Gastric cancer (GC), including cancer in the gastroesophageal junction (GEJ), is the third leading cause of cancer-related death worldwide, which is next only to lung cancer and liver cancer 1. The median survival of advanced GC has been prolonged to over 12 months owing to advances in chemotherapeutic drugs and targeted drugs 2. Meta-analyses suggest that second-line chemotherapy can improve patients’ survival compared with the best supportive care after failing first-line chemotherapy 3,4. According to the Clinical Practice Guideline of National Comprehensive Cancer Network (NCCN), second-line therapy of GC depends on previous adjuvant therapy and first-line treatment, as well as the patients’ performance status.
Apatinib is a small-molecule tyrosine kinase inhibitor that highly selectively binds to and strongly inhibits vascular endothelial growth factor receptor 2. Several studies have confirmed that blocking vascular endothelial growth factor receptor 2 was a promising therapy for inhibiting angiogenesis. Apatinib was also reported to be an effective choice for patients with advanced GC, non-triple-negative metastatic breast cancer, and advanced non-small-cell lung cancer 5–8.
Previous phase II and III clinical trials have shown its efficacy and safety in third-line or more therapy for patients with chemotherapy-refractory advanced or metastatic GC compared with placebo [median overall survival (mOS) 6.5 vs. 4.7 months, P=0.0149, hazard ratio (HR)=0.709; median progression free survival 2.6 vs. 1.8 months, P<0.001, HR=0.444] 6,7. In these trials, the therapeutic effect of apatinib on overall survival (OS) was mainly derived from prolonged progression-free survival (PFS) 9. However, the treatment of apatinib as a second-line agent remains unknown.
Therefore, this observational study aims to further study the efficacy and safety of apatinib in the second-line therapy for patients with GC and cancer of GEJ treated in our department.
Study design and ethics
This is a single-center observational study. This study was approved by the Institutional Review Board and Ethics Committee at the PLA General Hospital. Informed consent was reviewed and signed by the patients or their legal guardian in accordance with the institutional and federal guidelines.
Patients were eligible for the study on the basis of the following inclusion criteria: (a) patients with histologically confirmed advanced gastric adenocarcinoma or adenocarcinoma of the GEJ in the Oncology Department of the Chinese PLAGH between April 2015 and May 2017; (b) patients who had progressed or relapsed after undergoing standard treatments in first-line therapy in accordance with the guidelines of NCCN, or were considered unable to tolerate standard treatments, or willingly chose not to undergo certain standard treatments; (c) presence of at least one measurable or evaluable disease lesion defined by Response Evaluation Criteria in Solid Tumors 1.1 criteria; and (d) adequate organ function defined as an absolute neutrophil count of at least 1500/µl, platelet count of at least 100 000/µl, serum bilirubin up to 2 mg/dl, serum albumin of at least 2.5 g/dl, serum aspartate aminotransferase and alanine aminotransferase up to 2×the upper limit of normal for the institution (5×if because of hepatic metastases), and creatinine up to 5×the upper limit of normal for the institution or creatinine clearance of at least 60 ml/min.
Data were obtained from patients’ medical history. Demographic and clinical characteristics and previous treatment were evaluated in all patients.
Apatinib therapy was initiated from an oral administration dosage of 500 mg once a day, 4 weeks for a cycle, which could be adjusted according to the patients’ actual performance status to 250 mg once daily. The daily dosage could be decreased to 250 mg because of severe adverse events (AEs) in patients. Physicians determined whether the concurrent chemotherapy regimen was needed during apatinib therapy according to patients’ performance status.
Only patients who had completed at least one cycle of apatinib therapy and with efficacy evaluated were included in this study.
Efficacy and safety
The efficacy of apatinib was evaluated including PFS, OS, the objective response rate (ORR), and the disease control rate (DCR). PFS was defined as the time from initiation of apatinib to disease progression or death, whichever occurred first. OS was defined as the duration from the time of treatment initiation to the time of death of any cause or the last follow-up time. Tumor responses were evaluated by computed tomography, MRI, bone scan, and physical examination every cycle until disease progression, categorized as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), which was confirmed by physicians according to the Response Evaluation Criteria in Solid Tumors 1.1 criteria. ORR was estimated as the percentage of CRs and PRs. DCR was considered as the percentage of CRs, PRs, and SDs.
All AEs were reviewed and determined from patients’ medical history and laboratory examination results or from telephone follow-up according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
PFS and OS and their corresponding 95% confidence intervals (CIs) were estimated using the Kaplan–Meier method. An exploratory univariate analysis for potential factors to predict PFS and OS of Apatinib was carried out by Kaplan–Meier analysis and comparison was performed using the log-rank test. Quantitative variables are presented as median (range) or number of patients (percentage). Both responses and AEs were aggregated in the form of frequency counts and percentages. The ORR and DCR analyses were carried out on the basis of frequency counts.
All statistical analyses were two sided. A statistical significance cut-off of P=0.05 was used to retain the variables in the final model.
All the statistical analyses were carried out using SPSS for Windows (version 21; IBM, Armonk, New York, USA).
Patients and tumor characteristics
A total of 23 patients with advanced gastric adenocarcinoma or adenocarcinoma of the GEJ who had progressed or relapsed after undergoing a first-line systemic therapy at the Oncology Department of the Chinese PLA General Hospital (PLAGH) between April 2015 and May 2017 were enrolled. The median age of the patients was 60 years, ranging from 28 to 75 years. Eighteen patients were men and five were women. All patients had histologically confirmed adenocarcinoma, with or without some other components, which included mucinous adenocarcinoma or signet ring cell carcinoma. Fifteen patients were Her2 negative (65.2%), two patients were Her2 positive (8.7%), and six patients did not undergo this test because of personal preference, insufficient biopsy specimen, or financial difficulties (26.1%). All patients had advanced or metastatic disease and the most common metastatic sites were the distant lymph node (52.2%), the liver (47.8%), and the peritoneum (30.4%). All patients had an ECOG performance status of 0/1 (100%).
All patients had received previous treatment, including gastrostomy, chemotherapy, and radiotherapy. Nine (27.8%) patients had undergone radical surgery, whereas two (5.6%) patients had undergone palliative surgery and 12 (66.7%) patients had undergone palliative surgery. One patient had undergone radiotherapy because of positive surgical margin. All patients had received doublet or triplet chemotherapy as previous therapy and the most important chemotherapeutics in adjuvant chemotherapy and first-line therapy were platinum (n=22), taxanes (n=10), and fluoropyrimidine (n=23). The two patients with positive Her2 status stopped anti-Her2 therapy because of financial difficulties. None of the patients had received antiangiogenic therapy.
Complete clinical and pathologic characteristics at the initiation of apatinib therapy are shown in Table 1.
Nineteen (82.6%) patients had started apatinib therapy from the dosage of 500 mg, and four patients had started the therapy from 250 mg. Six (26.1%) patients had decreased their initial dosage because of intolerable toxicity. Seven patients (30.4%) had received concurrent chemotherapy during apatinib therapy and chemotherapy regimens involved Tegafur (4 patients, 17.4%) and Taxanes (3 patient, 13.0%). At the cut-off time (10 August 2017), all these 23 patients had discontinued apatinib therapy on account of disease progression.
All patients had progressed from apatinib therapy and 15 (65.2%) patients had died because of tumor progression. The median PFS was 4.43 months (95% CI: 1.63–7.22) and the median OS was 9.11 months (95% CI: 8.22–9.99). The Kaplan–Meier curves of PFS and OS are shown in Figs 1 and 2.
All 23 patients had been evaluated by an imageological examination. CR was not observed in any patient. Two patients achieved PR and 14 patients had SD status. The DCR was calculated as the sum of CR, PR, and SD, and the ORR was calculated as the sum of CR and PR. DCR in this study was 69.6% (16 in 23) and ORR was 8.7% (2 in 23). The details of the clinical responses are shown in Table 2.
There was no significant association of PFS and OS with age, sex, primary lesion, histology, metastasis in the liver, peritoneum, and distant lymph nodes, previous surgery, and combination therapy. The details of univariate analysis are shown in Table 3.
All 23 patients were included in the safety analysis. Twenty (86.9%) patients reported at least one AE during the study, whereas nine (39.1%) patients experienced grade 3 AEs. Dose modifications resulting from toxicity occurred in six patients. The reasons for dosage decrement were hypertension, thrombocytopenia, proteinuria, and leukopenia. None of the patients reported any grade 4 AEs.
The most common AEs included hypertension (34.7%), leukopenia (34.7%), thrombocytopenia (30.4%), proteinuria (26.1%), nausea and vomiting (21.7%), hand–foot syndrome (21.7%), and neutropenia (21.7%). Grade 3–4 AEs with incidences of 5% or greater were hypertension (8.7%) and thrombocytopenia (8.7%). All these severe AEs recovered to normal or grade 1/2 level after a decrease in dosage and symptomatic treatment.
No treatment-related death was documented during the drug administration. All AEs are listed in Table 4.
Patients with locally advanced or metastatic GC usually have poor prognoses. In first-line therapy, fluoropyrimidine-based and platinum-based chemotherapies have been used widely irrespective of two-drug regimens or three-drug regimens 10–13. Especially for patients with positive Her2 status, targeted therapy of trastuzumab has been identified to prolong survival and preserve quality of life 14. The latest edition of NCCN guideline also recommends five preferred regimens for second-line therapy, which involve both chemotherapy and antiangiogenic targeted therapy. Chemotherapeutic agents such as paclitaxel and irinotecan have been proven to benefit patients’ survival with an mOS of 5.8–9.5 months and a median progression free survival of 2.2–3.6 months 15,16. Ramucirumab monotherapy prolonged patients’ OS compared with placebo (mOS: 5.2 vs. 3.8 months, HR=0.776, P=0.047) and, in the meantime, ramucirumab showed good safety 17. Combination therapy of ramucirumab and paclitaxel yielded better efficacy and also more severe AEs than paclitaxel (mOS: 9.6 vs. 7.4 months, HR=0.807, P=0.017; G3/4 AEs: neutropenia 41 vs. 19%, leukopenia 17 vs. 7%, hypertension 14 vs. 2%) 18. Therefore, guidelines emphasize that second-line therapy should depend on previous therapy and performance status. Studies aimed at better balancing low toxicity and good efficacy are yet to be carried out.
Our study is a single-center observational study that enrolled only patients who had failed first-line standard therapy and refused to continue second-line chemotherapy. Given that ramucirumab is not yet accessible in the Chinese Mainland, apatinib has become a promising option for patients. By analyzing an unselected cohort of patients with advanced GC and cancer of GEJ treated using apatinib in second-line therapy, our study confirmed the clinical effectiveness and manageable toxicity of second-line apatinib for the first time. Apatinib dosage of 500 mg was selected mainly because of clinic trial results and our clinic practice experience. In the phase II trial in which apatinib treated advanced GC in third or more line therapy, dosages of 850 and 425 mg were compared with placebo. In a phase III trial, dosages of 850 mg were compared with placebo. From the two trials, the dosage of 850 mg yielded better efficacy, but more AEs such as proteinuria. In our practice, we chose a compromised dosage of 500 mg for third-line treatment, which was a new addition by the manufacturer, and we found that this dosage could also similarly benefit patients with lesser toxicities 19. We believed that this was the result of the interaction of apatinib itself and concomitant low-toxicity chemotherapy. Our data indicate that apatinib led to a median PFS of 4.43 months (95% CI: 1.63–7.22), a median OS of 9.11 months (95% CI: 8.22–9.99), a DCR of 69.6% (16 in 23), and an ORR of 8.7% as a second-line therapy. On the basis of these findings, apatinib seemed be an effective second-line drug in clinical practice.
In the present study, all patients had ECOG performance status 0/1 compared with previous studies of second-line chemotherapy, which enrolled some patients with a PS score of 2, which may have contribute toward the good efficacy of apatinib 15,16. Seven patients were administered apatinib plus a chemotherapeutic agent, including tegafur (n=4) and taxanes (n=3). Although in univariate analysis this combination therapy did not benefit patients’ survival comparing with apatinib monotherapy, the former led to a better objective response and disease control. Considering the promising results of ramucirumab plus paclitaxel and ramucirumab in RAINBOW and REGARD, the combination treatment may prove to be an effective therapy after wider validation in the future.
Besides the improvement in efficacy, apatinib’s toxicity has also drawn more and more attention of physicians and patients before beginning medication. Hypertension, proteinuria, and hand–foot syndrome are the most common AEs in antiangiogenic therapy 20–22. The most common AEs in our study are similar to those reported in previous apatinib studies. Besides the three main events, hematologic toxicities also occurred with a high incidence of nearly 20–30%. The total incidence of grade 3/4 AEs was 39.1% (9 in 23) and grade 3–4 AEs with incidences of 5% or greater were hypertension (8.7%) and thrombocytopenia (8.7%). 26% of patients (6 in 23) had decreased their initial dosage because of intolerable toxicity, which was similar to the phase III trial 7. All these severe AEs recovered to normal or grade 1/2 level after dosage decrement and symptomatic treatment, suggesting manageable toxicity of apatinib based on physician awareness and patient compliance.
This study presents first-hand efficacy and safety data of second-line apatinib in advanced GC, which are informative for physicians and patients. As an exploratory study, our results reflect the effectiveness of apatinib in second-line therapy, and suggest a future direction of combination therapy with chemotherapy. However, as a retrospective observational study, this study was limited because of the nature of the retrospective observational methodology, including potential missing data, heterogeneity in the population, small sample size, and lack of a control group. Moreover, quality of life was not assessed during the treatment, which could have provided more comprehensive information on apatinib toxicities. Therefore, our results should be confirmed in validation crowds. Four ongoing prospective clinical studies of apatinib will show the efficacy and safety of second-line apatinib therapy in patients with advanced GC: one for apatinib monotherapy versus docetaxel (NCT02409199) and three for apatinib plus chemotherapeutic agents involving paclitaxel, docetaxel, and irinotecan (NCT03144843, NCT02596256 and NCT03030937). Besides the four ongoing prospective clinical studies of apatinib by other centers, our center is also carrying out several researches including apatinib monotherapy and combination therapy with docetaxel in the second-line treatment for advanced GC. All these studies are still in the recruitment phase and prospective large-sample data will be reported in the next few years.
Taken together, the current results suggest that apatinib is an effective regimen for the second-line treatment of advanced GC and gastroesophageal cancer with manageable toxicity, but further prospective studies are required to establish a more specific and accurate description.
This research was supported by the projects from the National Key Research and Development (R&D) plan (2016YFC1303602).
Conception and design: Yong Zhang, Li Bai, Yi Hu, and Zhefeng Liu. Collection and assembly of data: Miaomiao Gou, Chun Han, Juan Li, and Qian Qiao. Data analysis and interpretation: Yong Zhang, Miaomiao Gou, and Li Bai. Manuscript preparation: Yong Zhang and Lijie Wang. Revision of the manuscript: Yong Zhang, Li Bai, and Zhefeng Liu. All authors approved manuscript.
Conflicts of interest
There are no conflicts of interest.
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