Independent Factors That Predict Apatinib Efficacy

The Cox proportional hazards model was used to determine the HRs of the abovementioned parameters for predicting the risk of disease progression after covariates were adjusted for all participants (Figure 2). PFS was set as the dependent variable, and parameters for which P < 0.10 in the univariate analysis were examined by multivariate analysis, including the Cox proportional hazard model and logistic regression, were set as independent variables. Based on the univariate analyses of AEs on PFS (Figure 2), we found that anorexia and hypertension were associated with improved clinical outcomes (HR, 0.35; P = 0.01 and HR, 0.44; P = 0.07, respectively) and these two factors were further testified into multivariate analyses. Hypertension was defined as maximum systolic blood pressure (BP) ≥140 mmHg and/or diastolic BP ≥90 mmHg at least three-fold that at resting state after the first day of treatment. In patients with and without hypertension, the median PFS was 6.63 (95% CI: 5.67–7.59) and 4.30 (95% CI: 3.51–5.09) months, respectively (P = 0.06; Figure 3); and in patients with and without anorexia, the median PFS was 6.27 (95% CI: 5.78–6.76) and 3.23 (95% CI: 2.01–4.45) months, respectively (P = 0.01; Figure 4). All of the observed clinical outcomes were not related to hypertension grading, whereas anorexia seemed to be related to weight loss (P < 0.00). AEs correlation analysis showed that fatigue was also correlated with hypothyroidism and weight loss (P = 0.07 and 0.00, respectively). When included in the multivariate analysis together with other clinicopathological factors that affected PFS,27 only anorexia was found to be an independent factor for prognosis (P = 0.04). Although it did not appear to greatly impact the PFS, the HR was reduced for myalgia/arthralgia, bilirubin increase, hypothyroidism, pneumothorax, and bleeding (HR = 0.59, 0.60, 0.58, 0.56, 0.46, respectively), which suggests that the occurrence of these toxicities might benefit prognosis.

Figure 2

Figure 3

Figure 4

DISCUSSION


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Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) play a critical role in angiogenesis in osteosarcoma.1 All of the VEGFR-TKIs with a high specificity and strong affinity only had a median PFS of 4–6 months for refractory osteosarcoma,2,3,5,27–29 suggesting an urgent need for a predictive marker that indicates benefits from VEGFR-TKI. The already explored potential predictive factors included patient-related factors, such as VEGFR gene polymorphisms;30 tumor-related factors, such as microvascular density, serum VEGF level and VEGFR-2 expression;31 and drug-related factors, such as treatment-induced hypertension and hand-foot syndrome.32–34 Most of the AEs reported with apatinib can be ascribed to VEGFR inhibition and are consistent with the AEs observed with other VEGFR TKIs.10,15,17,33 As tumor growth addiction to the specific pathway that is effectively targeted may be the link between a mechanism-based toxicity and efficacy, the biological basis of AEs might be pharmacological, with higher drug exposure being associated with greater toxicity and antitumor activity.10,15 Some TKI-associated AEs correlate with improved patient outcomes.17,33 An awareness of the mode of action can help the physician anticipate potential drug interactions, and an appreciation of the most common AEs but with appropriate management in case those AEs progressing into grades 3–4. The objectives of this single institution, phase two, open-label, single-arm study were to assess the efficacy and safety of apatinb in patients with heavily pretreated advanced osteosarcoma, and to evaluate the potential of apatinib-induced AEs for efficacy prediction.

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