Name	Grade	Attribution
Bronchopulmonary hemorrhage	5	Definite
Esophageal fistula	4	Definite
Abdominal Pain	3	Probable
Diarrhea	3	Definite
Fatigue	3	Definite
Fatigue	3	Probable
Palmar‐plantar erythrodysesthesia syndrome	3	Definite
Hematuria	3	Definite
Hypertension	3	Definite
Pantalgia	3	Definite
Pantalgia	3	Probable
Proteinuria	3	Definite
Thrombocytopenia	3	Definite
Adverse events were assessed throughout the treatment in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Most instances of toxicity were generally well tolerated. Detailed AEs are presented in Tables 2 and 3. Severe AEs occurred in 23 patients (57.5%). The most common severe AEs were fatigue (15%), hypertension (12.5%), and palmar‐plantar erythrodysesthesia syndrome (10%). Dose was decreased to 250 mg in 47.5% (19/40) of patients who experienced intolerable toxicity. The 500 mg once daily apatinib treatment was discontinued by 17.5% (7/40) of patients less than 2 weeks after beginning therapy, and 52.5% (21/40) of patients had dose reduction or discontinuation. The most common reasons for dose reduction or discontinuation were fatigue (15%), palmar‐plantar erythrodysesthesia syndrome (7.5%), bronchopulmonary hemorrhage (7.5%), and proteinuria (7.5%). Fatigue was the most common adverse effect among patients enrolled in this study. Three patients achieved partial response (7.5%). Among them, one patient terminated apatinib treatment because of severe fatigue. Hematologic toxicities were mostly moderate, and grade 3 to 4 hematologic toxicities were rarely noted. Three patients had an anal mucosal reaction (grade 2) that had not been reported before; symptomatic treatment was effective for them.
In our trial, five patients had a baseline progressive esophageal lesion. Among these patients, one died of massive fatal bronchopulmonary hemorrhage, and esophageal fistula occurred in two patients (Fig. 4; 3/5, 60.0%). Of the 40 patients enrolled in this study, two patients (5%) died of massive fatal bronchopulmonary hemorrhage, and two patients (5%) developed esophageal fistulas. Notably, both esophageal fistula cases and one massive fatal bronchopulmonary hemorrhage case occurred in patients with uncontrolled primary tumors (3/5, 60%). The other fatal bronchopulmonary hemorrhage was associated with major blood vessel invasion, highlighting potential safety concerns when administering apatinib to patients with uncontrolled esophageal lesions or with severe invasion of trachea, bronchi, or major blood vessels.