To the best of our knowledge, this is the first study to demonstrate that commonly occurring AEs during the treatment with apatinib predicts clinical outcomes in osteosarcoma patients. In this expanded safety analysis of the PKUPH-sarcoma study, the reported incidence and severity of AEs for apatinib differed from those previously reported.8–10 Some may think AEs were not predictive markers but just reflection of increased dose of apatinib.10 However, most of the common AEs reported were grades 1–2 in our study and had not reached dose reductions yet. We had summarized apatinib-related similar study in Table 2 and realized that there had been abundant study investigating these toxicities as potential signs for clinical outcome in patients treated with apatinib. Our population was much younger than those participants in trials, which might influence the distribution of the side effects. Although the tumor burden was significantly reduced by this apatinib, the QoL did not improve, leading to declined physical, functional, emotional, cognitive, and social functioning. The pain was not greatly relieved and became more severe during the initial 1–3 months. Although hand-foot skin actions, hypertension, and hypothyroidism were also quite common toxicities (overall incidence of 32.4%, 32.4%, and 21.6%, respectively), they could usually be manageable. We noticed that hypertension was not as severe in adolescents. We also used some traditional Chinese herbs to control fatigue and hand-foot skin reactions, which might be beneficial for preventing those AEs from developing to severity.

As a potential sign for efficacy, with regard to ORR, the only AE that had some impact was anorexia (P = 0.03). However, the onset of abdominal cramps might predict a partial response (P = 0.06). This is in accordance with the independent factors used to predict PFS for anorexia (P = 0.01). However, multiple factors could influence anorexia, including patients’ personal constitution, dietary habit, thyroid function, and oral stomatitis. In addition, anorexia is a subjective assessment that differs among patients. Thus, we could not objectively assess this AE, and as such, it may be difficult to use as a sign to assess drug efficacy.

For CBR, hypothyroidism indicated clinical benefit (P = 0.00) while hypertension and pneumothorax would also have some impact on the control of disease (P = 0.07 and 0.06, respectively). In this study, we merged hypothyroidism and subclinical hypothyroidism into hypothyroidism. The incidence of hypothyroidism was reported to be 18–85% during the use of sunitinib or sorafenib in metastatic renal cell cancer;34–36 however, the precise mechanisms were not well clarified. It was proposed that the inhibition of VEGFR-1, VEGFR-2, and PDGFR induces thyroid ischemia via capillary regression and constriction.37 VEGFR-TKI-mediated anti-angiogenesis inhibition may impair thyroid activity and induce hypothyroidism, because these angiogenesis pathways play a role in the normal physiology of the thyroid gland.37 Correlations between hypothyroidism during the treatment of VEGFR-TKIs and clinical outcomes were also investigated in several studies.34,37 Hypothyroidism may serve as a predictive marker of VEGFR-TKI treatment outcome in multiple solid tumors.3,13,34–36 In our study, several patients had tumor shrinkage and elevated TSH (>4.94 mIU/L) during apatinib treatment. Pneumothorax as a complication of anti-angiogenesis therapy in children and young adults with refractory/recurrent solid tumors has been shown to be an indicator of a favorable prognosis.17 Osteosarcoma tends to have pulmonary metastasis.1 The pathophysiologic mechanisms of pneumothorax in this setting are not clearly known, but may include fistula formation between the lung parenchyma and pleural space due to necrosis of a subpleural tumor nodule, infarction and necrosis of tumor emboli, over distension, and subsequent rupture of alveoli following VEGFR-TKI therapy.15,17 In our study, pneumothorax was reported far more frequently than other solid tumors and with appropriate management, the prognosis seemed to be far more better than those that did not have it.

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Based on univariate analyses of AEs on PFS (Figure 1), we observed that anorexia and hypertension were associated with improved clinical outcomes (HR, 0.35; P = 0.01 and HR, 0.44; P = 0.07, respectively). Further Kaplan-Meier analysis of PFS (Figures 3 and 4) showed that these two groups of patients could be separated obviously, indicating people with these one or two AEs would benefit more from the drug. Hypertension is observed with all of the VEGF pathway inhibitors and is likely linked to a decrease in nitric oxide (NO) leading to vasoconstriction.38 The VEGF pathway activates endothelial NO synthase (eNOS),39 and the inhibition of the VEGF pathway was reported to reduce the endothelial expression of eNOS in the kidney.40 Regular monitoring of blood pressure is essential for patients receiving apatinib, potentially with the aid of home monitoring. Although it was not an independent factor in our study according to multivariate analysis, hypertension indicated a longer PFS in previous studies.15,16,40 We tend to monitor it during the whole apatinib-treatment course and manage it with combination drug therapy.

The major limitation of our trial is the relatively small sample size and absence of a control group. In addition, personal discrepancy could easily influence the distribution and report of these toxicities. Further, larger sample analysis with a multi-center phase three trial is undergoing and more solid data are expected to better optimize apatinib-base therapy in advanced osteosarcoma.

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