Table 4.

Management of common adverse events associated with apatinib for advanced osteosarcoma.

Adverse Event	Recommended Management Strategies
HFSR	Prophylactic management (for grade 1 and 2): Skin examination before initiation of treatment, softening and removal of calluses; Protection against pressure and friction (i.e., plantar pads and wearing clothes with adequate room for the hands and feet); Frequent local administration of creams and moisturizers before treatment; Orally administration of compound vitamin B tablets; Sun exposure and unprotected cold exposure should be avoided; Keratolytic creams can be used on hyperkeratotic areas; Locally spray a solution of recombinant human basic endothelial growth factor or vitamin B on skin with minor wear out.
	AE management: Preventative measures should be continued; Moisturizers containing 20–40% urea, salicylic acid, ammonium lactate or alpha hydroxyl acid may be used to soften and exfoliate hyperkeratotic and callused areas (for grade 2); Consider using topical treatments such as cortisone and 0.05% clobetasol (for grade 3); Consider using antibiotic ointment to prevent infection (for grade 3); If HFSR is grade ≥2, a dermatologist consultation is suggested and local anesthetics are recommended for severe pain; Consider Chinese herbal preparation solution for external use (for all grades).
Stomatitis and Mucositis	Prophylactic management (for grade 1): Appropriate oral hygiene before treatment initiation; Avoid spicy, acidic, hard or hot foods and drinks; Oral administration of compound vitamin B tablets; Clean and dry the rectal area with mild soap and water and use a moisture-barrier ointment locally after cleaning.
	AE management: A high-energy diet and adequate fluid (for grade 2 and 3); In cases of severe mucositis, enteral or parenteral nutrition is recommended (for grade 3); Use gentle mouthwashes after meals and topical anesthetics or use products containing hyaluronic acid in composition locally (for grade 2 and 3); Consider using Chinese herbal preparation solutions that contain Portulacaria, geranium wilfordii maxim, rhizoma, Flos carthami, and cortex phellodendri locally (for grade 2 and 3); Locally spray a solution of recombinant human basic endothelial growth factor or vitamin B on stomatitis (for grade 2 and 3).
Diarrhea	Prophylactic management (for grade 1 and 2): Anti-diarrhea diet (avoid fiber, fat and acrimony excitant food); Use a stool diary to help identify foods that may trigger digestive problems; Consumption of bananas, rice, potatoes, apple sauce, toast and probiotics may be helpful; Caffeine, alcohol, spicy or fatty foods, dairy products and foods high in insoluble fiber should be avoided.
	AE management: In cases that cannot be managed by dietary changes, loperamide (4 mg then 2 mg every 4 h) may be prescribed. For patients who frequently experience diarrhea, loperamide may also be taken pre-emptively, 30 min before TKI treatment (for grade 3); Intensive oral rehydration containing water and electrolytes (for grade 2 and 3); Consider treatment with atropine-diphenoxylate, if appropriate (for grade 3); A pancreatic enzyme supplement might be considered to reduced diarrhea and improve digestion (for grade 2 and 3); Any concurrent gastrointestinal infection should be treated appropriately (for grade ≥ 3); If diarrhea is grade ≥ 3/4, absolute diet with parenteral nutrition and intravenous electrolytes and fluid supply is advised, and somatostatin analogs such as octreotide are commonly prescribed (for grade ≥ 3); Hospitalization or referral to a gastroenterologist should also be advisable, particularly in the event of severe cramping, nausea and vomiting, fever, or dehydration (for grade ≥ 3); Concomitant lactulose dose reduction may be necessary (for grade ≥ 3).
Fatigue	Prophylactic management (for grade 1 and 2): Other potentially treatable coexisting causes of fatigue, such as anemia, diarrhea, nausea, hypothyroidism, hypokalemia, and insomnia, should be corrected in case of deteriorating fatigue; For patients who are fit enough, daily exercise such as walking or weight-bearing exercises may be useful.
	AE management: Psychostimulants, such as caffeine, or methylphenidate or modafinil for more severe cases, may be considered; however, care should be taken when prescribing modafinil owing to potential interactions with apatinib (for grade 3); Based on preventative measures, steroid cortisol could be considered as a hormone supplement (for grade 3); Taking apatinib in the evening rather than the morning may reduce daytime fatigue (for all grades).
Blood Bilirubin Increases	Prophylactic management (for all grades): Various initiate work-up for competing etiologies; Ursodeoxycholic acid could be considered in individuals with cholestatic DILI.
	AE management: Consult with hepatologists for more advice and stopping apatinib (for grade ≥ 3); Corticosteroids are frequently administered to patients with certain DILI (for grade ≥ 3); Cholestyramine can be administered to patients with acute liver injury (for grade ≥ 2); When acute liver failure happens, considering artificial liver and liver transplantation (for grade ≥ 4).
TSH Increases	Prophylactic management (for grade 1): Levothyroxine supplement after consultation with an endocrinologist.
	AE management: Hospitalization with supply of hormones, electrolytes and fluids (for all grades); Monitoring patients’ vital signs (for all grades).
Anorexia and Weight loss	Prophylactic management (for all grades): Encourage patients to consume nutritious, high-calorie foods and to eat snacks throughout the day; Limit/avoid foods that could cause gastrointestinal events; Appetite and weight should be monitored in each treatment cycle.
	AE management: Appetite stimulants such as dronabinol or megestrol acetate should be considered (for grade ≥ 3); Any underlying nausea should be treated (for grade 2 and 3); High-calorie diet and dietary supplements should be recommended and nasogastric feedings should be considered (for grade ≥ 3); The presence of underlying conditions, including hypothyroidism, low testosterone in men and so on, should be managed well (for all grades); Be aware of asthenia-anorexia-cachexia syndrome, characterized by weight loss, weakness and fatigue. This condition can be treated with corticosteroids, although these may only be effective in the short term (for grade ≥ 3).
Hyperlipidemia	Prophylactic management (for all grades): Test the lipid profile at baseline and during the course of treatment.
	AE management: In the event of persistent hypercholesterolemia (higher than 6.2 mmol/L, considered high risk according to AACE guidelines), add an appropriate statin, which should be decided with caution because of cytochrome P450 (CYP3A) (for grade 2).
Wound Complications	Prophylactic management: Selecting an appropriate interval for stopping the use of apatinib before surgery is advised according to the location and complexity of the elective surgery (grade 1 and 2); Postoperatively, in the presence of advanced cancer, drug-induced impaired wound healing and organ perforation should be taken into account. The timing of reinitiation of therapy following a major surgical intervention should be based upon clinical judgment of recovery from surgery (grade 1 and 2).
	AE management: The surgeon and oncologist should collaborate on debridement and dressing changes for the patient (grade 3); Therapy should be discontinued in patients with wound dehiscence (for grade ≥3).
Hypertension	Prophylactic management (for all grades): Blood pressure should be controlled before initiating TKI treatment; Blood pressure should be monitored regularly for the first few months of treatment.
	AE management: ACEIs, ARBs or beta blockers should initially be encouraged to be used to treat hypertension (grade 1 and 2); Provide up to three standard antihypertensive agents, but do not combine ACEIs and ARBs (grade 3); Calcium channel blockers may be considered, but careful selection is necessary to avoid interactions with TKIs (avoiding CYP3A4 inhibitor/inducers, e.g., verapamil and diltiazem) (grade 3); Caution should be taken when using thiazide diuretics owing to the risk of diarrhea (grade 3).
Proteinuria	Prophylactic management: Monitor proteinuria regularly, monthly if possible (for all grades); Consider some Chinese patent medicines containing musk mallow and Paecilomyces hepiali (grade 1 and 2).
	AE management: Dose reductions and monitoring at the clinic multiple times per week (for grade ≥2); Considering ACEIs or ARBs to reduce proteinuria (grade 2 and 3).
Pneumothorax	Prophylactic management: Closely monitoring chest plain or dyspnea (for all grades).
	AE management: Consider using a pigtail catheter or chest tube to evacuate the pneumothorax and later using chemical or mechanical pleurodesis (grade 2, 3 and 4); In some severe situations, consider using video-assisted thoracoscopic surgery and chemical pleurodesis for patients with first time pneumothorax (grade 3 and 4); For pleurodesis, highly agglutinative staphylococcin is preferred (grade 2 and 3).
Hypokalemia	Prophylactic management (for all grades): Monitor serum potassium after every treatment cycle, especially in those with anorexia; An oral potassium replacement should be provided to patients with signs of hypokalemia.
	AE management: An oral or intravenous potassium replacement should be considered for those with mild or moderate hypokalemia (for grade ≥2); Hospitalization with an intravenous potassium supply and close monitoring with serum potassium and electrocardiogram (for grade ≥3).
Nausea and Vomiting	Prophylactic management: Chocolate, caffeine, alcohol and nicotine should be avoided (for all grades); Antiemetics may be provided prophylactically (grade 2 and 3).
	AE management: Pharmacological treatment with metoclopramide or levosulpiride may be considered (grade 2 and 3); 5-HT3 antagonists are recommended over the use of NK1 receptor antagonists, dexamethasone, or nabilone to avoid CYP3A4 modulation; ondansetron and granisetron should be used with caution owing to potential interactions with apatinib (grade 2 and 3); Consider guidelines for GERD, including lifestyle and dietary modifications and the use of proton-pump inhibitors (for grade ≥2).

AACE, American Association of Clinical Endocrinologists; ACEIs, angiotensin-converting enzyme inhibitors; AE, adverse event; ALT, alanine aminotransferase; ARBs, angiotensin receptor blockers; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; DILI, drug-induced liver injury; GERD, gastroesophageal reflux disease; HFSR, hand–foot skin reaction; TKI, tyrosine kinase inhibitor; TSH, thyroid-stimulating hormone.