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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 4  |  Page : 836-841

Efficacy of apatinib on multiple advanced-stage nongastric cancers


1 Department of Chemoradiotherapy, The First Affiliated Hospital of Wenzhou Medical University; Department of Clinical Medicine, The First Clinical Medical College of Wenzhou Medical University, Wenzhou, China
2 Department of Clinical Medicine, People's Hospital of Hangzhou Medical College, Zhejiang; Department of Interventional Medicine, Zhejiang Provincial People's Hospital, Hangzhou, China
3 Department of Clinical Medicine, The First Clinical Medical College of Wenzhou Medical University, Wenzhou, China

Date of Web Publication14-Aug-2019

Correspondence Address:
Wenfeng Li
Department of Chemoradiotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_24_19

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 > Abstract 


Background: Apatinib has been approved for the treatment of advanced gastric adenocarcinoma and gastric-esophageal junctional adenocarcinoma, but its efficacy is unknown for other advanced solid tumors.
Aims and Objectives: We retrospectively reviewed the use of apatinib for multiple advanced-stage non-gastric cancers. Ninety-two patients from 7 hospitals who received additional treatment except apatinib more than once were enrolled.
Materials and Methods: The primary end-point was the overall response rate (ORR), and the secondary end-points included progression-free survival (PFS), disease control rate (DCR), overall survival, and adverse reactions. We categorized all the patients into six groups according to their cancer type.
Results: In the lung cancer group, the ORR was 9% (95% confidence interval [CI], 3%–23%), DCR was 88% (95% CI, 74%–96%), and median PFS was 3 months (95% CI, 1.9–5.4 months). In the cervical cancer group, the ORR was 25% (95% CI, 3%–65%), DCR reached 100%, and median PFS was 3.5 months (95% CI, 0.6–9.0 months). There were different ORRs between the other cancer groups. In addition, the most common adverse effect of apatinib was palmar–plantar erythrodysesthesia syndrome (37%), followed by proteinuria (14%) and hypertension (13%).
Conclusion: These results suggest that apatinib might be effective for not only gastric cancer but also other carcinomas including lung cancer, colorectal cancer, cervical cancer, liver cancer, breast cancer, and nasopharyngeal cancer. Thus, apatinib is a promising targeted drug for multiple types of cancer.

Keywords: Apatinib, cervical cancer, disease control rate, lung cancer, overall response rate, vascular endothelial growth factor receptor


How to cite this article:
Wu X, Wang H, Wu Y, Jin J, Zhan Y, Zhu G, Zhang F, Zhang C, Gan J, Li W. Efficacy of apatinib on multiple advanced-stage nongastric cancers. J Can Res Ther 2019;15:836-41

How to cite this URL:
Wu X, Wang H, Wu Y, Jin J, Zhan Y, Zhu G, Zhang F, Zhang C, Gan J, Li W. Efficacy of apatinib on multiple advanced-stage nongastric cancers. J Can Res Ther [serial online] 2019 [cited 2019 Sep 20];15:836-41. Available from: http://www.cancerjournal.net/text.asp?2019/15/4/836/264282




 > Introduction Top


Apatinib, a tyrosine kinase inhibitor (TKI), is a selective inhibitor of the vascular endothelial growth factor receptor-2 (VEGFR-2) and a potent inhibitor of angiogenesis and tumor growth.[1] Apatinib is also known as YN968D1, derived from PTK787/ZK222584 (valatinib).[2] Phase II/III clinical trials have shown that apatinib can improve overall survival (OS) and progression-free survival (PFS) in patients with advanced gastric cancer who had failed treatment despite receiving two or more regimens.[3],[4] In 2014, apatinib was approved as a second-line treatment for metastatic gastric adenocarcinoma in China. It is the second antiangiogenic drug to be approved by the China Food and Drug Administration (FDA) following the approval of ramucirumab, another anti-VEGFR-2 targeting agent.

Angiogenesis was first reported to play a key role in tumor growth by Folkman in the 1970s.[5] The VEGFR signaling pathway has a central role in regulating angiogenesis and tumor growth and is the most promising target for antiangiogenic drugs.[6] The VEGFR family consists of three proteins: VEGFR-1, VEGFR-2, and VEGFR-3, each of which has a different effect.[7] VEGFR-1 is a negative regulator of the endothelial system, and VEGFR-3 plays a role in blood and lymphatic vessel biology. VEGFR-2 is the most important factor, mediating angiogenesis, mitosis, and permeability enhancement of VEGF. Once VEGFR-2 binds to its ligand, the downstream signal, ERK1/2, is activated.[8]

Angiogenesis is a potential target of apatinib, suggesting that apatinib might be an acceptable treatment method for more prevalent cancers.[9] A Phase I study of 46 cancer cases treated with apatinib, including 34 gastrointestinal cancer cases, 3 lung cancer cases, 3 breast cancer cases, and 6 other tumor type cases, showed relatively good results. Among the analyzed patients, the partial response rate to apatinib was 18.9%, stable disease (SD) rate was 64.9%, and disease control rate (DCR) was 83.8%.[2] In a multicenter, randomized, placebo-controlled, Phase II trial, 135 patients with nonsmall cell lung cancer (NSCLC) who failed two lines of therapy were evaluated to determine whether apatinib could improve PFS. As expected, the median PFS of patients treated with apatinib and those treated without apatinib was 4.7 months and 1.9 months, respectively, and the overall response rate (ORR) and DCR were better in patients treated with apatinib (12.2% and 68.9%, respectively) than in those treated without (0% and 24.4%, respectively).[10] In addition, a prospective Phase II trial of metastatic breast cancer showed that the median PFS and median OS were 3.3 months and 10.6 months, respectively.[11]

In our study, we included patients with various types of nongastric cancers including lung cancer, colorectal cancer (CRC), cervical cancer, liver cancer, breast cancer, and other cancers. Our study aimed to identify the efficacy of apatinib on solid tumors, thereby providing evidence for clinical decisions in the future.


 > Materials and Methods Top


We retrospectively analyzed 240 cancer patients, aged 18–80 years, from 7 hospitals, who failed at least two lines of therapy (except for 1 patient with lung cancer who had received concurrent TKI therapy and 5 patients with liver cancer who received concurrent interventional therapy) starting from January 1, 2002 to October 1, 2017. After excluding patients who lacked some information, those with missing follow-up data, and those with brain metastases at baseline, 92 patients were finally enrolled [Figure 1]. This research followed the ethical standards of the responsible committee on human experimentation and the Declaration of Helsinki. Written informed consent was obtained from all the patients.
Figure 1: Flow chart of the study

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The primary end-point was the ORR (the first radiologic evaluation after apatinib treatment) and the secondary end-points included the PFS, DCR, OS, and adverse events. Patients consumed apatinib orally for over 1 month; thereafter, they were examined by radiologic evaluation including computed tomography and magnetic resonance imaging performed at the following specific time points: Within 2 weeks before the start of apatinib and at least 1 month after starting apatinib. The Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) and the Easter Cooperative Oncology Group performance-status (ECOG PS) score were used in this study.

The patients took 850 mg/day of apatinib. During the course of taking apatinib, the dose was adjusted by the physician if patients experienced adverse reactions (for example, the dose was reduced to 750 mg/day, 500 mg/day, or discontinued). There were two treatment modes: oral apatinib monotherapy and oral apatinib combined with other drugs.

Data analyses were performed using SPSS version 20.0. (IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp). and EXCEL® Version 2010. All the statistical tests were two-sided. PFS and OS were analyzed using Kaplan–Meier survival analyses. The ORR (percentage of patients with either a complete or partial tumor response) and DCR (percentage of patients with either SD or a tumor response) were utilized to classify the patients into six cohorts. Waterfall plots were used to determine maximum tumor shrinkage at the first radiologic review, compared to baseline data. The ORR and DCR were reported along with their 95% confidence intervals (CIs).


 > Results Top


The demographic and clinical characteristics of the 92 patients are presented in [Table 1]. We classified these patients into six cohorts based on the type of cancer: lung cancer, CRC, cervical cancer, liver cancer, breast cancer, and other cancers. The most common cancer type was lung cancer, accounting for 46% of cases among the 92 patients. In lung cancer cohort, the median age was 60 years. Considering the ECOG PS score, 3 patients had a score of 0 (8%) and 5 patients had a score of 3 (12%), while 17 patients (40%) each had a score of 1 and 2. A total of 82% of lung cancer patients had received at least three lines of systemic but failed therapies previously; 14% of these patients had received two lines of treatment and 1 patient had received first-line combination treatment with apatinib and EGFR-TKI. Twenty-three (55%) patients with lung cancer had received radiation previously. In the cervical cancer cohort, 8 patients (100%) had received radiation previously, and all the patients had received more than three lines of failed therapies. However, in the liver cancer cohort, only 1 patient received radiation. Totally, 38% of the patients were orally administered apatinib as the first-line concurrent interventional therapy. In the other cancer cohort, no patients had an ECOG PS score of 3.
Table 1: Baseline patient demographic and clinical characteristics in each cohort

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Changes in tumor burden compared to baseline were observed on the first radiologic review in all patients [Figure 2]. Most of the waterfall plots in [Figure 2] are downward, indicating that most patients responded to apatinib, including 23 lung cancer patients (55%), 10 CRC patients (56%), 6 cervical cancer patients (75%), 10 liver cancer patients (77%), 1 breast cancer patient (33%), and 6 other cancer patients (75%). The tumor burden was not altered in 10 patients (11%), including 3 lung cancer patients (7%), 5 CRC patients (28%), and 2 cervical cancer patients (25%). The other plots in [Figure 2] were all upward, i.e., the tumors enlarged after using apatinib. In the lung cancer cohort, 4 patients had SD, but new lesions appeared during evaluation time, including 3 patients with bone metastasis and 1 with brain metastasis. Similar findings were also observed in liver cancer and other cancer cohorts.
Figure 2: Best percentage change from baseline in the tumor volume in patients with at least one postbaseline measurement

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The ORR was 13% (95% CI, 6%–20%) for all types of cancer [Table 2]. The ORR was 9% (95% CI, 3%–23%) in lung cancer patients, 17% (95% CI, 1%–35%) in CRC patients, 25% (95% CI, 3%–65%) in cervical cancer patients, 15% (95% CI, 2%–45%) in liver cancer patients, 33% (95% CI, 1%–91%) in breast cancer patients, and 0% (95% CI, 0%–37%) in other cancer patients. The DCR was 87% (95% CI, 80%–94%) among all patients, 88% (95% CI, 74%–69%) among lung cancer patients, 89% (95% CI, 65%–99%) among CRC patients, 100% (95% CI, 65%–100%) among cervical cancer patients, 85% (95% CI, 55%–98%) among liver cancer patients, 67% (95% CI, 9%–99%) among breast cancer patients, and 75% (95% CI, 35%–97%) among other cancer patients. Certainly, no patient showed complete remission.
Table 2: Preliminary best response in each cohort

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The overall median PFS was 6 months [95% CI, 3.6–6.1 months; [Figure 3]a. The median PFS was 3 months (95% CI, 1.9–5.4 months) for lung cancer patients [Figure 3]b; in this cohort, 3 patients (7%) did not experience progression and continued to use apatinib, 24 (57%) experienced disease progression and apatinib was discontinued, and the information was lost in 15 (36%) patients. The median OS was 30 months (95% CI, 16.6–37.3 months) for lung cancer [Figure 3]c; in this cohort, 11 patients (26%) were dead at the last follow-up and 12 patients (29%) were still alive. As for CRC and breast cancer, the PFS and OS did not receive and 4 (22%) patients still using apatinib at the end of follow-up. The PFS of the patients with other cancer cohorts was 16 months (95% CI, 3–13 months), 3.5 months (95% CI, 0.6–9.0 months), and 3.5 months (95% CI, 0.1–7.1 months), respectively, in liver cancer, cervical cancer, and other cancers. The median OS was 51.85 months (95% CI, 6.5–152 months) for patients with cervical cancer, 27.2 months (95% CI, 21.9–58.3 months) for those with liver cancer, and 31.25 months (95% CI, 1.3–86.5 months) for those with other cancers.
Figure 3: Kaplan–Meier curve of PFS and OS in all patients and cohorts. PFS in all patients (a), PFS in the six cancer cohorts (b), and OS in the six cancer cohorts (c). PFS = Progression-free survival, OS = Overall survival

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Palmar–plantar erythrodysesthesia syndrome, proteinuria, hypertension, abdominal discomfort, and abnormal liver function were the most common adverse events [Table 3]. Hematological adverse events (thrombocytopenia, anemia, and leukopenia) were also frequent, observed in 10 of 92 patients. The incidence of adverse events associated with the digestive system (nausea or vomiting, diarrhea, and decreased appetite) was also high (11%). The following adverse events were associated with antiangiogenic drugs among the 92 patients: oral ulcers were observed in 9 patients (10%), bronchitis in 5 (5%), fatigue in 4 (4%), hemorrhage in 3 (4%), abnormal renal function in 2 (2%), pharyngitis in 2 (2%), delayed wound healing in 1 (1%), hypothyroidism in 1 (1%), hair and skin bleaching in 1 (1%), desquamation in 1 (1%), and edema in 1 (1%). The follow-up information of 9 patients (10%) was lost.
Table 3: Adverse events

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 > Discussion Top


Since Folkman proposed the concept of treating cancer by inhibiting new blood vessel formation in tumors,[5] several antiangiogenic VEGF inhibitors have been approved by the FDA. Bevacizumab, the first antiangiogenic inhibitor approved by the FDA in metastatic CRC,[12],[13] has also been subsequently approved for several other cancers including recurrent glioblastoma,[14] metastatic nonsquamous NSCLC,[15] drug-resistant ovarian cancer,[16] metastatic cervical cancer,[17] and metastatic renal carcinoma.[18] Subsequently, other approved antiangiogenic agents such as sunitinib, sorafenib, and ramucirumab have been effective for multiple types of solid tumors.[19]

In 2014, the China FDA approved apatinib for advanced gastric cancer. Apatinib also has a limited effect for other tumor types.[20] A study analyzing the effect of apatinib on advanced nonsquamous NSCLC (NCT01270386)[21] showed that the median PFS was 4.7 months, and the ORR and DCR were 12.2% and 68.9%, respectively. However, the PFS of lung cancer was 3 months in our study, which was slightly less than that observed in the previous study. The ECOG PS score in our study was 0–3, while the patients in the previous study had an ECOG PS score of ≤1. Furthermore, our study was a retrospective study and the dose of apatinib was not fixed compared with the NCT01270386 trial. The end-point was also different. Finally, all the patients in our study did not have nonsquamous NSCLC: 2 patients (5%) had small-cell lung cancer and 2 had squamous cell lung cancer (5%). Moreover, 1 patient received apatinib as the first-line treatment with TKI. All these factors were different between our study and the previous study. In another study, apatinib enhanced the antitumor activity of EGFR-TKIs in NSCLC with TKI resistance.[22] In that study, 16 patients who received combination treatment of EGFR-TKI and apatinib were retrospectively evaluated, and the median PFS was 4.6 months, ORR was 28% (4 out of 14), and DCR was 100%. In another study of salvage treatment with apatinib for advanced nonsmall-cell lung cancer, the ORR was 9.5% and DCR was 61.9%.[22] Accordingly, apatinib can improve the effect of TKI and prolong PFS.

The efficiency of apatinib for CRC was also comparable. The ORR was 17% (95% CI, 1%–35%) and DCR was 89% (95% CI, 65%–99%), similar to the results for aflibercept (NCT00561470):[23] the RR was 19.8%, DCR was 84.7%, and median PFS was 6.9 months. However, in our study, the median PFS and OS were not reached. In addition, apatinib has antitumor effects and induces autophagy in colon cancer cells.[24]

When apatinib was used for cervical cancer, the ORR was 25% (95% CI, 3%–65%) and the DCR was 100%. As shown in [Figure 1], most plots for cervical cancers were downward. Moreover, 6 patients (75%) underwent surgery for cervical cancer and 2 patients (25%) had advanced cervical cancer; all the patients had received radiotherapy before apatinib. The median PFS was 3.5 months and median OS was 51.85 months. No previous studies have evaluated the use of apatinib for cervical cancer. To the best of our knowledge, our study is the first to investigate the effect of apatinib for cervical cancer, and it showed good efficacy.

The incidence and metastasis of liver cancer depends on neovascularization.[25] Apatinib was efficient for patients with advanced hepatocellular carcinoma as the first-line therapy.[26] In that study, the time to progression was 4.21 months. In our study, the PFS and OS were 16 months and 27.2 months, respectively. In another study, the ORRs at 3, 6, 9, and 12 months after treatment, respectively, were 60%, 50%, 45%, and 35% when transcatheter arterial chemoembolization (TACE) combined with apatinib was performed.[27] However, the ORR in our study was 15%, which was much lower. Among the enrolled patients, 2 were treated with apatinib monotherapy and 11 were treated with apatinib and TACE. The differences in the baseline characteristics of patients between our study and those in the previous studies might be the reason for the different results.

In a study that evaluated the efficacy of apatinib on metastatic breast cancer, the median PFS, median OS, and median time-to-treatment failure were 4.9 months, 10.3 months, and 3.93 months, respectively.[28] In other studies, the median PFS was 3.3 months [11] and the ORR and DCR were 16.7% and 66.7%, respectively.[29] In our study, patients with breast cancer received apatinib at fourth-line treatment, and the ORR was 33% and the DCR was 67%. The PFS and OS were not reached.

In the sixth cohort, the ORR and DCR were 0% and 75%, respectively. There were some researches involving apatinib in some cancer types. Apatinib can synergistically increase sensitivity to cisplatin in epithelial ovarian cancer.[30] In a case report, treatment with apatinib combined with chemotherapy improved the PFS of the patient with advanced epithelial ovarian cancer.[31] Among 62 patients with advanced esophageal squamous cell carcinoma, the median PFS and OS were 115 days and 209 days, respectively. The ORR and DCR were 24.2% and 74.2%, respectively.[32] In addition, some clinical trials investigated the use of apatinib as maintenance treatment for metastatic nasopharyngeal carcinoma; however, no clinical trials have evaluated the effect of apatinib for other types of cancer.

The most common adverse effects of apatinib in our study were similar to those observed in previous research reports.[22],[32],[33] Apatinib is generally well tolerated by patients. However, adverse effects also occurred although these are manageable. Management methods for these toxicities include dose reduction, interruption, and termination. In our study, the PFS was short, which may be owing to the lower ECOG PS score, poor compliance, and poor economic conditions.


 > Conclusion Top


The results of this study indicated that apatinib could be used not only for gastric cancer but also for other carcinomas including lung cancer, CRC, cervical cancer, liver cancer, breast cancer, and nasopharyngeal cancer. Hence, apatinib is a promising and safe targeted drug for a variety of cancer types.

Acknowledgments

The authors are grateful to the patients for their contribution to this research as well as to Jiangsu Hengrui Medicine Co., Ltd., Lishui People's Hospital, Lishui Central Hospital, The Fourth Affiliated Hospital of Medical College of Zhejiang University, Dongyang People's Hospital, Yiwu Central Hospital, Yiwu Fuyuan Hospital.

Financial support and sponsorship

This work supported by National Natural Science Foundation of China (81871318), Zhejiang University Students' Science and Technology Innovation Activity Plan and New Miao Talent Program (2018R413079).

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Mi YJ, Liang YJ, Huang HB, Zhao HY, Wu CP, Wang F, et al. Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters. Cancer Res 2010;70:7981-91.  Back to cited text no. 1
    
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Stockler MR, Hilpert F, Friedlander M, King MT, Wenzel L, Lee CK, et al. Patient-reported outcome results from the open-label phase III AURELIA trial evaluating bevacizumab-containing therapy for platinum-resistant ovarian cancer. J Clin Oncol 2014;32:1309-16.  Back to cited text no. 16
    
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Li F, Zhu T, Cao B, Wang J, Liang L. Apatinib enhances antitumour activity of EGFR-TKIs in non-small cell lung cancer with EGFR-TKI resistance. Eur J Cancer 2017;84:184-92.  Back to cited text no. 21
    
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Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012;30:3499-506.  Back to cited text no. 23
    
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Lu W, Jin XL, Yang C, Du P, Jiang FQ, Ma JP, et al. Comparison of efficacy between TACE combined with apatinib and TACE alone in the treatment of intermediate and advanced hepatocellular carcinoma: A single-center randomized controlled trial. Cancer Biol Ther 2017;18:433-8.  Back to cited text no. 27
    
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