Apatinib combined with docetaxel as a salvage treatment for metastatic esophageal squamous cancer: a case report.

The first-line treatment for metastatic esophageal squamous cell cancer (ESCC) is a platinum- or fluorouracil-based agent, followed by later treatment with taxanes or irinotecan. However, there is still no standard third-line treatment for patients with metastatic ESCC. We present a 62-year-old man initially diagnosed with locally advanced ESCC. After esophagectomy, the patient was administrated with six cycles of docetaxel and cisplatin combined with radiotherapy. After 8.0 months, computed tomography showed the left cervical lymph node metastasis. However, the metastatic lymph node was not significantly shrunk after locally palliative radiotherapy and the patient was intolerant of irinotecan as second-line systemic therapy. Then, the patient was rechallenged with six cycles of docetaxel combined with apatinib (an oral tyrosine kinase inhibitor to vascular endothelial growth factor receptor 2 [VEGFR2]), followed by single dose of apatinib as maintenance therapy. According to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 standard, partial response was achieved in this case after treating with docetaxel combined with apatinib. Now, the progression-free survival of this patient has been 7.5 months. After administrating with apatinib for 2 weeks, hypertension (grade III) was observed. Thus, the dose of apatinib was decreased from 850 to 500 mg and then the adverse effects were controllable and tolerable. In conclusion, apatinib with concurrent docetaxel provided potential efficacy as a salvage treatment for patients with metastatic ESCC. To our knowledge, this is the first case of ESCC who responded to apatinib combined with docetaxel.

Introduction

Esophageal cancer is the world’s eighth most common cancer and the sixth leading cause of cancer-related deaths.1 Different from the situation in western countries, esophageal squamous cell carcinoma (ESCC) is still the dominant pathological type in China, which accounts for more than 95% of clinical cases.2 The annual incidence of ESCC in China was about 260,000 and approximately half of the patients diagnosed with ESCC presented with metastatic diseases.2 The first-line treatment for metastatic esophageal cancer is a platinum or fluorouracil-based agent,3–5 followed by later treatment with taxanes6,7 or irinotecan.8,9 No treatment strategy has been defined for patients who have been failed or intolerant to current standard therapies.

Angiogenesis is a critical process for cell growth, especially for the tumor growth.10 The vascular epidermal growth factor (VEGF) could bind to vascular epidermal growth factor receptor (VEGFR) and activate the downstream pathway to stimulate the proliferation of vessel endothelium, then leading to the growth of tumor.11 Previous molecular pathology studies have revealed that VEGF overexpression could be detected in about 44.43% of esophageal cancer and the estimated mortality risk was 1.82-fold greater in patients with high VEGF expression,12,13 which indicated that antiangiogenic agents may have a therapeutic effect on esophageal cancer.

Apatinib, a novel small molecule tyrosine kinase inhibitor (TKI), exerts its anti-tumor effects by specifically acting on VEGFR-2.14 Phase II and III clinical trials suggested that apatinib could prolong overall survival (OS) of advanced gastric cancer patients who failed in the second-line treatment.15,16 In December 2014, China State Food and Drug Administration approved and launched apatinib as a treatment for patients with chemotherapy-refractory gastric cancer. Furthermore, many clinical studies have reported the satisfying efficacy of apatinib on various cancers including non-small-cell lung cancer,17 breast cancer,18,19 and pancreatic cancer.20 However, there is rare report to evaluate its efficacy and safety in patient with esophageal cancer. We herein report a unique case of ESCC receiving concurrent apatinib and docetaxel following failure of the second-line therapy. The progression-free survival (PFS) of this patient at least 7.5 months has been achieved now, demonstrating the potential of apatinib combined with chemotherapy in the treatment of ESCC. To our knowledge, this is the first case of ESCC who responded to apatinib combined with docetaxel.

Case report

A 62-year-old man suffered from dysphagia for almost 1 month was admitted to our hospital. Endoscopy biopsy suggested ESCC 28–35 cm away from incisors (Figure 1A and B) and computed tomography (CT) indicated that there was a space-occupying lesion at the lower esophagus (Figure 2). Physical examination did not show syndromes of hoarse voice and cough during drinking water, and no swelling superficial lymph node felt by touch. The patient had no history of hypertension, heart disease, diabetes, and kidney-related diseases.

Figure 1

Endoscopy biopsy (A) suggested esophageal squamous cell carcinoma; postoperative pathology (B) demonstrated moderately differentiated esophageal squamous cell carcinoma invading the full thickness of the esophageal wall.

Figure 2

The initial thoracic CT indicated that the middle thickening esophageal wall was markedly enhanced. Plain scan (A); arterial phase (B); venous phase (C).

Note: Red arrows represent the lymph node.

Abbreviation: CT, Computed tomography.

The esophagectomy was performed on September 2, 2016; postoperative pathological examination indicated moderately differentiated ESCC. The full thickness of the esophageal wall was invaded, with dimensions of 5 × 2 × 1.3 cm, and metastasis was observed in esophageal lymph nodes (3/7; Figure 1B) but not observed in the resection margin. According to the eighth edition Staging Guidelines of American Joint Committee on Cancer, the surgical-pathological staging was T3N2M0, stage IIIB. Since September 2016, the patient received six cycles of chemotherapy of docetaxel (75 mg/m2, day 1) and cisplatin (70 mg/m2, day 1) combined with radiation therapy (total dose=50 Gy/25 fractions). In the follow-up after therapy, the gastroscopy and imaging examination showed no tumor recurrence. Until May 1, 2017, a lump could be touched in the patient’s left neck, shown as left cervical lymph node metastasis by CT (Figure 3A and B). Subsequently, locally radiotherapy (total dose=50 Gy/25 fractions) and three cycles of irinotecan (CPT-11, 250 mg/m2, 21 days as one cycle) monotherapy were performed; however, the patient suffered intolerable myelosuppression (grade IV) and severe gastrointestinal disturbances. Since CT revealed that the left cervical lymph node was not narrowed, the treatment was terminated (Figure 3C). After symptomatic treatment, the patient’s leucocytes returned to normal level, and the gastrointestinal adverse reactions disappeared.

Figure 3

Cervical CT showed no lymphadenopathy before surgery (A); CT showed a significantly enlarged lymph node in the left neck which prompted PD after first-line chemotherapy (B); CT revealed the left cervical lymph node was not reduced after radiotherapy and irinotecan treatment (C); CT examination showed the swollen lymph nodes significantly narrowed and the border was not clear, suggesting that the patient achieved PR (D).

Note: Red arrows represent the lymph node.

Abbreviations: CT, Computed tomography; PD, disease progression; PR, partial response.

Since July 28, 2017, the patient received apatinib combined with six cycles of docetaxel (75 mg/m2, day 1, 21 days as one cycle) and then administrated apatinib as maintenance therapy. After treatment with apatinib for 1.4 months, CT examination showed cervical lymph node was decreased, without tumor recurrence or metastasis in other sites (Figure 3D). These results suggested that the patient achieved partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 standard. There was no sign of progression in the patient’s conditions until we reported this case and now the PFS was 7.5 months (until March 10, 2018). The treatment schedule is given in Figure 4.

Figure 4

The treatment schedule of the patient.

Abbreviations: CT, computed tomography; RT, radiotherapy; CPT-11, irinotecan.

After apatinib was administrated for two weeks, hypertension (grade III) appeared, so the dose of apatinib was adjusted from 850 to 500 mg. During the apatinib treatment cycles, the patient developed mild-to-moderate hypertension and hand-foot syndromes. After treating with appropriate agents, no other anti-angiogenesis-associated adverse event (AE) was reported. Toxicity was evaluated and graded according to the NCI-CTC for Adverse Events, version 4.0.

The study was approved by the Medical Ethics Committee of the Affiliated Lianyungang Hospital of Xuzhou Medical University and written informed consent was obtained from the patient. The patient also provided his written informed consent for the case details and accompanying images to be published in this case study.

Discussion

To date, there has been no effective therapy as standard third-line therapy for improving the survival of ESCC patients due to its aggressive nature. To the best of our knowledge, this is the first case report on apatinib combined with docetaxel for ESCC treatment achieving PFS of 7.5 months. In addition, the patient tolerated well to the treatment, and reported satisfactory quality of life.

As early as 1971, professor Folkman suggested that tumor growth relied on the formation of tumor blood vessels, thus “anti-tumor angiogenesis” would be a promising strategy for treating tumors.11 Based on previous researches, multiple antiangiogenic agents have been developed and studied in clinical trials. In the RAINBOW clinical trial, ramucirumab (a monoclonal antibody of VEGFR-2) combined with paclitaxel significantly increased OS compared with placebo combined with paclitaxel in advanced gastric or gastro-esophageal junction adenocarcinoma.21 This agent was also advocated in treatment guidelines for esophageal adenocarcinoma.22 Some clinical trials have demonstrated the effectiveness of bevacizumab as neoadjuvant therapy in ESCC.23,24 However, there are very few studies on anti-angiogenesis agents for metastatic ESCC.

Apatinib is a novel orally taken small molecular TKI, exerting its anti-angiogenesis function through highly and selectively competing with intracellular VEGFR-2’s adenosine triphosphate (ATP) binding sites. Thus, downstream signaling could be blocked to inhibit neovascularization in tumor tissue. The Phase II clinical trial of apatinib reported that median OS was increased to 4.83 months with apatinib 850 mg group, 4.27 months with apatinib 425 mg group, compared with 2.50 months with placebo group (P<0.001 and P=0.0017, respectively).15 Similar results were confirmed by the Phase III study (median OS was 6.5 months in the apatinib 850 mg vs 4.7 months in the placebo group, P=0.0149; HR=0.709, 95% CI 0.537–0.937, P=0.0156).16 The efficacy of apatinib on 62 advanced ESCC patients who failed the standard therapy was retrospectively analyzed,25 among which, 15 received PR, while 31 achieved stable disease, with a manageable safety profile. These results demonstrated the preliminary efficacy and safety of apatinib for advanced ESCC.

Although antiangiogenic therapies show remarkable antitumor activity, their efficacy is limited as monotherapy. Hence, these agents have been integrated with conventional chemotherapy or radiotherapy to enhance antitumor activity.26,27 In our case, the patient received the docetaxel plus cisplatin regimen as first-line treatment and a PFS of 8.0 months was achieved. After the failure of standard chemotherapy and local radiation therapy of metastatic lesion, the patient still showed performance status score of 1, with strong willingness to continue the treatment. Thus, the docetaxel plus apatinib was administrated as salvage treatment strategy. Beyond our expectation, for this patient, the PFS of third-line treatment can be favorably comparable with the first-line treatment, indicating a potentially synergistic effect between apatinib and docetaxel chemotherapy. Moreover, recent research showed that the cytotoxicity of paclitaxel could be significantly enhanced by apatinib in vitro and in vivo by reversing chemotherapy-resistance through blocking the function of multiple ATP-binding cassette transporters.28 Furthermore, apatinib can markedly increase the intracellular accumulation of conventional chemotherapy agents in side population cells sorted from K562 cells,29 and cisplatin-resistant non-small-cell lung carcinoma A549 cell could be resensitized through suppressing extracellular signal-regulated kinase signaling pathway.30 Currently, there are also multiple ongoing clinical trials investigating on apatinib for molecular targeted therapy in ESCC (Table 1).

Table 1

Selected ongoing trials with apatinib in metastatic ESCC

Clinical trial identifier	Phase	Setting	Treatment regimen	Primary endpoint	Status
NCT03224221	II	Second line	Apatinib+chemotherapy	One-year survival rate	Recruiting
NCT02645864	I	Second line	Apatinib+irinotecan	DLT, MTD	Recruiting
NCT03251417	II	Second line	Apatinib+irinotecan	DCR	Recruiting
NCT03274011	II	Third line	Apatinib	PFS	Recruiting
NCT02683655	II	Second line	Apatinib	PFS	Ongoing but not recruiting
NCT02976896	II	Second line	Apatinib	DCR	Recruiting
NCT03193424	II	Second line	Apatinib+docetaxel	PFS	Recruiting
NCT03320629	II	First line	Apatinib+S-1+radiotherapy	PFS	Recruiting
NCT03170310	II	Second line	Apatinib	PFS	Recruiting

Abbreviations: DLT, dose-limiting toxicity; MTD, maximum tolerance dose; DCR, disease control rate; PFS, progression free survival.

The common AEs of apatinib were hypertension and hand-foot syndrome.31 According to the instruction of apatinib, we first prescribed the patient with apatinib of 850 mg daily. Then, grade III hypertension was observed, leading to dosage adjustment to 500 mg. The AEs were controllable and tolerable. The bioavailability of apatinib in ESCC patients was noteworthily higher than those in patients with gastric cancer, which might be attributed to the fact that most gastric cancer patient had a subtotal gastrectomy surgery history.32

In conclusion, apatinib with concurrent docetaxel had potential efficacy for metastatic ESCC patients as a salvage treatment and the prospective clinical trials are ongoing (Table 1).