The Efficacy and Safety of Apatinib in Refractory/Relapse Advanced Pediatric Solid Tumor: A Retrospective Study.

BACKGROUND: The prognosis of recurrent or refractory advanced childhood solid tumor patients is very poor and new therapeutic strategies are in urgent need. This study aimed to determine the efficacy and safety of apatinib in pediatric refractory/relapse advanced solid tumor patients. PATIENTS AND METHODS: The study retrospectively reviewed recurrent or refractory advanced pediatric solid tumor patients who were treated with apatinib, an oral small-molecule tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor-2 (VEGFR2), at the Sun Yat-sen University Cancer Center (China) from January 2016 to March 2019.
RESULTS: Fifty-six patients were included in the safety evaluation and 49 patients were included in the efficacy evaluation. The objective responses rate (ORR) was 26.5% (95% CI 15-41): 0 CR (complete response) and 13 PR (partial response). Disease control rate (DCR) (CR+PR+SD) was 79.6% (95% CI 65-90). The median progression-free survival (PFS) was 4.0 months (95% CI 2.6-5.4). There was no significant difference for ORR or PFS between the A (apatinib monotherapy), A+MT (apatinib combined with oral metronomic therapy) and A+SC (apatinib combined with salvage combination chemotherapy) group (p>0.05). The most common grade 3 or 4 adverse events were neutropenia (9[16.1%]), thrombocytopenia (8[14.3%]), hand-foot syndrome (3[5.4%]), hypertension (3[5.4%]), anaemia (3[5.4%]) and mucositis (2[3.6%]). Hypertension was the most serious adverse event and one death that occurred was considered as drug-related.
CONCLUSION: Apatinib showed promising clinical activity in heavily treated recurrent or refractory advanced childhood solid tumor patients. However, it is necessary to pay special attention to monitoring blood pressure when using apatinib in children. Prospective randomized controlled clinical trial is warranted.

Introduction

Over the past few decades, survival rates for pediatric cancer have markedly improved.1 However, certain high-risk or relapsed/refractory pediatric cancers still show a very poor prognosis. There is a particularly urgent need for new therapeutic strategies for these patients.

Angiogenesis plays a key role in cancer growth and development. A correlation between high VEGF/VEGFR levels and poor outcomes in pediatric solid tumors such as neuroblastoma, Wilms tumor, Ewing sarcoma, osteosarcoma and rhabdomyosarcoma suggested that angiogenesis inhibitors might offer a therapeutic approach.2–14

Apatinib, an oral VEGFR-2 TKI, was approved by both the FDA (Food and Drug Administration) and CFDA (China Food and Drug Administration) for the treatment of patients with metastatic gastric cancer. It was also demonstrated to improve progression-free survival (PFS) and overall survival (OS) in patients with breast cancer,15 non-small cell lung cancer,16 ovarian cancer,17,18 hepatocellular carcinoma,19 bone and soft tissue sarcomas,20 etc. So far, the safety and efficacy data of apatinib in the treatment of pediatric cancers are still insufficient. As a result, apatinib has not been approved for the treatment of pediatric cancers. However, the status of lacking new drugs and clinical trials in pediatric cancer patients in china makes off-label therapy with apatinib is a very common phenomenon in the real world. In order to clarify the safety and effectiveness of apatinib in pediatric patients, we retrospectively reviewed the data of heavily treated refractory/relapse advanced pediatric solid tumor patients treated with apatinib between January 2016 and March 2019 at Sun Yat-sen University Cancer Center.

Patients and Methods

Eligibility Criteria

Children and young adults (<18 years old when primary diagnose) with refractory/relapsed advanced solid tumors (excluding central nervous system tumors) treated with apatinib in their first or further relapse or progression between January 2016 and March 2019 at Sun Yat-sen University Cancer Center were retrospectively evaluated. All patients 1) had tumors that were not amenable to curative treatment (with unresectable lesions or distant metastasis). 2) had at least one measurable lesion according to Response Evaluation Criteria for Solid Tumors (RECIST). 3) had failed after at least two lines of chemotherapy regimens.

Treatment Schedule

Written informed consent was obtained from all patients when they began treatment for apatinib. The subjects were generally classified into three subgroups according to the therapeutic regimen: apatinib monotherapy (A), apatinib combined with oral metronomic therapy (A+MT) and apatinib combined with salvage combination chemotherapy (A+SC). Oral apatinib was given at a dose of 250 mg (<25 kg), 500 mg (25 kg≤weight<50 kg) and 750 mg (weight≥50 kg) once daily continuously. Dose reduction (in patients≥25 kg) or interruptions for drug-related toxicity were allowed. One treatment cycle was 28 days long. Apatinib treatment continued until disease progression, unacceptable toxicity or patient withdrawal. Dose-limiting toxicity was defined as possibly/probably/definitely drug-related grade 3–4 toxic responses. For group A+MT, metronomic therapy included etoposide (oral: 25mg/m2 once daily for 21 days every month) or cyclophosphamide (oral: 50mg/m2 once daily) plus vinorelbine (oral: 40mg/m2 once weekly for 3 weeks every 4 weeks). For group A+SC, the majority (16/22, 72.7%) of patients received regimen VIT (intravenous vincristine 1.5mg/m2 on day 1, plus orally temozolomide 100mg/m2 on day 1–5 and intravenous irinotecan 50mg/m2 on day 1–5); the other regimens included intravenous topotecan+vindesine, Etoposide+cisplatin, and cyclophosphamide+pirarubicin. Detailed information on treatment option is shown in Table 1.

Table 1

Baseline Patients Characteristics

	All Patients Enrolled (n=56)
Sex, N (%)
Female	17 (30.4%)
Male	39 (69.6%)
Age, years (arrange)	9.5 (2.5–23)
Metastatic at initial diagnosis, N (%)	36 (64.3%)
Histology at diagnosis
Neuroblastoma	21
Embryonic rhabdomyosarcoma	12
Alveolar rhabdomyosarcoma	3
Ewing’s sarcoma/PNET	4
Wilms tumor	5
Malignant peripheral nerve sheath tumor	3
Desmoplastic small round cell tumor	2
Hepatoblastoma	1
Rhabdoid tumor	1
Pulmonary blastoma	1
Intimal sarcoma of the right atrium	1
Yolk sac tumor	1
Bromine neuroblastoma	1
Number of previous chemotherapy lines
2	19
3–4	14
5–6	23
Median cycles of previous chemotherapy	14(4–30)

Abbreviation: PNET, primitive neuroectodermal tumor.

Outcomes Evaluation

All patients underwent physical examination, laboratory tests (including haematology and serum chemistry) and 12-lead electrocardiogram every 3 weeks. Computed tomography (CT) or magnetic resonance imaging (MRI) was performed before treatment and after every 2 months during apatinib monotherapy or when new symptoms developed. Tumor response was evaluated according to RECIST 1.1. Progression-free survival, proportion of disease control, duration of response and safety were recorded. Progression-free survival was defined as the time interval from the beginning of first apatinib treatment to disease progression or death for any cause or last survival assessment without progression for patients alive. Duration of response was assessed in patients who achieved a response and defined as the time from the date of the first documented response until the date of documented progression or death from any cause. Proportion of disease control was defined as the proportion of patients who achieved a complete response, a partial response, or stable disease.

Toxicities Assessment

Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0 (NCI CTC v4.0) and recorded.

Statistical Analysis

Kaplan–Meier survival curves were used for PFS estimation. Data analyses were performed using SPSS 20.0 software (IBM Corporation, Armonk, NY, USA).

Results

Patients’ Characteristics

From October 1, 2015 to February 28, 2019, 101 patients who had taken apatinib were screened, of which 45 patients were excluded because no post-baseline efficacy evaluation and safety data were collected. At last, 56 patients were enrolled in this study. Clinical characteristics of patients are shown in Table 1. The median age at the beginning of taking apatinib was 9.5 (2.5–23) years old. All diagnoses were pathologically confirmed at Sun Yat-sen University Cancer Center, which included neuroblastoma (NBL)(n=21), Embryonic rhabdomyosarcoma (ERMS)(n=12), Alveolar rhabdomyosarcoma (ARMS)(n=3), Wilms’ tumor (WT)(n=5), Ewing sarcoma (ES)/PNET (n=4), Malignant peripheral nerve sheath tumor (n=3), Desmoplastic small round cell tumor (n=2), Hepatoblastoma (n=1), Rhabdoid tumor (n=1), Pulmonary blastoma (n=1), Intimal sarcoma of the right atrium (n=1), Yolk sac tumor (n=1) and Bromine neuroblastoma (n=1).

Thirty-six patients (64.3%) were in stage IV at initial diagnosis. Before treatment with apatinib, all patients were heavily pretreated including multiple cycles of chemotherapy and/or surgery and/or irradiation for local control. The primary and salvage chemotherapy regimens were used according to tumor type (not listed). Drugs used previously before apatinib include intravenous cyclophosphamide, pirarubicin, vincristine, ifosfamide, cisplatin, carboplatin, etoposide, methotrexate, actinomycin, irinotecan, nedaplatin, doxorubicin hydrochloride liposome, vinorelbine, temozolomide, docetaxel, topotecan, gemcitabine, fluorouracil and/or oral cyclophosphamide, vinorelbine, etoposide, celebrex or 13 cis-RA as maintenance/metronomic therapy. Two of the patients had been treated with other VEGFR inhibitors anlotinib and pazopanib, respectively.

Median cycles of previous intravenous chemotherapy were 14 cycles (range 4–30). Forty-nine (87.5%) patients had accepted at least one surgery, and 46 (82.1%) patients had received prior radiotherapy. Forty-seven (83.9%) patients presented with disease progression and 9 (16.1%) with recurrence. Apatinib alone or combined with chemotherapy was treated as 3rd line in 19 patients, 4th/5th line in 14 patients and 6th/7th line in 23 patients.

The median follow-up time was 3 months (range, 2.0–17.0 months). At the data cutoff point, only two patients (3.6%) remained on apatinib treatment. Fifty-four patients (96.4%) discontinued apatinib as a result of disease progression (29/54,53.7%), toxicity intolerance (12/54,22.2%), individual willingness withdrawal (8/54,14.8%), loss to follow-up (4/54,7.4%) and receiving other anticancer therapy (1/54,1.9%). Six patients who received apatinib less than one cycle were not involved in evaluating efficacy.

Efficacy Evaluation and Outcomes

A total of 49 patients were involved in the efficacy evaluation. No patients achieved CR, 13 (26.5%) patients achieved PR, 26 (53.1%) achieved SD, and 10 (20.4%) patients developed progressive disease (PD) (Table 2). Objective responses rate was 26.5% (95% CI 15–41). Disease control rate was 79.6% (95% CI 65–90) (Table 2). The median PFS was 4.0 months (95% CI 2.6–5.4) (Figure 1). Of the 13 patients who achieved an objective response, 8 (61.5%) had disease progression at data cutoff, only 1 (7.7%) patient remained on apatinib treatment. The median duration of response was 3.0 months (IQR 2.0–4.0). Three (23.1%) patients had remission lasting longer than 6 months. The best percentage change of the target lesion size from the baseline was a 70% reduction.

Table 2

Treatment Responses

Clinical Evaluations	All Patients	Group A	Group A+MC	Group A+SC
Total, n	49	12	16	21
CR, n	0	0	0	0
PR, n (%)	13 (26.5%)	5 (41.7%)	3 (18.8%)	5 (23.8%)
SD, n (%)	26 (53.1%)	4 (33.3%)	11 (68.8%)	12 (57.1%)
PD, n (%)	10 (20.4%)	3 (25.0%)	2 (12.4%)	4 (19.1%)
ORR (%, 95% CI)	26.5%, 15–41	41.7%, 15–72	18.8%, 4–46	23.8%, 8–47
DCR (%, 95% CI)	79.6%, 65–90	75.0%, 43–95	87.6%, 62–98	80.9%, 58–95

Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, disease progression; ORR, objective responses rate; DCR, disease control rate; Group A, patients received apatinib monotherapy; Group A+MT, patients received apatinib plus oral metronomic therapy; Group A+SC, patients received apatinib plus salvage combination chemotherapy.

Figure 1

Kaplan-Meier curve of progression-free survival (PFS) for patients treated with apatinib with at least one post-baseline efficacy assessment (n=49).

Among the 49 patients who could be evaluated the efficacy, 23 were soft tissue sarcomas (15 rhabdomyosarcomas) and 17 were neuroblastomas. In the group of patients with soft tissue sarcoma, the objective response rate was 30.4% (95% CI 13.0–53.0) and the disease control rate was 82.6% (95% CI 5.0–39.0). In the rhabdomyosarcoma subgroup, the objective response rate was 26.7% (95% CI 8.0–55.0) and the disease control rate was 80.0% (95% CI 4.0–48.0). In the group of patients with neuroblastoma, the objective response rate was 29.4% (95% CI 10.0–56.0) and the disease control rate was 76.5% (95% CI 7.0–50.0). There is no statistical difference in sensitivity to apatinib between rhabdomyosarcomas and neuroblastomas (p>0.05).

According to the different combinations of chemotherapy, 49 patients were divided into three groups. Twelve patients (24.5%) were in group A, 16 patients (32.7%) were in group A+MT and 21 patients (42.9%) were in group A+SC. Objective responses rate (ORR) of group A, A+MT and A+SC was 41.7% (95% CI 15–72), 18.8% (95% CI 4–46) and 23.8% (95% CI 8–47), respectively. Disease control rate (DCR) of group A, A+MT and A+SC was 75.0% (95% CI 43–95), 87.6% (95% CI 62–98) and 80.9% (95% CI 58–95), respectively. Median PFS of patients in the A group, A+MT group, A+SC group was 3.0 months, 3.0 months, 5.0 months, respectively. There is no statistical difference between any two groups (p>0.05) (Table 2).

Patients with hand-foot syndrome had a median PFS of 8.0 (95% CI 1.7–14.3) months, compared to 3.0 (95% CI 1.6–4.4) months in those without, but the significant difference was not achieved (p=0.163) (Figure 2). The sample size was too small to draw a definite conclusion.

Figure 2

Progression-free survival (PFS) for patients who had no hand-foot syndrome and had hand-foot syndrome during taking apatinib.

Safety and Toxicity

Fifty-six patients participated in safety assessment. Toxicities observed in the study are listed in Table 3. Regardless of causality, the incidence of any-grade adverse events was 89.0%. Adverse reactions (regardless of grade) observed included neutropenia (20 [35.7%]), thrombocytopenia (15[26.8%]), liver enzymes elevation (11[19.6%]), hand-foot syndrome (10[17.9%]), bleeding (9[17.9%]), anaemia (8[14.3%]), loss of hair pigmentation (5[8.9%]), hypertension (4[7.1%]), mucositis (4[7.1%]), diarrhea (2[3.6%]), nausea/vomiting (2[3.6%]), intestinal perforation (1[1.8%]), cough (1[1.8%]), menopause (1[1.8%]), pneumothorax (1[1.8%]), and pain (1[1.8%]). Bleeding is one of the common side effects, 9(16.1%) patients experiencing 1–2 degrees of bleeding, including epistaxis (5[8.9%]), gastrointestinal hemorrhage (2[3.6%]) and bloody sputum (2[3.6%]). Grade 3–4 toxicity was observed in 39.3% (22/56) patients, including neutropenia (9[16.1%]), thrombocytopenia (8[14.3%]), hand-foot syndrome (3[5.4%]), hypertension (3[5.4%]), anaemia (3[5.4%]), and mucositis (2[3.6%]). Severe adverse toxicities were mainly hypertension. Grade 5 hypertension and treatment-related death occurred in a relapsed and refractory neuroblastoma patient. After oral administration of apatinib 250 mg once daily continuously for a month, the 4-year-old boy developed headache symptoms and was found to have blood pressure up to 160/120mmHg at home. His parents gave him a tablet of anti-hypertensive medicine immediately and discontinued apatinib. After that, his blood pressure declined to normal. Recognizing the incurable nature of relapsed and refractory neuroblastoma, his parents did not take their son to any hospital. The child lapsed into a seizure, coma and died that night.

Table 3

Possible Treatment-Related Adverse Events

	Any Grade	Grade 1–2	Grade 3–4	Grade 5
Non-haematological
Elevated aminotransferase or bilirubin	11(19.6%)	11(19.6%)	0	0
Hand-foot syndrome	10(17.9%)	7(12.5%)	3(5.4%)	0
Bleeding	9(16.1%)	9(16.1%)	0	0
Hypertension	4(7.2%)	0	3(5.4%)	1(1.8%)
Mucositis	4(7.2%)	2(3.6%)	2(3.6%)	0
Hair hypopigmentation	4(7.2%)	4(7.2%)	0	0
Diarrhoea	2(3.6%)	2(3.6%)	0	0
Nausea/Vomiting	2(3.6%)	2(3.6%)	0	0
Intestinal perforation	1(1.8%)	1(1.8%)	0	0
Cough	1(1.8%)	1(1.8%)	0	0
Pain	1(1.8%)	1(1.8%)	0	0
Menopause	1(1.8%)	1(1.8%)	0	0
Haematological
Neutropenia	20(35.7%)	11(19.6%)	9(16.1%)	0
Anaemia	8(14.3%)	5(8.9%)	3(5.4%)	0
Thrombocytopenia	15(26.8%)	7(12.5%)	8(14.3%)	0

At the data cutoff point, 56 patients received apatinib with a median of 96 days (range 4–402). Twelve (21.4%) patients discontinued the treatment as a result of adverse events, including hypertension (n=4), hand-foot syndrome (n=3), hemorrhage (n=2), neutropenia (n=1), oral mucositis (n=1) and diarrhea (n=1).

Discussion

Antiangiogenesis is a potential therapeutic target for childhood solid tumors. Several Phase II studies analyzed the effectiveness of bevacizumab, a monoclonal antibody for VEGF, combining with chemotherapy in advanced/metastatic pediatric solid carcinoma, such as neuroblastoma,21 glioma,22,23 soft tissue sarcoma20,24 and osteosarcoma.25 But these studies have not yielded evidence of survival benefits of the addition of bevacizumab to chemotherapy. Recently, several VEGFR-TKIs, such as lenvatinib and regorafenib, have been shown promising results in pediatric osteosarcoma in phase II trials. A phase II clinical study has shown apatinib’s encouraging efficacy for the treatment of metastatic sarcomas in adolescents and adults.20 Pazopanib was shown to be effective in some case reports of pediatric osteosarcoma,26,27 desmoid tumors28 and synovial sarcoma.29 However, clinical data on efficacy/safety of VEGFR-TKIs are still limited in the literature on pediatric patients. We searched ClinicalTrials.gov website on June 1, 2020 with the keyword “child”, “apatinib” and “interactive studies” and subsequently excluded withdraw/retrospective studies. A total of 14 clinical studies including patients under 18 years old diagnosed with soft tissue sarcoma, osteosarcoma, glioma and lymphoma. Eleven of them are studies for bone and/or soft tissue sarcomas. Eight of these studies were not really for children because they only included adolescents over 14 and adults. Only one rhabdomyosarcoma study included children younger than 8 years old. Clinical studies of apatinib in early childhood tumors such as neuroblastoma and Wilms tumor are absent.

This retrospective study investigated the efficacy and safety of an oral VEGFR inhibitor apatinib alone or combined with chemotherapy in 56 pediatric patients with refractory/relapsed advanced solid tumors. We observed that 26.5% of patients achieved an objective response. The median progression-free survival was 4.0 months (95% CI 2.6–5.4). One of the best responses occurred in a patient diagnosed as the right atrium intimal sarcoma with left vertical spine muscle metastasis, who has sustained remission for more than 6 months after oral administration of apatinib alone (Figure 3). It demonstrated the effectiveness of the drug in a subset of patients. Neuroblastoma and rhabdomyosarcoma are the most common types of recurrent/refractory extracranial solid tumors and also the main tumor species causing the death in children. The results of our study show that there is no statistical difference in sensitivity to apatinib between rhabdomyosarcomas and neuroblastomas.

Figure 3

A boy (18 years old) patient was diagnosed as relapse right atrial endometrial sarcoma (A) with left vertical spine muscle metastasis (B) 18 months after primary surgery and chemotherapy. After rescue chemotherapy with ifosfamide, etoposide and cisplatin, the tumor did not shrink. Then apatinib +VIT (irinotecan + vincristine + temozolomide) was given, partial response was evaluated. After 5-course chemotherapy with apatinib +VIT, the patient continued to take apatinib monotherapy up to disease progression. Chest and abdominal axial computerized tomography showing (3/2/2016) prior to apatinib+VIT, (4/26/2016) after 55 days of therapy, (6/2/2016) after 92 days of therapy, and (9/12/2019) after 184 days of therapy. The child has sustained remission for more than 6 months (tumors are marked with white arrows).

VEGF-TKIs are considered to have synergistic effects with chemotherapy. In this study, patients were divided into three groups: group A (apatinib monotherapy), group A+MT (apatinib combined with metronomic chemotherapy) and group A+SC (apatinib combined with salvage combination chemotherapy). In our study, the main metronomic therapy (MT) was oral cyclophosphamide plus vinorelbine, which was commonly used in pediatric cancers.30 The metronomic therapy concepts continuously use of low-dose chemotherapeutic, anti-angiogenetic and immunomodulating drugs, which is demonstrated to obtain a sustained antitumor effect through modulating the tumor microenvironment.31 However, a recent randomized clinical trial showed that the metronomic chemotherapy only reached 3.5% ORR in progressive pediatric solid malignant tumors and did not prolong progression-free survival compared with placebo.32 In a phase II study, apatinib combined with MC reached 54% ORR and 8-month PFS in patients with platinum-resistant or platinum-refractory ovarian cancer.17 The salvage chemotherapy regimen in this study was mainly VIT (irinotecan, temozolomide and vincristine). VIT was reported to be promising and frequently used in combination with antiangiogenic agents in childhood tumors.33–35 The result of the study showed that median PFS of patients in the A group, A+MC group, A+SC group was 3.0 months, 3.0 months, 5.0 months, respectively. There was no significant difference between groups and failed to prove the synergistic effect of apatinib and metronomic therapy or salvage chemotherapy. However, it is worth noting that the number of cases in each subgroup is limited.

We observed grade 3–5 toxicity were mainly neutropenia, thrombocytopenia, hypertension and hand-foot syndrome. The most serious adverse was hypertension. In 56 patients, 3 had grade 3–4 hypertension and 1 had treatment-related death. All the four patients discontinuing taking drugs immediately after the onset of hypertension. This indicated that when using VEGFR-TKI in children, more attention should be paid to monitoring blood pressure. If blood pressure is more than 120/80mmHg, anti-hypertensive drugs should be taken simultaneously with apatinib. For uncontrolled hypertension (grade 3–4), it is suggested to discontinue apatinib. The hand-foot syndrome was proposed to be a predictive biomarker for assessing the efficacy of anti-angiogenic drugs.36,37 In our study, patients who had hand-foot syndrome had a median PFS of 8.0 (95% CI 1.7–14.3) months, compared to 3.0 (95% CI 1.6–4.4) months in those who did not, but the significant difference was not achieved (p=0.163).

This study had several limitations. The main limitation is that the study was a retrospective study with no placebo control for comparison, and selection bias could not be ruled out. Second, the number of patients in each subgroup was too limited to verify whether there was a synergistic effect with apatinib and chemotherapeutic drugs. The patient population was very heterogenous, and the multiple subgroups further limit conclusions in an already relatively small number of children. Third, the urine protein concentration was not regularly monitored during follow-up in this study, resulting in a significantly lower incidence of albuminuria than in previous reports.38

Conclusion

In conclusion, this study is a retrospective review of oral VEGFR2 inhibitor apatinib in pediatric cancer patients. We have seen that apatinib is effective in part of refractory/relapsed pediatric cancer patients, but the side effects of hypertension should be alert. The result may provide a valuable reference for supporting further clinical studies. Prospective randomized controlled clinical trial is warranted.