Preliminary study of the treatment effect of apatinib mesylate upon malignant ascites and its safety
Original Article

Preliminary study of the treatment effect of apatinib mesylate upon malignant ascites and its safety

Changmin Liu1*, Shaoshui Chen1*, Ping Wang2, Dianzhong Geng1, Weiming Zhang1, Jing Yang1, Judong Luo3, Fangling Ning1

1Department of Oncology, 2Department of Infection, Binzhou Medical College Affiliated Hospital, Binzhou 256603, China; 3Department of Oncology, Changzhou No.2 People’s Hospital, the Affiliated Hospital of Nanjing Medical University, Changzhou 213003, China

Contributions: (I) Conception and design: C Liu, F Ning; (II) Administrative support: P Wang, D Geng; (III) Provision of study materials or patients: J Yang; (IV) Collection and assembly of data: J Luo; (V) Data analysis and interpretation: W Zhang, S Chen; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

*These authors contributed equally to this work.

Correspondence to: Judong Luo. Department of Oncology, the Affiliated Changzhou No.2 People’s Hospital With Nanjing Medical University, Xinglong Road No 29, Changzhou, 213001, China. Email: judongluo@163.com; Fangling Ning. Department of Oncology, Binzhou Medical College Affiliated Hospital, the Yellow River two Road No 661, Binzhou 256603, China. Email: szlcm111333@163.com.

Background: This paper reports the effect of combining oral apatinib and abdominal cavity perfusion with cis-platinum for malignant ascites and its safety.

Methods: Seventeen malignant ascite patients were treated with oral apatinib (500 mg/d) and abdominal cavity perfusion of 60 mg/m2 cis-platinum (apatinib group), and 12 patients were treated with cis-platinum (60 mg/m2) only (control group). Twenty-one days was deemed as a cycle for both groups. Short-term treatment effects, quality of life (QOL), and toxicity were evaluated. Enzyme-linked immunosorbent assay (ELISA) was used to determine the vascular endothelial growth factor (VEGF) level in ascites.

Results: The response rates in apatinib and control groups were 70.6% and 33.3% (P<0.05), respectively. After treatment, the VEGF level of the apatinib group decreased dramatically (P<0.01) and was lower than that of the control group. Initial VEGF level in peritoneal fluid was significantly different between the SD (stable disease) + PD (progressive disease) and CR (complete response) groups (P<0.01). Emotion health as well as overall health conditions and appetite of the apatinib group after treatment improved in comparison with those before treatment (P<0.05). The patients felt more fatigue after treatment (P<0.05), but no statistically significant change was found in other symptoms (P>0.05). In the control group, no statistical difference was found in any parameter (P>0.05). The most common grade 3 or more severe adverse effects (AEs) in the apatinib group were fatigue and hypertension with 70.6% and 41.2% incidence rates, respectively. In the apatinib group, four patients suffered from intestinal obstruction, with two developing complete intestinal obstruction. However, in the control group, none suffered from intestinal obstruction.

Conclusions: A combination of apatinib and cis-platinum can improve short-term response rate of malignant ascites, enhance QOL and control adverse drug effects. VEGF level in the abdominal cavity may be a good predictor of treatment efficacy.

Keywords: Apatinib; malignant ascites; treatment effect; safety

Submitted May 06, 2017. Accepted for publication Aug 09, 2017.

doi: 10.21037/tcr.2017.08.24

Introduction

Ascites is a common symptom among advanced malignant tumor patients. They often suffer from abdominal distension, oliguria and poor appetite, and their living quality may be severely affected. At present, the major treatment method for malignant ascites is drainage, which is also combined with abdominal cavity perfusion. However, the overall treatment effect is modest, and patients can survive for only 2 to 6 months after treatment (1). Research has shown that vascular endothelial growth factor (VEGF) expression in malignant ascites is very high (2-5). This finding served as a theoretical basis for the application of anti-angiogenic drugs to treat malignant ascites in the current study.

Apatinib, a small molecule VEGF-2 tyrosine kinase inhibitor (TKI), is a first-generation oral anti-angiogenesis drug approved in the People’s Republic of China for use as second line of treatment for advanced gastric cancer. Previous research showed that, as small molecule TKIs, apatinib mesylate tablets mainly act on VEGFR as well as its downstream pathway that participates in controlling tumor angiogenesis. Their effectiveness against gastric, breast, and lung cancer has been validated in several lines of research (6-14). It was discovered in our clinical practice that malignant tumour patients with ascites had well-controlled ascites after taking apatinib orally. The current study was motivated by this observation. The application of apatinib in treating malignant ascites has not been reported so far. This paper aimed to explore the treatment effect of apatinib mesylate on malignant ascites and its safety.

Methods

Clinical data

Data on 42 cancer patients who suffered from malignant ascites and were treated in the Oncology Department of Binzhou Medical College Affiliated Hospital from June 2015 to June 2016 were collected. All patients were cases with first-line treatment failure. The PS score was ≤2, and it was predicted that their survival time was 3 months or longer. In the course of follow-up treatment, 13 patients were felled off. The remaining 29 patients were divided into two groups by randomized block design: one group was treated with oral apatinib and abdominal cavity perfusion of cis-platinum (apatinib group, 17 patients), and another group was treated only through abdominal cavity perfusion of cis-platinum (control group, 12 patients). Clinical characteristics of patient samples in both groups were comparable. The study was approved by the Ethics Committee of the Binzhou Medical College Affiliated Hospital, and the patients selected for the study signed the consent form. Their clinical characteristics are shown in Table 1.

Table 1
Table 1 Clinical characteristics of patient samples
Full table

Reagents and medicines

VEGF enzyme-linked immunosorbent assay (ELISA) Kit was purchased from USCN. ELIASA 550 was purchased from BIO-RAD. cis-platinum was purchased from Qilu Pharmaceutical Factory. Apatinib mesylate was purchased from Jiangsu Renghui Medicine Co. Ltd. (Lianyungang, China).

Ascites VEGF detection

About 10 mL of ascites was collected and placed into a centrifugal tube, which was then centrifuged at 2,000 r/min for 10 min. The supernatant was placed in EP tubes and operated following the instruction on the ELISA kit.

Therapeutic method

After ultrasonic localization, all patients were placed with single-cavity drainage tube after abdominal puncture to drain as much ascite as possible. The 17 patients in the apatinib group were treated with oral apatinib mesylate and abdominal cavity perfusion of 60 mg/m2cis-platinum (combined group). Three weeks was deemed as a cycle. Patients in the control group were treated with abdominal cavity perfusion of cis-platinum only, and the perfusion dose and time interval were the same as those of the combined group. Patients in both groups were observed continuously for at least two cycles.

Evaluation criterion

Peritoneal effusion was measured by color Doppler ultrasound, and the results were evaluated by two radiologists (with over 5 years of work experience), with the average value of measurements taken as the final result. The WHO Evaluation Criterion for Treatment Effects upon Unmeasurable Focus was taken as the evaluation standard, which was composed of complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). The response rate (RR) was calculated based on CR + PR. Adverse events were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE); it was composed of 1–5. The quality of life (QOL) was evaluated based on the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 (V3.0). It was conducted before treatment and after the second cycle. EORTC QLQ-C30 was composed of 30 items, including 5 function scales (somatic, role, cognitive, emotional and social functions), 3 symptom scales (fatigue, nausea/vomiting and pain), 5 single measurement items and 1 overall QOL scale (15-17). The subjects filled out questionnaires by themselves after they were given an introduction. Raw data of each scale was converted into a 0–100 scale based on the instruction of EORTC QLQ-C30. The standard score of each item was calculated. The higher scores of the function items and the overall health condition indicated that the patients had better physical condition, whereas the higher scores of the symptom items signified that the patients suffered more severe symptoms.

Statistical analysis

SPSS 16.0 was used for statistical analysis. Analysis of variance (ANOVA) was conducted for comparison of measurement data between both groups, and chi-square test was conducted for enumeration data. P<0.05 was deemed statistically significant.

Results

Short-term treatment effect

The apatinib group had 6 gastric cancer patients, 4 breast cancer patients, 2 ovarian cancer patients, 2 liver cancer patients, 2 non-small cell lung cancer patients and 1 colon cancer patient. On the other hand, the control group had 4 gastric cancer patients, 3 non-small cell lung cancer patients, 2 breast cancer patients, 2 ovarian cancer patients and 1 liver cancer patient. All patients, aged 32 to 71 years old, were diagnosed through ascites exfoliative cytologic examination to check if they were suffering from malignant ascites. All 29 patients completed the treatment, and the objective RR and safety were evaluated. A total of 5 patients obtained CR, 11 obtained PR, 13 obtained PD + SD and RR was 55.2%. The overall response rate of the apatinib group was 70.6% (12/17), whereas that of the control group was 33.3% (4/12). Statistical difference was found between both groups (x2 =3.948, P=0.047; see Table 2). Further analysis was conducted to evaluate control of ascites, and the results indicated that the ascite control rate in the apatinib group was 17.6% (3/17), whereas that in the control group was 8.3% (1/12) after one cycle. No statistically significant difference was found between both groups (x2 =0.513, P=0.474). After two cycles, the ascite control rate of the apatinib group was 64.7% (11/17), whereas that of the control group was 33.3% (4/12). A statistically significant difference was found between both groups (x2 =4.630, P=0.031), as shown in Table 3. The results indicated that the effects of treatment on the malignant ascites in the apatinib group became obvious starting the second or third week.

Table 2
Table 2 Comparison of malignant ascites control rate between both groups
Full table
Table 3
Table 3 Ascites control rate of both groups after each cycle
Full table

Comparison of VEGF level between both groups before and after treatment

The VEGF level of the apatinib group before treatment was 2,071.33±289.47 pg/mL, whereas the VEGF level of the control group before treatment was 2,398.19±333.20 pg/mL. No statistical difference was found between these groups (t =0.092, P=0.921). The VEGF level of the apatinib group after treatment was 586.10±129.46 pg/mL, which was significantly lower than the level before treatment 2,071.33±289.47 pg/mL (t =4.581, P<0.01) and also lower than the VEGF level of the control group after treatment 962.47±150.35 pg/mL. A statistically significant difference was found between these groups (t =2.173, P=0.038). Stratification analysis of the relationship between the initial ascites VEGF level and treatment effect showed that the VEGF level of the SD + PD group was significantly lower than that of the CR group (t =4.530, P<0.01) in the apatinib group. On the other hand, the VEGF level of the SD + PD group showed no statistically significant difference compared to that of the CR group (t =1.011, P=0.708) in the control group.

QOL

The results showed that in the apatinib group, no statistical difference was found in the function items (P>0.05) other than emotion (P<0.05) between before and after treatment. The overall health condition was improved after treatment (P<0.05). Evaluations of symptoms revealed a remarkable improvement in appetite (P<0.05), while fatigue intensified after treatment (P<0.05). Other symptoms, e.g., pain, showed some decrease but without statistically significant difference (P>0.05). In the control group, no statistically significant difference was found in any of the items (P>0.05) (see Table 4).

Table 4
Table 4 Detected changes in patients’ QOL based on EORTC QLQ-C30
Full table

Safety

In this study, all the adverse effects (AEs) related to apatinib mesylate were of grades 1 to 3, and no medicine-related grade 4 AEs or serious adverse events took place. The most common AE was fatigue, which was found in 12 patients. This was followed by hypertension, found in 7 patients. Grade 3 AE occurred in 7 person-times, including fatigue, hand-foot-skin reaction, hypertension, proteinuria and sore throat. Among them, the incidence of fatigue and hypertension was 70.6% and 41.2%, respectively, whereas the incidence of hand-foot-skin reaction and proteinuria was 17.6%. In the apatinib group, 4 patients suffered from intestinal obstruction, with 2 patients showing complete intestinal obstruction. No one in the control group suffered from intestinal obstruction (Table 5).

Table 5
Table 5 Statistics of adverse drug effect in the apatinib group
Full table

Discussion

Previous studies have shown that VEGF could facilitate neovascularization and promote the increase of vascular permeability in tumor by exerting biological effects. VEGF is a key factor that drives the tumor cells to infiltrate and transfer to the abdominal cavity to form ascites (18,19). The VEGF content in ascites is high, and anti-angiogenic drugs, e.g., bevacizumab, and recombinant human endostatin, can control the formation of ascites by inhibiting VEGF, implying that anti-VEGF therapy is a potential therapeutic approach (2,20-23). However, its efficacy needs to be further improved. Additionally, since this approach has a high treatment cost, its clinical application is limited. Seventeen patients who took apatinib mesylate orally in combination with abdominal cavity perfusion of cis-platinum were enrolled and compared with the control group, which was composed of the patients who were treated with abdominal cavity perfusion of cis-platinum only. The results showed that the combined group’s short-term effect was good, and the RR was 70.6%, which is apparently higher than that of the control group. Further stratification analysis showed that after apatinib mesylate treatment, the high VEGF expression group had achieved a striking effect. The VEGF level showed remarkable decline after treatment (P<0.05), implying that the initial high level of ascites VEGF may be a good predictor of reaction to apatinib treatment. The emotional health as well as overall health condition and appetite of the apatinib mesylate group showed notable improvements in comparison with those of the control group. The difference between the two groups was statistically significant (P<0.05). However, the incidence of fatigue was greater in the treatment group compared to the control group, which may be attributed to the AEs of apatinib mesylate.

Common AEs, including fatigue, hypertension, proteinuria, neutropenia, thrombocytopenia, sore throat, hyponatremia and intestinal obstruction, were often found in the patients of the apatinib group during the follow-up period. The incidence of grades 3–4 AEs was lower than that reported in the literature (24-27). It may be related to the low dose adopted by patients in the group. It is notable that four intestinal obstruction cases were found in the apatinib group during the follow-up period, but none were found in the control group. Our results suggest that apatinib mesylate can control neovascularization and improve vascular permeability and accordingly allow the ascites to be controlled within the short term. In addition, apatinib mesylate results in the deposit of fibrinogen of ascites on the surface of the intestinal canal and aggravates intestinal adhesion. Whether the incidence of intestinal obstruction could be reduced by avoiding drugs that may aggravate intestinal adhesion, e.g., cis-platinum, or by adjusting the dose of apatinib mesylate, remains to be confirmed in clinical studies.

In summary, the combination of apatinib mesylate and abdominal cavity perfusion of cis-platinum has high objective response rate in treating malignant ascites, and it is safe and effective. The level of VEGF in the abdominal cavity can be used to predict its efficacy. Intestinal obstruction caused by the therapy requires close clinical attention, and physicians should try to avoid using drugs that may aggravate intestinal adhesion, e.g., cis-platinum. Since only a few cases were enrolled in this study, the treatment effect and safety of the therapy needs to be further verified in larger patient samples.

Acknowledgments

Funding: This work is supported by the Natural Science Foundation of Shandong Province (ZR2016HM41), Shandong Postdoctoral Innovation Fund [201601006], Changzhou High-Level Medical Talents Training Project (2016CZBJ016), the Medicine and Health and Scientific Development Programme of Shandong Province (2015WSB30011), and Scientific Development Programme of Binzhou Medical University (BY2014KJ45).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2017.08.24). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of the Binzhou Medical College Affiliated Hospital (No. 2017-010-01), and the patients selected for the study signed the consent form.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Liu C, Chen S, Wang P, Geng D, Zhang W, Yang J, Luo J, Ning F. Preliminary study of the treatment effect of apatinib mesylate upon malignant ascites and its safety. Transl Cancer Res 2017;6(5):894-900. doi: 10.21037/tcr.2017.08.24

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