum-based chemotherapy in patients with non-squamous NSCLC in cTNM IIIA stage is unclear. The present study demonstrated that neoadjuvant bevacizumab plus platinum-based chemotherapy compared with chemotherapy alone did not significantly improve the pCR in these patients. This finding agrees with that of a previous study, which reported that although neoadjuvant bevacizumab plus chemotherapy was feasible, it did not improve the pCR rate in patients with stage III NSCLC (13).
The survival rate of current neoadjuvant chemotherapy is not ideal in patients with NSCLC (22,23). For example, previous research revealed rates of 21.2 and 50.0% for 3-year DFS and OS, respectively, for patients with NSCLC in cTNM IIIA stage who were treated with neoadjuvant chemotherapy (23). Another study reported that the 3-year OS rate ranged from 58–64% in patients with NSCLC who were treated with neoadjuvant chemotherapy (22). Notably, the present study demonstrated that the 3-year DFS was 82.5%, which was higher in patients with non-squamous NSCLC in cTNM IIIA stage who received neoadjuvant bevacizumab plus platinum-based chemotherapy in comparison with those who received chemotherapy alone. The possible explanations are as follows: Bevacizumab suppressed angiogenesis by targeting the VEGF signaling pathway, thus suppressing the progression of non-squamous NSCLC (24). However, it was demonstrated that bevacizumab plus chemotherapy did not prolong OS in patients with non-squamous NSCLC in cTNM IIIA stage after adjustment by the multivariate Cox's regression analysis. This finding indicates that the efficacy of bevacizumab plus chemotherapy in patients with non-squamous NSCLC in cTNM IIIA stage is limited, and further validation is needed.
Notably, the application of bevacizumab in the treatment of patients with NSCLC may cause certain adverse events (25,26). A previous study reported that bevacizumab increased the incidences of hypertension, hemorrhagic events, leukopenia, proteinuria, febrile neutropenia and neutropenia in patients with advanced NSCLC (26). In the present study, the incidence of delayed incision healing was markedly increased in patients with non-squamous NSCLC in cTNM IIIA stage who received neoadjuvant bevacizumab plus platinum-based chemotherapy compared with those who received chemotherapy alone. This may be because bevacizumab inhibited VEGF, which prevented wound healing. Nevertheless, there was no statistical difference demonstrated. Moreover, there was no significant difference in the number of adverse events between the two groups. This may be due to the fact that the sample size was inadequate and the dose of bevacizumab was relatively low in the present study (27). Furthermore, in the neoadjuvant bevacizumab plus platinum-based chemotherapy group, grade 1–2 adverse events were the most commonly reported. These findings indicate that the safety of neoadjuvant bevacizumab plus platinum-based chemotherapy in patients with non-squamous NSCLC in cTNM IIIA stage is reliable.
In recent years, the treatment strategies of NSCLC have been continuously explored. Although neoadjuvant immunotherapy has been successful in treating patients with NSCLC to a certain extent, more neoadjuvant treatment options are required for patients with non-squamous NSCLC in cTNM IIIA stage (28). Neoadjuvant chemotherapy is still one of the predominant neoadjuvant options for the treatment of patients with NSCLC (4). Current optional neoadjuvant chemotherapy regimens report unsatisfactory efficacy in patients with non-squamous NSCLC in cTNM IIIA stage with negative driver genes (8). Notably, previous studies have reported that bevacizumab (an inhibitor of VEGF that inhibits the growth of tumors by inhibiting angiogenesis) plus platinum-based chemotherapy as a neoadjuvant chemotherapy regimen exhibits survival benefits to a certain extent in patients with non-squamous NSCLC (13–15). However, more studies are required to make a solid conclusion on supporting the clinical usage of bevacizumab-based neoadjuvant therapy in patients with stage III lung cancer.
The present study used a dose of 7.5 mg bevacizumab plus platinum-based chemotherapy as a neoadjuvant treatment regimen, and revealed that 7.5 mg bevacizumab was effective for the treatment of patients with non-squamous NSCLC in cTNM IIIA stage. This provides a potential optional treatment strategy with a low-dose of bevacizumab. Moreover, the tumor driver gene detection in the present study was based on a panel of the following genes: EGFR, Kirsten rat sarcoma viral oncogene homolog, Harvey rat sarcoma virus oncogene, neuroblastoma RAS viral oncogene homolog, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, ALK, ROS1, BRAF, human epidermal growth factor receptor 2, rearranged during transfection, tumor protein p53, mesenchymal to epithelial transition factor, mitogen-activated protein kinase kinase 1, fibroblast growth factor receptor 1 (FGFR1), FGFR2, AKT serine/threonine kinase 1, phosphatase and tensin homolog, smoothened, frizzled class receptor, KIT proto-oncogene, receptor tyrosine kinase, platelet derived growth factor receptor alpha, discoidin domain receptor 2, Retinoblastoma transcriptional corepressor 1, tuberous sclerosis complex 1, mitogen-activated extracellular signal-regulated kinase 1, breast cancer susceptibility gene, Tet methylcytosine dioxygenase 2, DNA methyltransferase 3 alpha and G protein subunit alpha 11. In the screening process of the present study, EGFR, ALK, ROS1 fusion and BRAF V600E mutation in patients with non-squamous NSCLC in cTNM IIIA stage were regarded as positive driver genes, and no mutation in any of the above four genes was demonstrated to be negative. The present study did not define the mutations of other driver genes as positive as patients with lung cancer with mutations of other driver genes lacked specific treatment drugs in Dazhou Central Hospital.
Certain limitations exist for the present study: i) Although the sample size in the present study was larger than in previous studies (13,14), future studies with an even larger sample size are required to verify the efficacy and safety of neoadjuvant bevacizumab plus platinum-based chemotherapy in patients with non-squamous NSCLC in cTNM IIIA stage; and ii) the present study is retrospective, and therefore it may have confounding factors (such as body mass index and diseases history) causing a certain degree bias.
In conclusion, neoadjuvant bevacizumab plus platinum-based chemotherapy is associated with improved DFS but has limited efficacy in improving pCR and OS rates in comparison with neoadjuvant chemotherapy alone in patients with stage-IIIA non-squamous NSCLC. Therefore, a larger sample size and randomized controlled studies are is required for further validation of the findings of the present study.
Supplementary Material
Supporting Data
Acknowledgements
Not applicable.
Funding
The present study was supported by the Project of Dazhou Science and Technology Bureau (grant no. 22ZDYF0020).
Availability of data and materials
The data generated in the present study may be requested from the corresponding author.
Authors' contributions
HW conceived and designed the study. DJ, YR, CZ, DW and XJ performed data acquisition and data analysis. DJ and HW confirm the authenticity of all the raw data. All authors wrote and revised the manuscript. All authors read and approved the final version of the manuscript.
Ethics approval and consent to participate
The Ethics Committee of Dazhou Central Hospital approved the present study [approval no. 2023100]. Each subject or their guardian provided written informed consent.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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