Summary of AEs

Of the 41 patients recruited, 37 received treatment and constituted the safety population. Baseline characteristics have been reported.27 The overall incidence of apatinib-related AEs was 89.2%. In general, drug-related AEs were limited to grade one or two. With a median follow-up time of 7.37 months (interquartile range [IQR], 6.33–11.07) for the safety analysis, 22/37 (59.5%) patients had dose-reduced treatment, and 11/37 (29.7%) patients had temporary treatment interruption.27 The frequency of apatinib administration was 40.5% of the planned administration dose. The mean temporary interruption duration was 8 days (95% confidence interval [CI], 4–10). The following grades 3 and 4 toxic effects impacted the dose reductions: pneumothorax (6 [16.2%] of 37 patients); wound dehiscence, (4 [10.8%]); proteinuria, (3 [8.1%]); diarrhea, (3 [8.1%]); palmar-plantar erythrodysesthesia syndrome, (3 [8.1%]); rash acneiform, (2 [5.4%]); abdominal cramps, (2 [5.4%]); anorexia, (2 [5.4%]); pleural infection, (1 [2.7%]); bladder perforation, (1 [2.7%]); hypertriglyceridaemia, (1 [2.7%]); weight loss, (1 [2.7%]); anemia, (1 [2.7%]); hypokalemia, (1 [2.7%]); palpitations, (1 [2.7%]); back pain, (1 [2.7%]); anorectal infection, (1 [2.7%]); cholecystitis, (1 [2.7%]); and fatigue, (1 [2.7%]).27 All of these AEs were causally related to the study drug. No deaths were related to the experimental treatment; all of the deaths were attributed to disease progression. The most common any-grade AEs (reported in ≥15% of patients) included bilirubin increase (18.9%), diarrhea (18.9%), hypertriglyceridemia (27.0%), hypertension (18.9%), hypercholesterolemia (16.2%), hypothyroidism (21.6%), fatigue (32.4%), weight loss (32.4%), anorexia (35.1%), pneumothorax (32.4%), rash acneiform (16.2%), and palmar-plantar erythrodysesthesia syndrome (21.6%). Due to the small sample size, we did not observe some rarely seen AEs (overall incidence ≤5% of patients) and merged some of the AEs into one bigger group for more appropriate statistical analyses. For example, we merged hypertriglyceridemia and hypercholesterolemia into hyperlipemia and merged palmar-plantar erythrodysesthesia syndrome and rash acneiform into hand-foot skin reaction since this appeared to be different severity degrees of the same AE.

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Time to Onset of AEs of Interest and Management

The most common AEs of clinical interest were anorexia, weight loss, fatigue, pneumothorax, hyperlipemia, and hypothyroidism. Time to initial occurrence of these AEs is summarized with a median AE onset of 20 to 165 days (Figure 1). For adolescents and young adults with advanced osteosarcoma, hand-foot skin reactions usually had an early onset, with majority of patients experiencing the AE within the first three cycles of treatment. During the trials, we actively used prophylactic measures such as emollients, protection of pressure-sensitive areas, urea cream and clobetasol cream, and analgesics if pain control was needed. We also used some traditional Chinese herbs to control hand-foot skin reactions, which is beneficial for restricting AEs within grades 1–2. These herbs included portulacaria, geranium wilfordii maxim, rhizoma, flos carthami, and cortex phellodendri, all of which have been formulated into medical treatments in some clinics in Beijing. The time to resolution clearly differed in our population with different management methods. Anorexia was the most common AE, with a median onset time of 90 days (95% CI, 36–185), for which methyl diprogesterone acetate tablets were our first treatment measure. Hypothyroidism with elevated TSH levels was observed in eight patients with a median onset time of 126 days (95% CI, 48–303); most cases were subclinical with abnormal hormone levels. Hypothyroidism can aggravate patient fatigue and anorexia and is usually treated with levothyroxine sodium supplementation. Weight loss was a frequently observed AE, accompanied by anorexia and hypothyroidism with a median onset time of 64 days (95% CI, 48–107). There was limited information on the weight maintenance strategies among patients receiving apatinib. A similar time to onset was observed for abdominal cramps, diarrhea, hypertension, fatigue, oral mucositis, and myalgia/arthralgia, with a median time to onset of 1–2 months after starting treatment, with the exception of proteinuria, hyperlipemia and pleuritic pain for which the median time to onset was slightly longer (4–5 months). Wound dehiscence usually occurred early in patients who previously had operations or wounds. Repetitive dressing changes and debridement should be required for these patients with interruption of apatinib for at least 3–4 weeks. Wound dehiscence generally occurred in patients again after apatinib treatment resumed, even if the wound had previously healed. Pneumothorax was particularly frequent for pulmonary metastatic lesions with a median occurrence of 106 days (95%, 61–218). Surgical intervention, such as thoracotomy, is usually not recommended to avoid the interruption of apatinib and further disease progression; rather, chest tube placement with chemical or mechanical pleurodesis is preferable. However, chest tube usually lasts for months because of the failure of mechanical pleurodesis and secondary infection develops afterwards. Thus, final progression is often inevitable because of dose reductions or interruptions of apatinib.

Toxicity as Signs for Antitumor Efficacy

We evaluated the relationship between AEs and drug efficacy in the 37 patients who had completed at least 2 months of apatinib treatment. Hypothyroidism or subclinical hypothyroidism at baseline was not observed in any patient. For 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). For CBR, hypothyroidism obviously indicated a clinical benefit (P = 0.00), while hypertension and pneumothorax also had some relationship with more clinical benefit (P = 0.07 and 0.06, respectively) (Table 1).

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