Patients and Treatment
This Peking University People’s Hospital Sarcoma Group (PKUPH-sarcoma) study was a single-arm, non-blind, single institution, phase two study that evaluated the efficacy and safety of apatinib in patients ≥16 years with advanced osteosarcoma progressing upon chemotherapy. Patients were required to have measurable disease according to the response evaluation criteria for solid tumors version 1.1,18 and had received prior treatment with high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide in an adjuvant and/or advanced disease setting. Participants received 500 or 750 mg apatinib according to body surface area once daily until disease progression or unacceptable toxicity. The primary outcomes of this trial were Objective Response Rate (ORR) and 4-month PFS. However, the aim of this sub-study was to explore the potential signs of Adverse Events (AEs) for apatinib-treated osteosarcoma. The study was approved by the Institutional Review Board of Peking University People’s Hospital (Beijing, China), and was conducted in accordance with the provisions of the Declaration of Helsinki and the International Conference on Harmonisation guidelines for Good Clinical Practice. All of the patients provided written informed consent.
Safety and Serological Assessments
In addition to standard safety evaluations and imaging assessment, physical examination was performed at each follow-up. Laboratory tests included full blood count, serum chemistry, electrocardiogram, measurement of thyroid and cortisol levels, and urinalysis, in which levels of protein in urine were quantitatively measured after 24 h. The first time point for evaluation was set at 1 month and then repeated every 2 months thereafter. During each evaluation, all of the patients underwent ophthalmic, cardiac, and dermatologic surveillance examinations. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.19 In cases of grade 3 or 4 toxicity, apatinib was reduced by one dose level (from 750 mg to 500 mg daily or from 500 mg to 250 mg) or by two dose levels (750 mg once daily to 250 mg). Whenever feasible, patients were returned to a higher dose. Safety evaluation was continued until 28 days after the last dose of apatinib or recovery to grade one or zero from any acute toxicity associated with apatinib. The European Organization for Research and Treatment of Cancer 30-item core Quality of Life (QoL) questionnaire20–22 and Numerical Pain Rating Scale23,24 were adopted to evaluate QoL. Before initiation of treatment, all participants should be in a state without obvious AE except for the disease. We excluded all those who had hypertension that could not be well controlled through antihypertensive drugs or those who had a previous hypertensive crisis or hypertensive encephalopathy. Here hypothyroidism was defined as abnormal thyroid function including serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4), all of which were assessed using the enzyme-linked immunosorbent assay.25 Our institutional laboratory reference ranges were 0.35–4.94 mIU/L for TSH, 1.71–3.71 pmol/L for FT3, and 0.7–1.48 pmol/L for FT4. Subclinical hypothyroidism was defined as an increase in TSH above the upper limit of the normal TSH range (>4.94 mIU/L) with normal FT3 and FT4 levels. However, for better analysis, we merged hypothyroidism and subclinical hypothyroidism into hypothyroidism.
Patients who received at least 2 months of apatinib were included in the survival and safety analyses. The results used descriptive statistics. The data cut-off date was December 30, 2017. All of the statistical analyses were performed using SAS for Windows version 9.1.3. Statistical analysis of 2 × 2 contingency tables of categorical variables was conducted using the Fisher’s exact test. Median durations of PFS were calculated using the Kaplan–Meier method, and comparisons between cohorts were made using log rank tests. Correlations between parameters were evaluated with the Pearson’s test. Factors with P < 0.10 in an univariate analysis were examined with multivariate analysis including the Cox proportional hazard model and logistic regression, which defined as independent predictive factors.26 Most of the statistical tests were two-tailed, with significance defined as P < 0.05. This trial is registered with ClinicalTrials.gov, number NCT02711007.
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