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. 2017 Aug 7;10:3965–3969. doi: 10.2147/OTT.S132756

Efficacy and safety of apatinib treatment for advanced esophageal squamous cell carcinoma

Jianqiang Li 1, Lifen Wang 2,
PMCID: PMC5558584  PMID: 28860804

Abstract

Objective

No standard chemotherapy is available for patients with advanced esophageal squamous cell carcinoma (ESCC) who have failed prior first-line chemotherapy. The aim of this study was to evaluate the efficacy and safety of apatinib, an oral VEGFR-2 inhibitor, as salvage treatment for advanced ESCC.

Patients and methods

After apatinib dosing, the efficacy and toxicity were evaluated in 62 patients with pretreated advanced ESCC from 2014 to 2016 at Zhejiang Cancer Hospital. In addition, survival analysis was performed by the Kaplan–Meier method.

Results

Among the 62 patients, 15 achieved partial response while 31 had stable disease with a response rate of 24.2% and a disease control rate of 74.2%. Median progression-free survival (PFS) and overall survival were 115 and 209 days, respectively. Grade 3/4 toxicities (59.7%) were acceptable. Patients with grade 3/4 toxicities showed a longer PFS than those without (136 vs 63 days, P=0.044).

Conclusion

Apatinib is efficacious as second- or further-line treatment for advanced ESCC.

Keywords: esophageal squamous cell carcinoma, apatinib, vascular endothelial growth factor, toxicity

Introduction

Esophageal carcinoma is one of the leading causes of cancer-related death worldwide, especially in Asia.1 Most Asian patients are diagnosed as having esophageal squamous cell carcinoma (ESCC), and the histology is somewhat different from non-Asian populations.2,3 Despite timely surgical interventions at an early stage, many cases tend to recur during the follow-ups.4,5 Currently, platinum-based regimens are a standard first-line treatment for advanced ESCC with a median progression-free survival (PFS) under 6 months.6 No definitive chemotherapeutic regimen has been properly established for those who have failed prior first-line chemotherapy.

Vascular endothelial growth factor (VEGF) could stimulate the growth of new blood vessels, regulate vascular permeability and exert anti-apoptotic effects in endothelial cells. It frequently becomes overexpressed in esophageal cancers.7,8 In addition, its overexpression was identified as a poor prognostic predictor for advanced ESCC.9

Previous studies have indicated that apatinib, a VEGFR-2 inhibitor, was potentially efficacious for solid carcinomas.10 As a small-molecule, VEGFR tyrosine kinase inhibitor improved PFS and overall survival (OS) in pretreated patients with advanced gastric cancer.11,12 However, no clinical studies have examined the efficacy and safety of apatinib treatment for advanced ESCC.

A retrospective study was conducted to evaluate the efficacy and safety of apatinib for advanced ESCC after failed prior first-/further-line treatment.

Patients and methods

Patient eligibility

Patients with advanced ESCC receiving apatinib as second/further-line treatment between March 2014 and June 2016 were included. All histological diagnoses of ESCC were made according to the histopathological criteria of WHO 2015 version. No local radiotherapy or interventional therapy was offered during apatinib dosing. The study protocol was approved by our institutional review board of Zhejiang Cancer Hospital. All participants provided informed consent prior to treatment.

Treatment regimen

Apatinib was administered at a daily dose of 500 mg, and one treatment cycle lasted 28 days. In addition, one dose reduction (500–250 mg) was allowed for drug-related toxicity.

Responses and toxicities

Tumor efficacy was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Objective tumor responses included complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). In addition, toxicities were assessed by the National Cancer Institute Common Toxicity Criteria version 4.0 (CTC 4.0). Tumor responses were evaluated for every two cycles when no noticeable sign of progression was present.

Follow-ups and statistical analyses

PFS denoted the time from the first dosing day of apatinib to documented progression or mortality from any cause. In addition, OS was defined as the time from the first dosing day to mortality or the last follow-up. Survival analysis was conducted using the Kaplan–Meier method and compared using log-rank test. The survival curves were plotted according to the Kaplan–Meier method. Statistical analysis was performed using SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). The median follow-up period was 10.2 (2.0–22) months. Follow-ups were conducted up to October 30, 2016.

Results

Patient characteristics

A total of 62 patients diagnosed with ESCC were included in the current study. Among them, 54 were male and eight were female with a median age of 60.5 years. In addition, 46 of them were previous or current smokers and 16 belonged to never smoker category. All of them received platinum-based first-line chemotherapy. Apatinib was prescribed as second-line (n=21) and further-line (n=41) treatments. Performance status (PS) was 0–1 in 52 patients and 2 in 10 patients. Patient characteristics are summarized in Table 1.

Table 1.

Clinical characteristics of 62 patients

Variables N (%)
Gender
 Male 54 (87.1)
 Female 8 (12.9)
Age (years)
 Median (range) 60.5 (40–72)
 >60 32 (51.6)
 ≤60 30 (48.4)
PS
 0–1 52 (83.9)
 2 10 (16.1)
Smoking history
 Yes 46 (74.2)
 No 16 (25.8)
Alcohol use
 Yes 49 (79.0)
 No 13 (21.0)
Location of tumor
 Upper third 9 (14.5)
 Middle third 24 (38.7)
 Lower third 29 (46.8)
Line of apatinib therapy
 Second 21 (33.9)
 Further 41 (66.1)
Prior therapies in advanced stage
 Chemotherapy 44 (71.0)
 Chemoradiotherapy 18 (29.0)
Post-progression therapy after apatinib
 Chemotherapy 16 (25.8)
 Palliative treatment 46 (74.2)

Abbreviation: PS, performance status.

Clinical efficacies

The clinical responses were as follows: CR (n=0), PR (n=15), SD (n=31) and PD (n=16). The values of objective response rate (ORR) and disease control rate (DCR) were 24.2% and 74.2%, respectively. The median PFS was 115 days (95% CI, 97–133; Figure 1), and the median OS was 209 days (95% CI, 165–253; Figure 2).

Figure 1.

Figure 1

Kaplan–Meier curve of PFS after apatinib dosing.

Abbreviation: PFS, progression-free survival.

Figure 2.

Figure 2

Kaplan–Meier curve of OS after apatinib dosing.

Abbreviation: OS, overall survival.

No significant correlation existed in PFS among gender (P=0.51), age (P=0.43), line of therapy (P=0.43), smoking history (P=0.23), location of tumor (P=0.44) and PS (P=0.06). Univariate analysis is detailed in Table 2. Patients with grade 3/4 toxicities showed a longer PFS than those without grade 3/4 toxicity (136 vs 63 days, P=0.044; Figure 3). Interestingly, PFS in individuals with grade 3/4 hypertension and hand-foot syndrome was longer than that in other patients (153 vs 112 days, P=0.037).

Table 2.

Univariate analysis of the current population (n=62)

Characteristics PFS 95% CI P-value OS 95% CI P-value
Gender 0.51 0.24
 Male 95 72–125 176 165–256
 Female 122 87–142 234 199–277
Age (years) 0.43 0.34
 >60 110 107–133 231 168–266
 ≤60 117 87–121 201 176–254
PS 0.06 0.04
 0–1 132 106–157 254 226–312
 2 87 55–125 156 117–204
Line of therapy 0.43 0.45
 Second 126 75–131 234 176–265
 Further 111 87–129 199 167–254
Smoking history 0.23 0.55
 Yes 98 67–119 204 187–255
 No 124 89–132 255 211–269
Location of tumor 0.44 0.25
 Upper and middle third 101 78–125 187 167–254
 Lower third 117 111–135 231 207–288

Abbreviations: OS, overall survival; PFS, progression-free survival; PS, performance status.

Figure 3.

Figure 3

Comparison of PFS between patients with and without grade 3/4 toxicities.

Abbreviation: PFS, progression-free survival.

Among 46 SD patients, 13 had a PFS of >6 months, and the patient characteristics are summarized in Table 3.

Table 3.

Clinical profile of patients with PFS >6 months

Case Gender Age (years) Smoking Line of therapy Grade 3/4 toxicity PFS (days) OS (days)
1 Male 56 Yes Second Yes 188 252
2 Male 63 Yes Third Yes 181 254
3 Male 64 No Second Yes 195 357+
4 Female 54 No Fifth No 251 661
5 Male 65 Yes Second Yes 304 564
6 Female 48 No Fifth No 189 216
7 Male 63 Yes Third Yes 242 458
8 Male 64 No Second Yes 511 583
9 Female 62 No Second Yes 251 279
10 Female 54 No Third No 274 348
11 Male 57 Yes Third Yes 191 303
12 Male 54 Yes Second No 182 191
13 Male 50 Yes Fourth No 211 351

Abbreviations: OS, overall survival; PFS, progression-free survival.

Toxicity evaluations

The median dose of apatinib was 500 (250–500) mg. Ten dosage reductions were available. The rate of grade 3/4 toxicities was 59.7% (37/62). Five patients presented with grade 4 toxicity, including worsening proteinuria (n=2), hypertension (n=2) and hand-foot syndrome (n=1). The most common grade 3/4 adverse events were as follows: hand-foot syndrome (n=10), hypertension (n=7), proteinuria (n=7), hepatic injury (n=5), fatigue (n=3), esophagitis (n=3) and nausea/vomiting (n=2; Table 4).

Table 4.

Major toxicities of apatinib dosing

Toxicity Total (%) Grades 3/4 (%) Dosage reduction (%) Discontinuation (%)
Hand-foot syndrome 32 (51.6) 10 (16.1) 2 (20.0) 1 (33.3)
Hypertension 13 (21.0) 7 (11.3) 2 (20.0) 1 (33.3)
Proteinuria 15 (24.2) 7 (11.3) 2 (20.0) 1 (33.3)
Hepatic injury 12 (19.4) 5 (8.1) 0 (0.0) 0 (0.0)
Fatigue 9 (14.5) 3 (4.8) 2 (20.0) 0 (0.0)
Esophagitis 4 (6.5) 3 (4.8) 2 (20.0) 0 (0.0)
Nausea/vomiting 9 (14.5) 2 (4.8) 0 (0.0) 0 (0.0)

Discussion

To sum up, apatinib had some potential efficacy as a salvage treatment for advanced ESCC therapy. To the best of our knowledge, it represented the first-ever attempt of examining the efficacy and safety of apatinib for advanced ESCC.

Platinum-based agents are currently a standard first-line treatment for advanced ESCC, and the median PFS has a range of 4–6 months.1315 Half of the patients unresponsive to first-line treatment might receive a second-line therapy. Yet, the median PFS remains at a range of 2–4 months.16,17 For patients who have failed second-line chemotherapy, no definitive chemotherapeutic regimen has been recommended. New treatment strategy is urgently needed for achieving a better PS.

Several studies have identified the blockage of VEGFR-2 as a promising therapy for inhibiting angiogenesis.18,19 Apatinib, the first oral VEGFR-2 inhibitor, has previously demonstrated survival benefits for metastatic gastric cancer.12 Although approved domestically for gastric cancer treatment, apatinib was also effective for patients with advanced breast carcinoma and lung cancer who are unresponsive to standard pretreatment.20,21 In the current study, the values of DCR and ORR were 74.2% and 24.2%, respectively. There was a trend of better efficacy compared with second-line chemotherapy for advanced ESCC.5 Interestingly, patients with grade 3/4 toxicities had a longer PFS than those without grade 3/4 toxicities. Patients with hypertension and hand-foot syndrome benefited more than those with other adverse events. Together with previous study,12 our results indicated that some toxicities would be predictive factors for the efficacy of apatinib treatment.

Hand-foot skin reaction, proteinuria and hypertension were the most common adverse events in apatinib treatment, with grade 3/4 adverse events occurring in over 60% of patients with gastric carcinoma.11,12 Over 20% of patients experienced dose modifications with a recommended daily dose of apatinib (850 mg) treatment in a Phase III trial.12 In another trial, the recommended daily dose was 500 mg and grade 3/4 toxicities significantly decreased, and the efficacy was similar to those of high dose for breast carcinoma.20 In the current study, a recommended dose of 500 mg was used. The results showed that grade 3/4 toxicities occurred in over half of the patients. Although different daily apatinib doses were used for gastric carcinoma (850 mg) and breast carcinoma (500 mg), similar toxicities were observed. It was considered that several patients with gastric carcinoma underwent previous gastrectomy, and the absorption ability of apatinib might be lowered.

Retrospective nature and a small sample size were two major limitations of the current study. In addition, the dose of 500 mg apatinib adopted in this study was not widely recommended. Hence, this dose must be confirmed by further prospective studies. However, without prospective clinical studies in the literature, our study may be deemed as meaningful.

Conclusion

Our results support that apatinib is efficacious for advanced ESCC as salvage treatment. However, further prospective studies are required to fully elucidate its efficacy and toxicity.

Footnotes

Disclosure

The authors report no conflicts of interest in this work.

References

  • 1.Zheng R, Zeng H, Zuo T, et al. Lung cancer incidence and mortality in China, 2011. Thorac Cancer. 2016;7(1):94–99. doi: 10.1111/1759-7714.12286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Zhang Y. Epidemiology of esophageal cancer. World J Gastroenterol. 2013;19(34):5598–5606. doi: 10.3748/wjg.v19.i34.5598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Low DE. Evolution in surgical management of esophageal cancer. Dig Dis. 2013;31(1):21–29. doi: 10.1159/000343650. [DOI] [PubMed] [Google Scholar]
  • 4.Song ZB, Lin BC, Li B, et al. Preoperative elevation of serum C-reactive protein as an indicator of poor prognosis for early-stage esophageal squamous cell carcinoma. Kaohsiung J Med Sci. 2013;29(12):662–666. doi: 10.1016/j.kjms.2013.01.016. [DOI] [PubMed] [Google Scholar]
  • 5.Song Z, Zhang Y. Second-line docetaxel-based chemotherapy after failure of fluorouracil-based first-line treatment for advanced esophageal squamous cell carcinoma. Onco Targets Ther. 2014;7:1875–1881. doi: 10.2147/OTT.S66525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Hamamoto Y, Kitagawa Y. Current perspective of treatment for advanced esophageal squamous cell carcinoma. Nihon Shokakibyo Gakkai Zasshi. 2014;111(2):253–259. [PubMed] [Google Scholar]
  • 7.Qu W, Fu JD, Yang F, et al. Clinical implications of PTEN and VEGF expression status, as well as microvessel density in esophageal squamous cell carcinoma. Oncol Lett. 2015;10(3):1409–1415. doi: 10.3892/ol.2015.3431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Shih CH, Ozawa S, Ando N, Ueda M, Kitajima M. Vascular endothelial growth factor expression predicts outcome and lymph node metastasis in squamous cell carcinoma of the esophagus. Clin Cancer Res. 2000;6(3):1161–1168. [PubMed] [Google Scholar]
  • 9.Yang PW, Hsieh MS, Huang YC, Hsieh CY, Chiang TH, Lee JM. Genetic variants of EGF and VEGF predict prognosis of patients with advanced esophageal squamous cell carcinoma. PLoS One. 2014;9(6):e100326. doi: 10.1371/journal.pone.0100326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Ding J, Chen X, Gao Z, et al. Metabolism and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor apatinib in humans. Drug Metab Dispos. 2013;41:1195–1210. doi: 10.1124/dmd.112.050310. [DOI] [PubMed] [Google Scholar]
  • 11.Li J, Qin S, Xu J, et al. Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial. J Clin Oncol. 2013;31(26):3219–3225. doi: 10.1200/JCO.2013.48.8585. [DOI] [PubMed] [Google Scholar]
  • 12.Li J, Qin S, Xu J, et al. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol. 2016;34:1448–1454. doi: 10.1200/JCO.2015.63.5995. [DOI] [PubMed] [Google Scholar]
  • 13.Chen MQ, Chen C, Lu HJ, Xu BH. The efficacy and toxicities of combined lobaplatin with paclitaxel as a first-line chemotherapy for advanced esophageal squamous cell carcinoma. J Thorac Dis. 2015;7(10):1749–1755. doi: 10.3978/j.issn.2072-1439.2015.10.23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Lee SJ, Kim S, Kim M, et al. Capecitabine in combination with either cisplatin or weekly paclitaxel as a first-line treatment for metastatic esophageal squamous cell carcinoma: a randomized phase II study. BMC Cancer. 2015;15:693. doi: 10.1186/s12885-015-1716-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Shi Y, Qin R, Wang ZK, Dai GH. Nanoparticle albumin-bound paclitaxel combined with cisplatin as the first-line treatment for metastatic esophageal squamous cell carcinoma. Onco Targets Ther. 2013;6:585–591. doi: 10.2147/OTT.S44406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Tian J, Shang M, Shi SB, Han Y, Xu J. Cetuximab plus pemetrexed as second-line therapy for fluorouracil-based pre-treated metastatic esophageal squamous cell carcinoma. Cancer Chemother Pharmacol. 2015;76(4):829–834. doi: 10.1007/s00280-015-2854-0. [DOI] [PubMed] [Google Scholar]
  • 17.Li X, Lin W, Wang H, Lin W, Lin S, Lin Y. Phase II trial of second-line chemotherapy with docetaxel and capecitabine in advanced esophageal squamous cell carcinoma. Med Oncol. 2013;30(4):746. doi: 10.1007/s12032-013-0746-x. [DOI] [PubMed] [Google Scholar]
  • 18.Aziz MA, Serya RA, Lasheen DS, et al. Discovery of potent VEGFR-2 inhibitors based on furopyrimidine and thienopyrimidne scaffolds as cancer targeting agents. Sci Rep. 2016;6:24460. doi: 10.1038/srep24460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Ghavamipour F, Shahangian SS, Sajedi RH, Arab SS, Mansouri K, Aghamaali MR. Development of a highly-potent anti-angiogenic VEGF8-109 heterodimer by directed blocking of its VEGFR-2 binding site. FEBS J. 2014;281(19):4479–4494. doi: 10.1111/febs.12956. [DOI] [PubMed] [Google Scholar]
  • 20.Hu X, Zhang J, Xu B, et al. Multicenter phase II study of apatinib, a novel VEGFR inhibitor in heavily pretreated patients with metastatic triple-negative breast cancer. Int J Cancer. 2014;135(8):1961–1969. doi: 10.1002/ijc.28829. [DOI] [PubMed] [Google Scholar]
  • 21.Song Z, Yu X, Lou G, Shi X, Zhang Y. Salvage treatment with apatinib for advanced non-small-cell lung cancer. Onco Targets Ther. 2017;10:1821–1825. doi: 10.2147/OTT.S113435. [DOI] [PMC free article] [PubMed] [Google Scholar]

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